Physiology

Physiology

HEARTS AND HEART-LIKE ORGANS

Volume 2

GEOFFREY H. BOURNE

Saint George’s University, School of Medicine, Grenada, West Indies

Table of Contents

Cover image

Title page

Contributors

Copyright

List of Contributors

Preface

Contents of Other Volumes

Chapter 1: Effects of Hormones on the Heart

Publisher Summary

I General Concepts

II Corticosteroids

III Pancreatic Hormones

IV Renin-Angiotensin System

V Pituitary Hormones

Acknowledgment

Chapter 2: Prostaglandins and the Heart

Publisher Summary

I A Historical Outline

II Chemistry and Biochemistry of Prostaglandins

III Cardiac Biosynthesis of Prostaglandins

IV Physiological and Pharmacological Interference with Cardiac Biosynthesis

V Effects of Prostaglandins on Cardiac Tissue

VI Physiological Significance of Cardiac Prostaglandins

VII Cigarette Smoking, Nicotine, and Cardiac Prostaglandins

Chapter 3: Thyroid Hormone Effects on the Heart

Publisher Summary

I Thyroid Hormone Synthesis, Metabolism, and Mechanisms of Action

II Thyroid Hormone Excess: Its Effects on the Heart

III Thyroid Hormone Deficiency: Its Effects on the Heart

IV Summary

Chapter 4: Catecholamines and the Heart

Publisher Summary

I Historical Background

II Catecholamine Metabolismml: Biosynthesis, Storage, Release, and Inactivation

III Adrenergic Receptors and Responses

IV Neural Regulation of the Heart

V Adrenergic Involvement in Cardiac Pathophysiology

VI Concluding Remarks

Acknowledgment

Chapter 5: Emotion and the Heart

Publisher Summary

I Emotional Stress as a Major Risk Factor in Coronary Heart Disease

II Emotional Stress and Standard Coronary Risk Factors

III Pathogenetic Interrelationship between Psychic Stress and Dietary Fat

IV Emotional Stress and Tobacco Consumption

V Emotional Stress and the Pathogenesis of Atherosclerosis

VI The Mastery of Stress

VII Stress, Adaptation, and Evolution

VIII Augmented Sympathetic Arousal and Ischemic Heart Disease

IX Primary and Secondary Prevention in Ischemic Heart Disease

Acknowledgment

Chapter 6: The Nature of Stress and Its Relation to Cardiovascular Disease

Publisher Summary

I Stress and Adaptation

II Stress and Cardiovascular Disease

Chapter 7: Hypoxia and the Heart

Publisher Summary

I Introduction

II Anatomical and Histological Changes of the Hypoxic Heart

III Coronary Vessels and Coronary Flow

IV Myocardial Metabolism

VIII Exercise Tolerance–Myocardial Resistance to Ischemia or Necrosis

IX Conclusions

Acknowledgment

Chapter 8: The Heart and Exercise Training

Publisher Summary

I Introduction

II Effects of Training on the Cardiac Muscle Cell

III Effects of Training on Papillary Muscle and Isolated Heart

IV Effects of Training in the Intact Animal and Human

V Conclusion

Acknowledgment

Chapter 9: Cardiac Hypertrophy

Publisher Summary

I Introduction

II Biochemical Aspects of Cardiac Enlargement

III Cellular Responses During Heart Growth

IV Future Directions and Considerations

Acknowledgment

Chapter 10: Effects of Bedrest and Weightlessness on the Heart

Publisher Summary

I Introduction

II Mission Experience

III Physiological Responses Associated with Postural Changes

IV Changes in Resting Hemodynamic parameters Resulting from Bedrest, Immersion, and Immobilization

V Conclusions

Chapter 11: Chemical and Nervous Control of the Coronary System

Publisher Summary

I Hemodynamics of Coronary Circulation

II Regulation of Coronary Resistance

III Mechanism of Myocardial Reactive Hyperemia

IV Coronary Reserve in Normal and Hypertrophic Hearts

V Autoregulation of Coronary Flow

VI Coronary Flow Responses to Natural Stresses

VII Local Metabolic Control of Coronary Resistance

VIII Neural Regulation of Coronary Resistance: Sympathetic and Parasympathetic Regulation of Coronary Blood Flow

IX Conclusions

Index

Contributors

Russell T. Dowell, Allan M. Lefer, William M. Manger, Germano Marchetti, P.R. Moret, Henry I. Russek, Linda G. Russek, H. Sandler, Hans Selye, Robert C. Smallridge, H. Lowell Stone, George J. Trachte and Åke Wennmalm

Copyright

COPYRIGHT © 1980, BY ACADEMIC PRESS, INC.

ALL RIGHTS RESERVED.

NO PART OF THIS PUBLICATION MAY BE REPRODUCED OR TRANSMITTED IN ANY FORM OR BY ANY MEANS, ELECTRONIC OR MECHANICAL, INCLUDING PHOTOCOPY, RECORDING, OR ANY INFORMATION STORAGE AND RETRIEVAL SYSTEM, WITHOUT PERMISSION IN WRITING FROM THE PUBLISHER.

ACADEMIC PRESS, INC.

111 Fifth Avenue, New York, New York 10003

United Kingdom Edition published by

ACADEMIC PRESS, INC. (LONDON) LTD.

24/28 Oval Road, London NW1 7DX

Library of Congress Cataloging in Publication Data

Main entry under title:

Hearts and heart–like organs.

Includes bibliographies.

CONTENTS:

v. 2. Physiology.

1. Heart. I. Bourne, Geoffrey Howard, Date.

QP111.4.H4 591.1′16 80-18121

ISBN 0-12-119402-7 (v. 2)

PRINTED IN THE UNITED STATES OF AMERICA

80 81 82 83 9 8 7 6 5 4 3 2 1

List of Contributors

Numbers in parentheses indicate the pages on which the authors’ contributions begin.

Russell T. Dowell(419),     Department of Physiology and Biophysics, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73190

Allan M. Lefer(1),     Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107

William M. Manger(161),     Associate Professor of Clinical Medicine, National Hypertension Association, Inc., New York University Medical Center, New York, New York 10016

Germano Marchetti(525),     Gruppo Lepetit S.p.A., Via Durando, 38 Milan, Italy

P.R. Moret(333),     University of Geneva, Center of Cardiology Hospital, Geneva, Switzerland

Henry I. Russek(263),     One North Ocean Boulevard, Boca Raton, Florida 33432

Linda G. Russek(263),     One North Ocean Boulevard, Boca Raton, Florida 33432

H. Sandler(435),     Biomedical Research Division, National Aeronautics and Space Administration, Ames Research Center, Moffett Field, California 94035

Hans Selye(289),     International Institute of Stress, 2900 boul. Edouard-Montpetit, Montreal, Quebec H3C 3J7, Canada

Robert C. Smallridge(93),     Division of Medicine, Walter Reed Army Institute of Research, Washington, D.C. 20012

H. Lowell Stone(389),     University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73190

George J. Trachte(1),     Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107

Åke Wennmalm(41),     Department of Clinical Physiology at Karolinska Institutet, Huddinge University Hospital, S-141 86 Huddinge, Sweden

Preface

The exchange of oxygen between the atmosphere and living tissues was a problem for the first life on earth. This problem of respiration became mechanically complex once multicellular organisms evolved. The more complicated such organisms became, the more difficult logistically the problem became. Eventually in animals, a specialized fluid capable of carrying oxygen was developed, together with a series of pipes to convey it to the most distant tissues and with a centrally-placed pump to push the fluid to its destination. Some animals developed one pump and some depended on several. The originally simple pump became more complex as air breathing added to the respiratory problems. The original straight tubular heart evolved into a two, a three, and eventually a four-chambered heart, reaching the apex of its development in mammals.

Many factors in civilized life affect the normal functioning of the heart in modern humans, and heart attacks afflict one million people a year in the United States alone. Of these, less than half survive. The structure and function of the heart are therefore central themes in the orchestration of medical research and practice, which incorporates knowledge and discoveries from diverse disciplines.

The present series of volumes has been designed to give biological and biomedical researchers anatomical and physiological perspectives of the heart from invertebrates to humans. It has not been possible to be comprehensive (I cannot even guess how many volumes that would take), but at least we have picked out the highlights in the areas covered.

Volume 1 traces the heart through the invertebrates and the lower vertebrates to humans. Volume 2 deals with the physiology of the heart, its evolution, the effects of hormones, exercise, stress, bedrest, hypoxia, and the control of the coronary system. Volume 3 takes up the area of pathology and surgery of the heart, viruses of the heart, and the status of cardiac surgery and cardiac transplantation. In this volume, especially, only a limited number of fields can be covered, but we hope in later volumes (still being planned) specifically to cover heart attacks and the fundamentals of the structure and functioning of the cardiac cell.

This treatise is intended to provide a basis for the continued study of the heart for a greater understanding of its complexities and to help generate ideas for further research on this vital organ.

Geoffrey H. Bourne

Contents of Other Volumes

Volume 1: Comparative Anatomy and Development

Some Invertebrate Myogenic Hearts: The Hearts of Worms and Mollusks

A. W. Martin

The Heart of Urochordates and Cephalochordates

D. J. Randall and P. S. Davie

Cardiovascular Function in the Lower Vertebrates

K. Johansen and W. Burggren

Fine Structure of the Fish Heart

A. Yamauchi

On the Fine Structure of Lymph Hearts in Amphibia and Reptiles

Y. Satoh and T. Nitatori

The Amphibian and Reptilian Hearts: Impulse Propagation and Ultrastructure

A. Martínez-Palomo and J. Alanís

Neural Control of the Avian Heart

J. B. Cabot and D. H. Cohen

Functional and Nonfunctional Determinants of Mammalian Cardiac Anatomy

U. Rowlatt

Postnatal Development of the Heart

K. Rakusan

Anatomy of the Mammalian Heart

V. Navaratnam

The Anatomy of the Human Pericardium and Heart

J. E. Skandalakis, S. W. Gray, and J. S. Rowe, Jr.

Index

Volume 3: Pathology and Surgery of the Heart

Mammalian Heart Cells in Culture

R. L. McCarl, C. K. Hartzell, N. Schroedl, N. Kunze, and P. D. Ross

Regulation of Myocardial Cell Volume

M. B. Pine, J. B. Caulfield, and W. H. Abelmann

Aspects of Cation Physiology in the Myocardium

T. J. Regan and P.O. Ettinger

Nutrition and the Heart

L. H. Opie

Protein Metabolism in Cardiac Stress

S. S. Schreiber, M. Oratz, and M. A. Rothschild

The Old Heart

R. Harris

Effects of Viruses on the Heart

J. H. Gainer

Status of Cardiac Surgery: Surgical Embryology of the Heart

S. W. Gray, J. E. Skandalakis, J. S. Rowe, and P. N. Symbas

The Surgical Treatment of Ischemic Heart Disease

J. S. Rankin and D. C. Sabiston, Jr.

Cardiac Transplantation

J. G. Losman

Index

1

Effects of Hormones on the Heart

Allan M. Lefer and George J. Trachte

Publisher Summary

The heart is a significant target organ for a wide variety of humoral agents, including many hormones. This chapter discusses the effects of four major groups of hormones that exert prominent cardiac actions. These are the corticosteroids, anterior and posterior pituitary hormones, pancreatic hormones, and the major components of the renin–angiotensin system. In case of the adrenal cortex, the active hormones are steroids. If the inotropic, chronotropic, and coronary vascular effects are known, it could be determined whether a given hormone would be a good candidate to protect the ischemic myocardium against the extension of the infarct size. In the case of coronary vasoactivity, coronary vasoconstriction can be dangerous because it can restrict blood flow to the myocardium, although a profound vasodilation might result in systemic hypotension or a redistribution of coronary blood flow so as to produce subendocardial ischemia. The two major naturally occurring glucocorticoids—corticosterone and cortisol—have not been shown to exert a significant inotropic effect.

I. General Concepts

II. Corticosteroids

A. Effects in Isolated Cardiac Tissue

B. Effects in Whole Animals

C. Coronary Vascular Effects

D. Uptake of Corticosteroids by the Heart

E. Glucocorticoids in Myocardial Infarction

III. Pancreatic Hormones

A. Glucagon

B. Insulin

C. Somatostatin (SRIF)

IV. Renin–Angiotensin System

A. Renin

B. Angiotensin I

C. Angiotensin II

D. Angiotensin III

V. Pituitary Hormones

A. Anterior Pituitary

B. Neurohypophyseal Hormones

References

I General Concepts

In reviewing the effects of hormones on the heart, one is impressed with the diversity of types of humoral agents that influence cardiac function. The heart appears to be a significant target organ for a wide variety of humoral agents, including many hormones. Several of these important relationships are covered in other chapters of this treatise (i.e., prostaglandins and the heart, the thyroid and the heart, and catecholamines and the heart). Therefore we will not duplicate these efforts. We will discuss the effects of four major groups of hormones that exert prominent cardiac actions. These are the corticosteroids (i.e., adrenal cortical steroids), anterior and posterior pituitary hormones, pancreatic hormones, and the major components of the renin-angiotensin system. In the case of the adrenal cortex, the active hormones are steroids, whereas all the other groups of hormones considered in this chapter are polypeptides of various molecular weights ranging from the small heptapeptide (e.g., angiotensin III) to adrenocorticotropic hormone (ACTH), which comprises 39 amino acid residues.

We will discuss each hormone in terms of three major effects: (1) inotropic (i.e., effect on contractile mechanisms), (2) chronotropic (i.e., effect on heart rate), and (3) coronary vasoactivity (i.e., effect on the caliber of the coronary vasculature). With these three critical parameters the reader will be able to obtain a reasonably comprehensive picture of the overall effects of a given hormone on the status of cardiac performance. This will be of value in ascertaining the overall effect of a hormone in situations in which hormone therapy may be considered for a circulatory disturbance. Thus if the inotropic, chronotropic, and coronary vascular effects are known, one could determine whether a given hormone would be a good candidate to protect the ischemic myocardium against the extension of infarct size.

In the case of myocardial ischemia, one would prefer an agent that did not have significant positive or negative inotropic activity (e.g., increased inotropic activity increases myocardial oxygen demand, whereas cardiodepression could impair the noninvolved portion of the myocardium). Obviously any agent that increased heart rate would also increase myocardial oxygen demand, whereas a modest bradycardia may be somewhat beneficial by improving cardiac efficiency. In the case of coronary vasoactivity, coronary vasoconstriction would be dangerous because it would further restrict blood flow to the myocardium, whereas a modest vasodilation might be beneficial, although a profound vasodilation might result in systemic hypotension or a redistribution of coronary blood flow so as to produce subendocardial ischemia.

II Corticosteroids

A Effects in Isolated Cardiac Tissue

Many investigators have found that relatively low concentrations of corticosteroids exert cardiotonic actions on isolated heart preparations. Although some preparations are more sensitive to corticosteroids than others, only rabbit atria appear to be unresponsive to corticosteroids (Briggs and Holland, 1959; Levy and Richards, 1962, 1964).

1 Mineralocorticoids

Aldosterone, the most potent naturally occurring mineralocorticoid, has been shown to exert a positive inotropic effect in papillary muscles isolated from cats (Lefer, 1967a,b; Loubatières and Sassine, 1963; Loubatières et al., 1964; Sayers et al., 1966; Tanz, 1960), guinea pigs (Sayers et al., 1966), and monkeys (Nayler, 1965). This cardiotonic effect occurs at concentrations on the order of 10−9 M. Aldosterone was found to be ineffective over a wide range of concentrations in isolated frog hearts (Gross, 1960; Hajdu, 1957), and in rat trabeculae carneae (Ullrick and Hazelwood, 1963). This unresponsiveness is probably not due to a temperature effect, because aldosterone was shown to exert a slightly greater positive inotropic effect in mammalian cardiac tissues at 27° than at 37°C (Lefer, 1967b). Sayers and Solomon (1960) found a similar lack of temperature specificity with other corticosteroids in the rat heart–lung preparation.

In the blood-perfused rat heart–lung preparation, physiological concentrations of aldosterone enabled the heart to perform two to four times as much work as that performed without aldosterone (Ballard et al., 1960). However, this effect may not have been due solely to an inotropic action, since one cannot exclude beneficial effects on the pulmonary vasculature in this preparation. In contrast, aldosterone (Areskog, 1962; Imai et al., 1965) failed to exert a positive inotropic effect in the blood-perfused dog heart–lung preparation. This lack of response in the dog heart–lung preparation was probably not due to a concentration effect. More likely, aldosterone may exert a restorative effect only on the corticosteroid-deficient myocardium and may be ineffective in the presence of normal corticosteroid concentrations, since it was ineffective when perfused with normal blood (Areskog, 1962; Imai et al., 1965) but was effective when perfused with corticosteroid-depleted blood (Ballard et al., 1960).

Aldosterone exerts a maximum positive inotropic effect of only 20–35%, a value considerably less than that exerted by cardiac glycosides or catecholamines (Sayers et al., 1966; Tanz and Kerby, 1961) under comparable experimental conditions. Therefore the modest cardiotonic effect of aldosterone should not be considered a substitute for cardiac glycosides or other inotropic agents in cardiac failure.

Other mineralocorticoids also exert positive inotropic effects in isolated cardiac tissue. Deoxycorticosterone (DOC) stimulates the isolated frog heart (Hajdu, 1957; Hajdu and Szent-Györgyi, 1952; Hoffmann, 1954; Loynes and Gowdey, 1952 Loynes and Gowdey, 1952) and the dog heart–lung preparation (Areskog, 1962). Low doses of DOC have been reported to stimulate beating rat and chick heart fragments in tissue culture (McCarl et al., 1965), but high doses of DOC are depressant in these preparations (Cornman and Gargus, 1957; Cornman et al., 1957). Similar biphasic effects occur in perfused guinea pig hearts (Hoffmann, 1954) and in isolated cat papillary muscles (Emele and Bonnycastle, 1956). In general, DOC in moderate doses (e.g., 10−8 to 10−7 M) exerts a small positive inotropic effect. High doses of DOC are generally depressant, although in some cases this depressant effect may be due to the steroid vehicle.

The potent synthetic mineralocorticoid 9α-fluorocortisol (9αFF) is also a cardiotonic steroid. Nayler (1957) found that 9αFF increased the work and efficiency of the isolated toad heart, but to a lesser extent than cardiac glycosides. Tanz and collaborators (1956, 1957) reported that 9αFF protected the cellular integrity of isolated cardiac muscle cells subjected to electrical stimulation in an isolated tissue bath. However, 2α-methyl-9α-fluorocortisol, which has mineralocorticoid potency similar to that of aldosterone, did not exert a significant inotropic effect in isolated cat papillary muscles (Lefer, 1967c). In this case the ethanol as a vehicle may have masked a potential inotropic effect. Several of these studies emphasize the importance of careful controls for the steroid vehicle, which may have direct cardiodepressant effects independent of the steroid molecules.

Most mineralocorticoids appear to exert positive inotropic effects that are modest when compared to the much larger inotropic effects observed with cardiac glycosides or catecholamines tested under the same conditions as the mineralocorticoids. There is a relatively long latent period for the inotropic effect of mineralocorticoids (i.e., about 20–60 min for attainment of the peak effect). This latency is similar to that observed with aldosterone in the intact animal and may represent a period of enzyme induction (Edelman et al., 1963) or tissue binding (Hollander et al., 1966) that may be obligatory for the action of these steroids. The inotropic effect of mineralocorticoids is probably not directly mediated by sodium and potassium transport or by coronary blood flow changes, since it can occur in the absence of these changes. The inotropic effect is enhanced under conditions of cardiac hypodynamia, a feature shared with many other inotropic agents (e.g., ouabain, norepinephrine) (Blinks and Koch-Weser, 1963).

2 Glucocorticoids

The two major naturally occurring glucocorticoids, corticosterone and cortisol, have not been shown to exert a significant inotropic effect. Several investigators have failed to find any significant inotropic activity of cortisol in the isolated frog (Hajdu and Szent-Györgyi, 1952), cat, or guinea pig heart (Sayers et al., 1966); in the dog heart–lung preparation (Imai et al., 1965); or in isolated papillary muscle preparations (Emele and Bonnycastle, 1956; Sayers et al., 1966). Cortisol has been shown to stimulate the rate of embryonic chick heart fragments (Cornman and Gargus, 1957; Cornman et al., 1957), the endurance of rat heart–lung preparations (Sayers and Solomon, 1960), and the overall performance of acidotic dog heart–lung preparations (Nobel-Allen et al., 1973), but no direct inotropic measurements were made in any of these studies. Thus the beneficial or cardiotonic action of cortisol may have been due to a metabolic or cellular action independent of an inotropic effect.

Corticosterone did not stimulate the frog heart (Hajdu, 1957; Hajdu and Szent-Györgyi, 1952) or the dog heart–lung preparation (Areskog, 1962), and a cardiodepressant effect of corticosterone was reported in isolated rat hearts (Nasmyth, 1957) and in embryonic chick heart fragments (Cornman and Gargus, 1957). However, corticosterone was a potent cardiotonic agent in the rat heart–lung preparation (Sayers and Solomon, 1960; Solomon et al., 1959). In these same experimental preparations, high doses of corticosterone clearly depressed the heart. Thus the evidence does not favor the view that corticosterone exerts a direct positive inotropic effect, even though it may improve cardiac function indirectly by other actions.

Several other glucocorticoids have been tested for inotropic activity in isolated heart preparations. Cortisone, in low to moderate concentrations, exerts a small cardiotonic effect in several mammalian preparations (Cornman et al., 1957; Hoffmann, 1954; Tanz, 1960; Tanz and Kerby, 1961), but not in the isolated frog heart (Hajdu and Szent-Györgyi, 1952), whereas high doses of cortisone uniformly depressed the heart (Emele and Bonnycastle, 1956; Tanz, 1960). Prednisolone (Areskog, 1962; Lefer, 1967b; Tanz and Kerby, 1961), methylprednisolone, dexamethasone, and betamethasone (Lefer, 1967b) appear to have no significant inotropic activity in a variety of cardiac preparations.

Thus glucocorticoids exert little or no inotropic effects at moderate concentrations and only modest negative inotropic effects at high concentrations. The inotropic action of these steroids may be partially due to the mineralocorticoid effects exerted by these steroids at high doses. In this regard several of the more potent synthetic glucocorticoids that lack salt-retaining properties (e.g., prednisolone and methylprednisolone) are devoid of inotropic activity. Despite the lack of prominent inotropic effects, glucocorticoids may be essential for the maintenance of normal cardiac function by some other action, since glucocorticoids may be essential for the maintenance of normal cardiac performance in adrenalectomized animals.

B Effects in Whole Animals

The cardiac effects of corticosteroids are more difficult to interpret in the whole animal. The rate of inactivation of corticosteroids is more rapid in the intact animal than in isolated systems because of the presence of the liver, kidneys, and other metabolic systems (e.g., plasma enzymes and blood cells). Furthermore, one cannot be sure of the directness of the effect in the whole animal unless cardiac or peripheral factors are rigidly controlled. Thus one must interpret effects in the whole animal with some degree of caution.

Loubatières and co-workers (1962, 1964; Loubatières and Sassine, 1963) studied the inotropic activity of a variety of corticosteroids in intact dogs and found that almost all the steroids tested demonstrated positive inotropic effects of greater magnitude than that observed in isolated heart preparations. Dexamethasone (Bouyard, 1965; Bouyard and Klein, 1963; Loubatières et al., 1964) exerted a 70–80% increase in cardiac contractile force, whereas methylprednisolone, betamethasone, and triamcinolone exerted a 40–50% increase in contractile force (Bouyard, 1965; Bouyard and Klein, 1963; Loubatières et al., 1964) in the anesthetized dog. These investigations also showed that small doses of aldosterone exerted a 15–25% increase in contractile force in anesthetized (Loubatières et al., 1962) and in conscious dogs (Loubatières and Sassine, 1963). All these steroids were injected intravenously, so that systemic pressor effects (e.g., change in outflow resistance of the heart) may have modified the cardiac effects in these studies. The large magnitude of these changes is also surprising in view of the much smaller inotropic effects usually observed in isolated cardiac tissue. However, the responses were reported in percentage increases with no absolute values reported, and if the hearts were depressed from the anesthetic or the surgery, one would expect a relatively larger response than in normal animals. Moreover, these large effects have not been duplicated elsewhere (Lefer, 1967a,b; Novak et al., 1970), even in dogs subjected to bilateral vagotomy and carotid sinus denervation (Jefferson et al., 1971) in order to remove the neural regulatory mechanisms, which could mask potential myocardial or peripheral vascular effects, or both.

Cortisol usually is either inactive or only very weakly inotropic in the whole animal (Dalton et al., 1968; Jefferson et al., 1971; Kadowitz and Yard, 1970; Lefer, 1967a; Small et al., 1959). However, Bouyard (1965) reported that moderate doses of cortisol exerted a negative inotropic effect in the dog heart. Since the aqueous form of cortisol was employed, the depressant effect obtained could not be attributed to a vehicle effect. Thus, as in isolated heart preparations, glucocorticoids are only very weakly cardiotonic or are ineffective. This, of course, does not rule out possible actions of these steroids on other aspects of cardiac function (i.e., myocardial metabolism).

C Coronary Vascular Effects

Very few studies have been published on the coronary vascular effects of corticosteroids. These few studies all concern the effects of glucocorticoids. Vyden and co-workers (1974) reported that methylprednisolone (50 mg/kg) administered to dogs in acute myocardial ischemia resulted in a coronary vasodilation of about 20%. This effect occurred several hours after administration of the steroid and no vehicle controls were used. Moreover, it was really a reduction in the rate of decline in coronary flow rather than an absolute increase in flow. Previously, Spath et al. (1973) showed that methylprednisolone exerts a vasodilator effect in the pancreatic vasculature, but this effect was small, transient, and found to be due solely to the benzyl alcohol in the vehicle.

Vinas et al. (1977) recently reported that methylprednisolone (30 mg/kg) increased coronary blood flow in dogs undergoing cardiopulmonary bypass, but the flow in the control group was quite low. Therefore, in all probability, methylprednisolone prevented the decline in coronary flow observed in control dogs (i.e., cardiopulmonary bypass dogs not given steroid). Again, no vehicle controls were used, which also could have contributed to this effect, as was shown by Nayler and Seabra-Gomes (1976) in the perfused hypoxic rat heart.

In a well-controlled study, Beardsley et al. (1976a) studied the coronary vascular and inotropic action of isolated cat hearts perfused at constant coronary perfusion pressure. Moreover, this preparation was studied in control as well as in hearts subjected to myocardial ischemia. No significant coronary vascular or inotropic effect occurred over the 2-hr observation period at concentrations of methylprednisolone and dexamethasone up to 1 × 10−3 M. It is therefore unlikely that glucocorticoids exert any significant coronary vasoactive effect acutely.

D Uptake of Corticosteroids by the Heart

Several important studies have appeared in recent years on the uptake of corticosteroids by cardiac tissue. Funder et al. (1973) showed that dexamethasone binds specifically to cardiac cytosol in the rat and dog. The higher-degree affinity was similar in both species and is suggestive of a cardiac receptor for glucocorticoids. Aldosterone also was taken up by hearts of both species; the process was not indicative of mineralocorticoid specific receptors in the heart. Beardsley et al. (1976b) extended these findings to cat cardiac tissue and reported a dramatic uptake of both dexamethasone and methylprednisolone under a variety of experimental conditions. Glucocorticoid uptake was temperature and pH dependent, being optimal at 37°C and pH 7.3–7.4. Maximal uptake occurred within 60 min and was independent of energy-requiring processes. Recent studies also indicate similar effects in the mouse heart (Coutard et al., 1978) and the pig heart (Bottoms et al., 1969).

Additional work has been conducted on the tissue uptake of [³H]methylprednisolone (Lefer et al., 1977; Okuda and Lefer, 1977) and [³H]dexamethasone (Young et al., 1977) in acute myocardial ischemia. Surprisingly, after the liver, kidney, and pancreas, the heart was the next highest organ extracting glucocorticoids both in normal and ischemic cats. Myocardial uptake was rapid, being essentially complete by 60 min. Moreover, myocardial tissue metabolized only about 15% of the ³H-labeled steroid taken up after 2 hr. This very low rate of metabolism of corticosteroids by myocardial tissue confirms the earlier finding of Travis and Sayers (1958), who reported a 10% degradation of cortisol by the rat heart over 90 min. These findings are consistent with an important role of glucocorticoids in cardiac tissue.

Okuda and associates (1976) studied the cellular localization of tritiated dexamethasone and methylprednisolone in the normal and ischemic cat heart. Although lesser amounts of steroid were taken up by ischemic hearts compared with nonischemic cardiac tissue, considerable amounts of steroid accumulated in ischemic tissue. Cardiac homogenates were subjected to sucrose-density gradient centrifugation to localize the organelles taking up the steroids. Most of the glucocorticoid was associated with a plasma membrane fraction and with a lysosomal fraction. These two fractions accounted for 90% of the label taken up by the heart. These data are consistent with a membrane stabilizing action of the glucocorticoids both in nonischemic and ischemic hearts and help explain the beneficial action of glucocorticoids in preserving ischemic myocardial tissue in the absence of significant inotropic, chronotropic, or coronary vasodilator effects.

E Glucocorticoids in Myocardial Infarction

In recent years increasing attention has been given to pharmacological means of modifying the degree of ischemic damage in acute infarction. In 1965 Ebaid and co-workers reported that large doses of cortisol in patients and in dogs reduced S-T segment elevation of the electrocardiogram. These results were extended by Libby et al. (1973), who showed that cortisol given intravenously at a dose of 50 mg/kg shortly after occlusion of the left anterior descending coronary artery effectively reduced electrocardiographic, histological, and enzymatic indices of infarct extension.

In 1974 Spath et al. found that the synthetic glucocorticoid methylprednisolone, at a dose of 30 mg/kg, prevented the spread of ischemic damage in the cat subjected to acute myocardial ischemia. Methylprednisolone was even more effective when given 1 hr after the onset of ischemia than when it was given before ischemia. These workers also provided firm evidence that stabilization of lysosomal membranes may be one of the major mechanisms of its protective effect. These findings were also confirmed using dexamethasone (Spath and Lefer, 1975) in the same experimental model, which also stabilized lysosomes in the ischemic portion of the myocardium.

In the last few years, many papers on the effect of glucocorticoids in myocardial ischemia in man and in experimental animals (Beardsley et al., 1976a; Busuttil et al., 1975; Da Luz et al., 1976; Hoffstein et al., 1976; Masters et al., 1976; Morrison et al., 1975, 1976; Osher et al., 1976; Roberts et al., 1976; Shatney et al., 1976; Toyama and Reis, 1975) have been published. Most of these indicated that steroids exert a beneficial effect. Two prominent clinical studies showed data indicating a preservation of jeopardized myocardial tissue with one or two doses of methylprednisolone (Morrison et al., 1975, 1976). In these important clinical series, the steroid was given acutely and resulted in a decreased mortality as well as a reduction in infarct size. This protective action of methylprednisolone was challenged by Roberts et al. (1976), who reported that multiple doses of glucocorticoid (i.e., every 6 hrs for 48 hrs) were deleterious to patients with myocardial infarction. Unfortunately, these investigators waited at least 7 hr after the first elevation in plasma creatine phosphokinase before initiation of treatment. These results indicate that care must be taken in giving an appropriate dose of glucocorticoid very soon after the onset of myocardial ischemia and that administration of the glucocorticoid should not be prolonged beyond about 8 hr after the first dose. Another group of investigators failing to observe a beneficial effect of methylprednisolone observed the effects of this steroid for only 2 hr after its administration (Osher et al., 1976), which may not have been long enough to observe a protective effect on myocardial performance and integrity.

Other studies have helped clarify the mechanism of the protective effect of glucocorticoids in myocardial ischemia. Busuttil and co-workers (1975) reported that methylprednisolone preserves myocardial lysosomal integrity and modulates cyclic GMP levels in myocardial ischemia. Moreover, the interrelationship between cyclic GMP and cyclic AMP may be important in the regulation of lysosomal membrane integrity (Busuttil et al., 1975). Additional evidence for the preservation of myocardial lysosomal integrity by methylprednisolone in ischemia was provided by Hoffstein and co-workers (1976), who showed ultrastructurally that lysosomal disruption is an early consequence of ischemia and that this can be prevented by methylprednisolone. Similarly, Nayler and Seabra-Gomes (1976) showed methylprednisolone to prevent the loss of intracellular enzymes, including creatine phosphokinase in the hypoxic perfused rat heart consistent with a cellular protective effect.

Recently Toyama and Reis (1975) reported that cortisol can significantly reduce the decrease in myocardial compliance observed in myocardial ischemia. This would prevent impairment of ventricular performance and enable the jeopardized myocardium to function more normally. Other investigators have proposed metabolic actions as the mechanism of the protective effect of glucocorticoids in myocardial ischemia (Da Luz et al., 1976; Masters et al., 1976). In this regard, methylprednisolone has been thought to improve coronary collateral flow or to enhance carbohydrate metabolism (i.e., producing a positive lactate balance or enhancing cardiac glucose uptake). However, these effects of glucocorticoids are neither well established nor are they able to account completely for the protective effect in myocardial ischemia. Thus carefully obtained data suggest that glucocorticoids are ineffective in improving collateral flow in the coronary bed during ischemia (Eckstein, 1954).

One of the most important recent studies of glucocorticoids in myocardial ischemia was reported by Shatney and collaborators (1976). These investigators measured infarct volume in the dog heart with a combination of histochemical and morphological techniques, and they clearly showed that methylprednisolone reduces the size of the developing infarct. Furthermore, the optimal time for methylprednisolone administration was found to be 1 hr after the onset of the ischemic event. This agrees closely with earlier studies that 1-hr post-ischemia is appropriate for glucocorticoid administration (Spath et al., 1974; Spath and Lefer, 1975).

It now appears clear that pharmacological administration of glucocorticoids early in the infarction process is of definite benefit to the jeopardized myocardial tissue and helps to prevent the extension of the infarcted myocardium. This beneficial effect occurs in man as well as in experimental animals (e.g., cat, dog). Although the mechanism of the protective effect of glucocorticoids is not fully known, several groups of investigators have suggested hemodynamic, metabolic, and membrane stabilization as their major mode of action. Present data favor lysosomal and cell membrane stabilization as an important phase of the protective effect, although other mechanisms may be involved. Clearly, additional work on this important subject is necessary to resolve these questions.

No direct data are available on the effects of mineralocorticoids in myocardial ischemia. However, based on their physiological properties (e.g., positive inotropic effect) the relative lack of cardiac receptors for them, and their failure to stabilize lysosomal and cellular membranes, it would be unlikely that they would be of benefit in acute myocardial ischemia. Similar conclusions have been drawn between the efficacy of the glucocorticoids and mineralocorticoids in circulatory shock (Lefer and Spath, 1977).

Table I summarizes the cardiac effects of glucocorticoids and mineralocorticoids and their actions in the ischemic myocardium.

TABLE I

Cardiac Effects of Corticosteroids

III Pancreatic Hormones

The pancreas secretes three hormones: glucagon, insulin, and somatostatin. Glucagon and insulin function in the regulation of blood glucose concentration and metabolism, whereas somatostatin is known to inhibit both glucagon and insulin release from the endocrine pancreas. In addition to their basic metabolic actions, glucagon and insulin produce cardiac effects at pharmacological levels and these actions may be of potential interest in certain cardiovascular disorders.

A Glucagon

Glucagon, the pancreatic hyperglycemic factor, has been extensively examined for cardiac actions. It is a polypeptide hormone consisting of 29 amino acid residues and has a molecular weight of 3485 daltons (Bromer et al., 1975). Farah and Tuttle (1960) demonstrated positive inotropic and chronotropic responses to glucagon in a variety of species. Subsequently, other investigators have confirmed cardiac activity of glucagon and have attempted to establish the mechanism of action and potency of the cardiac action of this hormone.

Farah and Tuttle’s initial work (1960) revealed an increased force of contraction in isolated atria from rats, dogs, cats, and guinea pigs at glucagon concentrations ranging from 3 to 170 nM. Physiological concentrations of glucagon fluctuate around 57 pM (200 pg/ml) (Goodner et al., 1977), indicating that cardiac stimulation occurs at concentrations three orders of magnitude greater than those present in vivo. Therefore physiological actions of glucagon do not include alteration of cardiac contractile strength, but pharmacological doses of this agent can produce significant positive inotropic effects.

Many investigators also found substantial positive inotropic effects of glucagon on ventricular tissue. Farah and Tuttle (1960) observed an increase in contractility of the dog heart–lung preparation at a final circulating glucagon concentration of 15 nM. Isolated right ventricular cat papillary muscles increased active tension development 0–50% in response to glucagon in the concentration range from 14 nM to 14 μM (Marcus et al., 1971; Glick et al., 1968). Glucagon also elicited elevations in contractile activity of isolated perfused rat hearts (Mayer et al., 1970) and intact canine hearts (Glick et al., 1968), the latter experiencing a 73% increase in the first derivative of left ventricular pressure development (dP/dt max) after a bolus dose of 50 μg/kg glucagon. These studies firmly established inotropic activity attributable to glucagon.

Investigators attempting to determine the potency of glucagon often compared its inotropic actions to those of epinephrine. Mayer et al. (1970) found glucagon and epinephrine to increase contractility equally in isolated perfused rat hearts at concentrations from 30 to 300 pM, but higher concentrations of epinephrine continued to increase contractile activity, whereas glucagon did not (Mayer et al., 1970). Maximal responses to the two agents revealed epinephrine to elevate contractility double the extent of glucagon. Regan and co-workers (1964) also noted similar increases in left ventricular dP/dt max in dogs with 14 nmoles glucagon or 28 nmoles epinephrine. Thus glucagon is a moderately potent inotropic agent, with its maximal stimulation of the heart being less than that elicited by catecholamines.

The mechanism by which glucagon stimulates the myocardium was initially believed to be mediated by β-adrenergic receptors, because dichloroisoproterenol, a β-adrenergic antagonist, prevented cardiac actions (Farah and Tuttle, 1960). Reserpine, a catecholamine depleting agent, did not reduce the glucagon response (Farah and Tuttle, 1960), and therefore, glucagon was assumed to stimulate the β-adrenergic receptor directly rather than act via a catecholamine releasing action. However, subsequent studies using more effective β-adrenergic antagonists, such as propranolol, did not reduce cardiac responsiveness to glucagon (Glick et al., 1968; Lucchesi, 1968). These reports indicated that glucagon is devoid of β-adrenergic agonistic properties and does not require the release of catecholamines to stimulate cardiac tissue.

Cardiac actions of glucagon were also found to be independent of changes in blood sugar, which result from glucagon administration. Farah and Tuttle (1960) subjected the dog heart–lung preparation to low (9 mg/dl) and high (280 mg/dl) glucose concentrations and found unaltered inotropic responses to glucagon. Inotropic actions of glucagon, therefore, cannot be attributed to alterations in blood sugar.

The basis for the cardiac activity of glucagon is now presumed to be related to its well-known ability to stimulate adenyl cyclase, which increases cyclic AMP production. Brunt and McNeill (1978) recently reported increased cyclic AMP levels preceding contractility responses to glucagon in the isolated perfused rat heart. These investigators also found low doses of theophylline, a phosphodiesterase inhibitor, to potentiate the inotropic responses to glucagon (1978), as have others (Marcus et al., 1971). Lucchesi (1968), employing higher levels of theophylline (10 mg/kg) in dogs, eliminated inotropic actions of glucagon. These results implicate cyclic AMP as the mediator of glucagon-induced contractility responses, because high doses of theophylline eliminated glucagon responses, whereas lower doses potentiated them. These two agents, therefore, appear to act via a common mechanism of action, with theophylline being the more potent agent.

Nevertheless, cyclic AMP has not gained universal acceptance as the basis for the cardiac activity of glucagon (Mayer et al., 1970). These investigators demonstrated a separation of inotropic and cyclic AMP responses to glucagon in the isolated rat heart. After treatment with dichloroisoproterenol, glucagon increased cyclic AMP levels without changes in contractility. These investigators also found the initiation of the inotropic response to glucagon in normal tissue to precede cyclic AMP increases, thus making a cyclic AMP mediation of the inotropic response unlikely because of the temporal sequence of events (Mayer et al., 1970). Despite this challenge, activation of adenyl cyclase remains the most attractive explanation of the cardiac actions of glucagon.

Although the exact relationship between glucagon, cyclic AMP, and contractility has not been clearly established, one agent known to be essential for the contractile activity of glucagon is calcium. Visscher and Lee (1972) demonstrated increased inotropic responses to glucagon, as external calcium was reduced in isolated perfused cat heart preparations. No inotropic effect of glucagon was observed in calcium-free perfusate where the heart was arrested. Entman et al. (1969) revealed a cyclic AMP stimulation of calcium uptake by isolated microsomal fractions of dog hearts. Glucagon stimulated adenyl cyclase to increase calcium uptake by these fractions. Actions of glucagon required more time than those of cyclic AMP, thus supporting the role of cyclic AMP as a second messenger (Entman et al., 1969). This increase in sarcoplasmic binding of calcium is also in agreement with Visscher and Lee’s work (1972), since they could not detect an increase in calcium accumulation by hearts after glucagon treatment. Glucagon, therefore, may act to alter intracellular calcium distribution in producing its inotropic actions.

Other cardiac effects of glucagon include an increased heart rate and coronary vasodilation. The chronotropic action has been observed in a variety of species (Farah and Tuttle, 1960), including man (Dhingra et al., 1974). Chronotropic responses to glucagon were sustained after wide variations in extracellular glucose levels (Farah and Tuttle, 1960). The chronotropic action of glucagon, therefore, is unrelated to adrenergic mechanisms or blood sugar alterations, but it is believed to result from elevation of cyclic AMP.

The chronotropic activity of glucagon discussed previously referred to glucagon effects on the sinoatrial node, the primary pacemaker of the heart. Chronotropic effects of glucagon are not restricted to this node but also influence other pacemaker tissue in the heart. Lucchesi and others (1969) demonstrated a 300% increase in heart rate when glucagon (4 μg/kg) was administered to dogs after their sinoatrial nodes were crushed. Glucagon has also been shown to enhance canine atrioventricular (A-V) conduction (Lipski et al., 1972) and was capable of eliminating A-V block in some studies in dogs (Steiner et al., 1969) and in humans (Kones, 1971), thereby suggesting it as a possible therapeutic agent for conduction abnormalities. Glucagon, then, affects the cardiac conduction system to increase the frequency of action potentials in nodal tissue and to stimulate the conduction of impulses from the atria to the ventricles.

Glucagon increases coronary perfusion in dogs (Nayler et al., 1970) and man (Manchester et al., 1970). Goldschlager and associates (1969) and Nayler et al. (1977), however, noted parallel elevations in coronary flow and oxygen utilization in humans and dogs. This relationship between flow and oxygen demand suggests that the glucagon-induced coronary dilation resulted from increased oxygen demand rather than from a direct action of glucagon. Moir and Nayler (1970) confirmed this supposition in the potassium-arrested isolated perfused dog hearts. Glucagon had no effect on coronary flow in the arrested heart, whereas other dilators (e.g., isoproterenol and nitroglycerin) retained their effectiveness. Glucagon, therefore, is an indirect dilator of the coronary circulation, the dilation stemming from increased oxygen demand produced by its inotropic action.

In summary, glucagon produces significant increases in cardiac contractility and modest increases in rate, and only indirectly dilates coronary vasculature. Inotropic and chronotropic actions are not related to glucose concentrations, adrenergic receptors, or endogenous catecholamine release. The cardiac actions of glucagon probably result from a stimulation of adenylate cyclase to increase cyclic AMP levels, which may increase calcium storage in the sarcoplasmic reticulum. Calcium has been firmly established as a requisite cofactor for the inotropic action of glucagon.

These marked cardiac effects of glucagon have made it a potential therapeutic agent for selected cardiovascular disorders. The inotropic effects of glucagon stimulated interest in its applicability to conditions of heart failure and myocardial infarction. However, the inotropic action of glucagon in experimental heart failure has been reported to be inconsistent, being either absent (Gold et al., 1970; Winokur et al., 1975) or present under a variety of experimental conditions (Cornman et al., 1957; Nobel-Allen et al., 1973). Although heart failure was induced by identical procedures in those studies reporting glucagon inotropic activity, hearts were examined in vivo, and in those hearts not responding to glucagon, they were tested in vitro. The data on glucagon in chronic heart failure, therefore, is inconclusive, although glucagon remains a possibility for treatment of this disorder.

Glucagon has been examined in cases of myocardial infarction by a host of investigators. Diamond and associates (1971) revealed an increase in contractility in humans suffering from myocardial infarction, as have Puri and Bing (1969) in dogs. The benefit of increasing myocardial contractility remains doubtful, though, because glucagon increases oxygen demand in conjunction with increases in contractility. The elevated requirement for oxygen could further jeopardize the ischemic myocardium. Alternatively, subinotropic concentrations of glucagon have been found to improve recovery of isolated perfused rat hearts subjected to brief hypoxic episodes (Busuttil et al., 1976). Reduced cyclic GMP concentrations were cited by these investigators as the basis for the salutary action of glucagon. Although the inotropic activity of glucagon appears to be of little value in treatment of myocardial infarction, its influence on cell biochemistry may be beneficial. The myocardial actions of glucagon and their applicability to ischemic states are listed in Table II.

TABLE II

Cardiac Effects of Pancreatic Hormones

The most successful clinical application of glucagon to a cardiac abnormality is in myocardial conduction defects. In addition to abolishing a complete A-V block in man (Kones, 1971), it has also been shown to be effective in dogs after A-V block of different etiologies. After blockade of the A-V node with formalin, glucagon (50 μg/kg) increased ventricular rate by 33%, indicating a stimulation of ventricular pacemaker tissue (Hurwitz, 1971). A reversal of depressed conduction produced by propranolol again indicated no β-adrenergic receptor involvement in cardiac actions of glucagon and also exhibited another potential clinical application for glucagon in instances of propranolol overdoses (Whitsitt and Lucchesi, 1968). Myocardial clinical uses of glucagon, then, primarily center around treatment for depressed or blocked conduction of electrical impulses. Alternative possibilities include treatment of chronic heart failure, and in small doses glucagon may improve recovery from ischemic injuries of short durations.

B Insulin

Insulin is the major hormone secreted by the pancreas. Insulin produces cardiac actions of a lesser magnitude than does glucagon, and thus has generated less interest than glucagon. Insulin, however, is essential for normal myocardial function and is also considered to have therapeutic potential.

Insulin has been reported to produce modest positive inotropic actions in isolated tissues in piglets, cats (Lee and Downing, 1976), and rabbits (Snow, 1976; Sassine et al., 1975) and in vivo in lambs (Downing et al., 1977) and piglets (Nudel et al., 1977). Insulin increased tension development (i.e., dP/dt max) in these preparations by 20–40% at concentrations of 1 mU to 1 U/ml. Physiological concentrations of insulin are 20 μU/ml (Sherwin et al., 1977), indicating cardiac stimulation at values two to four orders of magnitude greater than physiological concentrations. No contractile response to insulin was observed at concentrations lower than 100 μU/ml in isolated perfused rat hearts (Gmeiner et al., 1974), emphasizing the requirement for extremely high insulin levels to obtain an inotropic action.

Insulin produced moderate increases in contractility without β-adrenergic receptor involvement; Nudel and co-workers (1977) reported the β-receptor antagonist, practolol, potentiated the inotropic action of insulin. Lee and Downing (1976) also reported no change in time to peak tension development after addition of insulin to cat papillary muscles, whereas catecholamines markedly decrease this parameter. Alterations in glucose concentrations also have no effect on cardiac responsiveness to insulin (Lee and Downing, 1976). Insulin, therefore, increases contractility of myocardial tissue independent of glucose alterations or catecholamine receptors.

However, insulin may affect cardiac contractility by altering responses to other humoral agents. Lee and Downing (1976) found insulin to depress contractility responses to norepinephrine, and a similar suppression of the inotropic activity of epinephrine was also observed (Nudel et al., 1977). Additionally, Regan et al. (1963) reported the positive inotropic effect of acetylstrophanthidin to be reduced in the presence of insulin. Insulin actions on the heart, therefore, are not restricted to direct effects; they also include modulation of other hormonal actions, including those of catecholamines.

Insulin probably does not alter heart rate; most investigators have found no chronotropic action except in the presence of an epinephrinelike impurity (Puri and Bing, 1969). The increase in coronary perfusion by insulin in lamb hearts appears to be accompanied by a decrease in oxygen extraction (Downing et al., 1977), and this finding has been confirmed in man (Rogers et al., 1977). These data indicate the coronary vasodilator action of insulin to be unrelated to an increase in oxygen demand produced by its inotropic effect.

In summary, insulin has been demonstrated to produce a weak positive inotropic effect, increasing contractility in animal hearts maximally about 20–30% above control values. Insulin does not alter heart rate, but it dilates the coronary vasculature independently of a metabolic effect. Cardiac actions of insulin also include depression of other hormonal inotropic actions, insulin being capable of eliminating the responses to catecholamines and acetylstrophanthidin.

Other cardiac actions of insulin are of greater importance physiologically. Regan and co-workers (1974) found diabetic dog hearts to have an increased resistance to filling, possibly caused by increased glycoprotein content of the interstitium. Insulin (0.1 U/ml) increased protein synthesis in ribosomes of diabetic rat hearts (Stirewolt and Wool, 1966) and decreased protein degradation (Goodner et al., 1977). The reduction in protein catabolism may involve an insulin action to lower the lysosomal enzyme content of hearts, as Wildenthal (1973) has described. Actions of insulin, as revealed by these studies, also include regulation of cardiac protein balance, with insulin increasing protein synthesis and inhibiting degradation.

Another prominent metabolic action of insulin and one that has received extensive clinical attention is its stimulation of myocardial glucose uptake (Morgan et al., 1960; Gmeiner et al., 1974; Regan et al., 1974). Insulin stimulation of glucose uptake persists in anoxia, with anoxia and insulin acting together to accelerate glucose uptake greater than either factor alone (Gmeiner et al., 1974). Morgan et al. (1960) also found insulin to increase transmembranal transport of glucose, whereas anoxia stimulated transport and intracellular phosphorylation. It was reasoned that insulin in combination with hypoxia, such as that encountered during coronary occlusion, would increase glucose uptake and stimulate glycolysis to result in increased high-energy phosphate production. However, Liedtke and co-workers (1976) revealed a worsened mechanical function of globally ischemic swine hearts receiving insulin than in those receiving no treatment. Hearts treated with insulin also survived for shorter periods despite an elevation in glocuse uptake (Liedtke et al., 1976). All hearts rendered ischemic showed inhibition of glycolysis at the glyceraldehyde-3-phosphate dehydrogenase step, which indicates that insulin is not capable of elevating anaerobic glycolysis sufficiently to supply myocardial energy demands in low-flow conditions.

Another function of insulin thought to promote improved functioning of infarcted myocardium is a reduction in free fatty acid content of plasma (Ahmed et al., 1978). Rogers and co-workers (1976) attributed a significant improvement in survival of patients with myocardial infarction to this reduction of free fatty acids. In contrast, Ahmed et al. (1978) found insulin to improve myocardial function and electrolyte distribution after coronary artery occlusion in dogs whether fatty acid levels were reduced or sustained at high levels. Beneficial actions of insulin in patients with coronary artery disease are not universal findings, however; Lesch and co-workers (1974) observed worsened signs of acute myocardial ischemia and elevated left ventricular end-diastolic pressures during atrial pacing in patients with coronary artery disease. Thus the benefit of insulin in ischemic heart disease is somewhat questionable, both positive and negative effects being noted in cardiac patients. The major cardiac actions of insulin and their applicability to ischemic heart disease are summarized in Table II.

C Somatostatin (SRIF)

Somatostatin, the most recently discovered pancreatic hormone, has not been extensively investigated previously for cardiac actions. Trachte and Lefer (1979) examined effects of somatostatin in final bath concentrations of 1 ng/ml to 1.0 μg/ml on right ventricular cat papillary muscles and isolated cat coronary arteries perfused at a constant flow. Papillary muscles responded with a slight increase of 5 ± 1.5% in active tension development at the highest concentration utilized (i.e., 1 μg/ml). Coronary vessels did not react to somatostatin with a change in perfusion pressure at any concentration employed. These data reveal no marked effects of somatostatin on cardiac tissue, the inotropic effect being trivial when compared to other known inotropic substances.

IV Renin-Angiotensin System

The renin-angiotensin system is a diffuse humoral system that generates several biologically potent vasoconstrictors (i.e., angiotensin II, angiotensin III). Renin is released by the kidneys and enzymatically cleaves angiotensinogen, which is produced by the liver, to the decapeptide angiotensin I. Angiotensin I is then converted to the biologically active octapeptide angiotensin II by converting enzyme (EC 3.4.15.1), with the pulmonary circulation containing the highest titer of this enzyme. Angiotensin II can be reduced to a heptapeptide with biologic activity, angiotensin III, by aminopeptidases. Two excellent reviews of this system have appeared recently (Reid et al., 1978; Peach, 1977) and should be consulted further for clarification of this system. Each component of the system produces different degrees of cardiac stimulation and will be discussed separately.

A Renin

Renin, the initiator of the system, is simply an endopeptidase that cleaves a decapeptide fragment (angiotensin I) from the angiotensinogen molecule. Renin produced no noticeable cardiac effects in the isolated perfused cat heart, according to Hill and Andrus (1940), which indicates an inability of renin to stimulate cardiac tissue directly.

B Angiotensin I

Angiotensin I, which has some biologic activity in certain vascular beds, stimulates isolated rabbit atria to maximally increase tension development 60% at 10−6 M (Bonnardeaux et al., 1977). Right atrial myocardial tissue exhibited a greater sensitivity to the decapeptide than left atrial tissue (Bonndardeaux et al., 1977). The enhancement of contractility in these preparations was reduced after application of converting enzyme inhibition (CEI), revealing a dependency on conversion to angiotensin II for biologic activity (Ackerly and Peach, 1975). Inotropic actions of angiotensin I, however, were not reduced by converting enzyme blockade in isolated right ventricular cat papillary muscles, as is shown in Fig. 1 (Trachte and Lefer, 1979). Angiotensin I produced moderate increases in active tension development (maximal stimulation 50%), being the least potent angiotensin inotropically in ventricular myocardial tissue.

Fig. 1 ; angiotensin II (6); •—•, angiotensin III (12). The number in parenthesis is the number of entries studied.

Angiotensin I has been reported to have slight positive chronotropic activities (Bonnardeaux and Regoli, 1974) and is capable of constricting the coronary vasculature. However, both Gerlings and Gilmore (1973) and Britton and Di Salvo (1973) observed reduced coronary vascular responses to angiotensin I after converting enzyme blockade in dogs, indicating angiotensin II as the primary coronary constrictor. Recent data in isolated cat coronary arteries also show a reduction in constriction (i.e., smaller increase in pressure) in response to angiotensin I after converting enzyme inhibition (Trachte and Lefer, 1979). These data are depicted in Fig. 2. The results suggest a slight direct action of angiotensin I on the coronary vasculature with the majority of the decapeptide action being due to angiotensin II formation.

Fig. 2 , angiotensin II (9); •—•, angiotensin III (7). The number in parenthesis is the number of entries studied.

C Angiotensin II

Angiotensin II is the most potent angiotensin regarding cardiac actions, as can be clearly seen in Figs. 1 and 2. Angiotensin II has been known to increase the contractility of cardiac tissue in a variety of preparations, including isolated cat hearts (Hill and Andrus, 1940), cat papillary muscles (Koch-Weser, 1964; Lefer, 1967), isolated cat (Koch-Weser, 1964) and rabbit atria (Bonnardeaux et al., 1977), and dog heart–lung preparations (Mayer et al., 1970). The increase in contractility produced by angiotensin II in papillary muscles can be seen in Fig. 1. The maximal stimulation occurred at 10−6 M and produced a 100% increase in active tension development. Koch-Weser (1964) found the maximal increase in contractility to angiotensin II to be less than that of norepinephrine (100% vs. 190%). Thus, although angiotensin II is a stronger inotropic stimulus than other angiotensins or pancreatic hormones, it is not as potent as the catecholamines in this respect.

Angiotensin II actions on the myocardium were initially suspected to result from release of catecholamines, an action of angiotensin known to occur at adrenal medullary (Peach, 1971) and nerve terminal sites (Peach, 1977). Koch-Wester (1965) demonstrated no catecholamine component of cardiac actions of angiotensin II. Neither β-blockade with nethalide nor catecholamine depletion with reserpine altered the contractile responses to angiotensin II (Koch-Weser, 1965). Additionally, Koch-Weser (1965) demonstrated a slight prolongation of the time required to develop peak tension after angiotensin, unlike catecholamines, which are known to shorten this period. Dempsey et al. (1971) also found intact angiotensin II responses after β-blockade with propranolol in cat papillary muscles. Thus, although angiotensin II can release catecholamines, inotropic effects appear to be exerted by a direct angiotensin action on the myocardium. This dual action of angiotensin II in cardiac tissue was recently clarified by Blumberg and co-workers (1975), who found angiotensin II to potentiate inotropic responses to tyramine (a catecholamine releasing agent) as well as to produce an inotropic effect through stimulation of angiotensin receptors. The predominant action of angiotensin II is probably its direct stimulation of angiotensin receptors, since catecholamine depletion or receptor blockade did not reduce its cardiac stimulation.

The threshold for inotropic responses to angiotensin is about 1 nM. Circulating physiological levels of angiotensin II, however, usually do not exceed 100 pM (Morton et al., 1977), probably indicating no major role of angiotensin II in physiological regulation of cardiac contractility. However, during hemorrhage, circulating angiotensin II plasma concentrations exceed 1 nM (Morton et al., 1977), a concentration greater than that required for myocardial activity. Therefore angiotensin II may influence cardiac contractility during certain situations, especially if these states also are characterized by increased sympathetic stimulation, such as in hemorrhage. In these instances angiotensin can influence cardiac contractility by potentiating sympathetic actions in addition to stimulating the heart directly.

The inotropic actions of angiotensin II appear to result primarily from stimulation of myocardial angiotensin II receptors. Catecholamine receptors are not involved, as was demonstrated by catecholamine depletion and β-adrenergic receptor blockade. Angiotensin II, however, can potentiate the release of catecholamines from nerve terminals and in this way can potentiate cardiac sympathetic responses. Maximal inotropic actions of angiotensin II were large but of a smaller magnitude than those of catecholamines.

Angiotensin II was observed to produce a decrease in heart rate when injected into intact dogs (Farr and Grupp, 1967); however, an increase in heart rate was noted with angiotensin II after baroreceptor denervation or buffering of blood pressure (Krasney et al., 1965). Sympathetic nervous blockade with bretylium tosylate or β-adrenergic blockade prevented the cardioaccelerator response to angiotensin II, revealing an adrenergic component to chronotropic actions of angiotensin II.

Krasney and co-workers (1965, 1967) observed no alteration of the chronotropic response to angiotensin II after adrenalectomy, thus eliminating catecholamines of adrenal origin from involvement in angiotensin II-induced heart rate changes. These results indicate that angiotensin II releases catecholamines at the level of the heart to produce increases in heart rate. Adrenal catecholamine release was shown not to be involved in this action. Positive chronotropic responses to angiotensin II were only observed in the absence of baroreceptor reflexes; a decrease in heart rate resulted when these reflexes were present.

Angiotensin II constricts all vascular beds, including the coronary vasculature. Lorber (1942) and Hill and Andrus (1940) noted a constrictor action of angiotensin II in isolated cat hearts, as did Gerlings and Gilmore (1973) in isolated dog hearts. Trachte and Lefer (1979) expanded on this work utilizing isolated perfused coronary arteries, and, as can be seen in Fig. 2, angiotensin II constricts these vessels in concentrations exceeding 1 ng/ml. The degree of constriction was similar to that of angiotensin III but was much more potent than that of angiotensin I.

The coronary constrictor activity of angiotensin II may be of significance in control of coronary blood flow in vivo. Gavras et al. (1978a) found an increased coronary blood flow after administration of an angiotensin converting enzyme inhibitor (i.e., teprotide) in sodium-depleted dogs. However, it had no effect in animals having normal