Neurogenic Heart Lesions

NEUROGENIC HEART LESIONS

I.S. ZAVODSKAYA

E.V. MOREVA

N.A. NOVIKOVA

USSR Academy of Medical Sciences

Table of Contents

Cover image

Title page

Copyright

FOREWORD

INTRODUCTION

Chapter 1: Methods for Producing Experimental Neurogenic Lesions

Publisher Summary

STRUCTURAL MYOCARDIAL LESIONS PRODUCED BY ELECTRICAL STIMULATION OF THE HYPOTHALAMUS

ULTRASTRUCTURAL AND MICROSCOPIC CHANGES PRODUCED BY REFLEX LESIONS OF THE MYOCARDIUM

PHARMACOLOGICAL AND PHYSIOLOGICAL ANALYSIS OF THE PROPAGATION PATHS OF THE IMPULSES PRODUCING NEUROGENIC LESIONS OF THE HEART

Chapter 2: Pharmacological Analysis of the Participation of the Sympathetic Nervous System and its Transmitters in the Development of Neurogenic Lesions of the Myocardium

Publisher Summary

NORADRENALINE LEVELS IN MYOCARDIAL TISSUE DURING EXCESSIVE STIMULATION

EXPERIMENTS WITH THE PRECURSOR OF NORADRENALINE – L-DOPA

EXPERIMENTS WITH THE CENTRAL α-ADRENOBLOCKER IEM-611

EXPERIMENTS WITH ETHYMISOL *

EXPERIMENTS WITH THE GANGLIOBLOCKER BENZOHEXAMETHONIUM

EXPERIMENTS WITH THE β-BLOCKER PROPRANOLOL

EXPERIMENTS WITH TOXIC DOSES OF CATECHOLAMINES

Chapter 3: Changes in Energy Metabolism and in Functional Conditions of the Myocardium caused by Neurogenic Lesions

Publisher Summary

GLYCOGEN LEVELS AND THE PROCESS OF GLYCOLYSIS DURING EXCESSIVE STIMULATION OF THE ANIMALS

OXIDATIVE PHOSPHORYLATION IN MITOCHONDRIA OF THE HEART PRODUCED BY ITS NEUROGENIC LESION AND THE INJECTION OF TOXIC DOSES OF NORADRENALINE

HIGH-ENERGY ADENOSINE TRIPHOSPHATE (ATP), CREATINE PHOSPHATE (CP) AND INORGANIC PHOSPHORUS (IP) LEVELS IN THE MYOCARDIUM PRODUCED BY EXCESSIVE STIMULATION

THE ACTIVITY OF THE FIRST STAGE OF THE PENTOSE-PHOSPHATE PATHWAY, GLUCOSE-6-PHOSPHATE DEHYDROGENASE (G-6-P DH)

ELECTROCARDIOGRAPHIC DATA OBTAINED DURING NEUROGENIC LESIONS OF THE MYOCARDIUM AND INJECTION OF LARGE DOSES OF NORADRENALINE

Chapter 4: Pharmacoprophylaxis and Pharmacotherapy of the Biochemical Changes Produced by Neurogenic Lesions of the Myocardium

Publisher Summary

EXPERIMENTS WITH THE PRECURSOR OF NORADRENALINE, L-DOPA

EXPERIMENTS WITH ETHYMISOL

EXPERIMENTS WITH THE CENTRAL α-ADRENOBLOCKER, IEM-611

EXPERIMENTS WITH THE GANGLIOBLOCKER, BENZOHEXAMETHONIUM

EXPERIMENTS WITH THE β-BLOCKER, PROPRANOLOL

Chapter 5: The Analysis of Experimental and Clinical Data

Publisher Summary

REFERENCES

INDEX

Copyright

Copyright © 1980 Pergamon Press Ltd.

All Rights Reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic tape, mechanical, photocopying, recording or otherwise, without permission in writing from the publishers.

First edition 1980

British Library Cataloguing in Publication Data

Zavodskaya, I S

Neurogenic heart lesions.

1. Heart - Muscle - Diseases

2. Heart - Diseases - Chemotherapy

I. Title II. Moreva, E V

III. Novikova, N A

616.1′24 RC682 80-40436

ISBN 0-08-025482-9

This is a translation of the first Russian edition Vliyaniye neirotropnykh sredstv na neirogenniye porazheniya serdtsa published by Meditsina © 1977.

In order to make this volume available as economically and as rapidly as possible the authors typescripts have been reproduced in their original forms This method has its typographical limitations but it is hoped that they in no way distract the reader.

Printed in Great Britain by A. Wheaton & Co. Ltd, Exeter

FOREWORD

Modern cardiology places great importance on nervous factors in the development of cardiovascular disease. Emotional stress, prolonged negative emotions and psychological strain may also be regarded as extraordinary influences on the organism which result in neurogenic lesions of the cardiovascular system. The credit for the recognition of nervous-psychical aetiopathogenesis of myocardial diseases, referred to as cardiac dystrophy, belongs to Professor Lang. The authors of the present monograph, scientific workers in the Laboratory of Experimental Pharmacology of the Institute of Experimental Medicine in the Academy of Medical Sciences of the USSR (Head – Professor I.S. Zavodskaya) are studying neurogenic dystrophies of the internal organs and, in particular, neurodystrophies of the heart. In the monograph Neurogenic dystrophies and their pharmacotherapy, published in 1969, there was a short chapter devoted to the neurogenic lesions of the heart. Since that time, Zavodskaya and her collaborators have obtained new data which considerably extend our knowledge of the problem. In their recent investigations the authors of the monograph have successfully used modern methods, including electron microscopy, histochemistry, and ultracentrifugation, i.e. methods which permit observation of the events at the intracellular level. The results of these investigations led to important conclusions as to the causes and character of metabolic disorders caused by neurogenic lesions of the myocardium. Pharmacological analysis has assisted both in revealing the direct cause of these disorders and in providing rational methods of pharmacotherapy. The concluding chapter of the monograph presents clinical observations and discussion based on the preceding experimental data and theoretical premises.

The results of these investiga tions led to important conclusions as to the causes and character of metabolic disorders caused by neurogenic lesions of the myocardium. Pharmacological analysis has assisted both in revealing the direct cause of these disorders and in providing rational methods of pharmacotherapy. The concluding chapter of the monograph presents clinical observations and discussion based on the preceding experimental data and theoretical premises. The results of the clinical studies confirmed the experimental data and permitted their use in practical medicine. Simultaneously with the presentation of their own investigations, the authors have reviewed the main publications concerned with the problem of neurogenic lesions of the heart. Great attention is paid to investigations carried out in the USSR, since the most important publications on the problem are contributed by outstanding Russian scientists. The authors of the monograph are experimental pharmacologists, but the content of the book is of great interest not only for pharmacologists and pathologists, but also for the large circle of clinicians and physicians concerned with new achievements in the field of cardiology.

S.V. Anichkov,     Academician of the Academy of Medical Sciences of the USSR

INTRODUCTION

One of the urgent problems of modern cardiology is the study of the role of nervous factors in the development of dystrophic lesions of the cardiovascular system.

The concept of nervous regulation of metabolism and neurogenic dystrophies originated from classical works of Magendie 150 years ago (Magendie, 1924).

The deep neurogenic damage to the internal organs which develops as a result of the application of strong stimulation to various parts of the nervous system, both central and peripheral, were described in the 19th century (Samuel, 1860; Schiff, 1867; Broun-Sequard, 1876). Since then, numerous physiological and pathological investigations which have established the close dependence of tissue disorders on the change in the function of those parts of nervous systems, both central and peripheral, have been devoted to the problem of nervous control of metabolic processes (Pavlov, 1920; Speransky, 1930, 1935; Bykov,& Kurtsin, 1949).

The original reports on the important role of the nervous system in the development of cardiovascular disease appeared in the last century. The great Russian clinician, S. Botkin, wrote that „the changes in the function of the heart are not only related to the changes in the heart itself, but also frequently depend on the central nervous system" (1912). S. Botkin also showed the existence of the close reflex relation of the heart to all the internal organs.

His pupil, Simanovsky, performed extensive experimental investigation on the influence of the stimulation of sensitive nerves on cardiac activity and myocardial nutrition. Prolonged stimulation of peripheral sensory nerves (nerves of the arm, radial, median and sciatic nerves, as well as nerves of the stomach and gall bladder) produced severe morphological lesions of the myocardium, from albumin degeneration to fatty degeneration. The author considered this phenomenon to be a reflex response to the stimulation of the nerves (N. Simanovsky, 1881).

In his work, The reinforcing nerve of the heart (1888), Pavlov provided the basis for the principle of nervous system influences on the vital processes of the myocardium. As an example of a „trophic" nerve, Pavlov described the vagus nerve of the heart which, irrespective of the changes in blood supply, enhances all the vital properties of the myocardium: excitability, conduction, and contractility. In his famous report On trophic innervation (1922) Pavlov clearly formulated the main principles of the nervous „trophic processes. He showed that the reflex principle is the basis of the „trophic function of the nervous system and, for the first time, suggested the concept of „trophic reflexes participating in the origination, development and termination of the various dystrophic effects. On the basis of his observations, Pavlov concluded that the „trophic disorders which he discovered in chronic experiments on the digestive tract of dogs could be explained by reflexes connecting „abnormally stimulated centripetal nerves of the digestive tract to the special inhibiting „trophic nerves of the various tissues. In his opinion „the vital chemical activity of tissue is controlled by special centripetal nerves and, moreover, these nerves have two effects. Some nerves intensify this process and thus increase tissue vitality; others lower it during conditions of ‚extraordinary’ stimulation and deprive the tissue of the ability to resist destructive influences of all kinds acting both inside and outside the organism."

The participation of the nervous system in the control of the „trophic processes is indisputable. Disturbances of the neurotrophic control caused by „extraordinary or unusual influences produce dystrophic disorders.

Pavlov’s views on the nervous control of „trophic" processes and on the disorder of this control as the cause of neurodystrophies strongly influenced the work of his pupils: L.A. Orbeli, A.D. Speransky, K.M. Bykov and their schools. Orbeli proposed a theory of adaptive-trophic influence of the nervous system (Orbeli, 1933, 1936, 1948). This concept „is the idea of the totality of those changes which are produced by sympathetic innervation. On the one hand, it (the sympathetic nervous system) alters functional properties, and adaptation, and, on the other, causes substantial chemical, physico-chemical and physical changes (‚trophic’ effect)" (1937).

The works of Speranksy and his school (Skoblo, 1930; Vishnevsky & Golysheva, 1932; Pigalev, 1932; Lebedinskaya & Babkova, 1938) provided a great contribution to the development of the problem of the nervous system influence on „trophic processes and neurogenic dystrophies. These theories became the basis for the general ideas of Speransky on the cause and course of many pathological states. Speransky elaborated the concept, based on experiments, of the role of reflex mechanisms in the development of dystrophic disorders in various organs and tissues. He wrote that „any reflex can become a pathological one if in any portion of its arc temporary or permanent changes are produced by extraordinary stimulation originating from the environment (Speransky, 1955).

Consequently, any direct extraordinary influence on the nervous system can affect the control of the „trophic" processes and cause neurodystrophy.

At present it is quite evident that negative emotions, psychical overstrain, and so-called „stress caused by extraordinary influence on an organism, should be considered as factors leading to the development of neurogenic lesions of the internal organs, including the cardiovascular system. The great contribution to the effects of extreme stimulation on an organism was made by Selye, who introduced the idea of stress as the reaction to „overstrain. It should be noted that, at present, the term „stress is often interpreted not only as this reaction, but also as the various situations caused by extreme influences. Selye elaborated a theory of the standard response of an organism to extreme influence (1960, 1961). However, the problem has now developed beyond his concepts, which are not always acceptable and require substantial correction. Selye interprets the term „stress as the sum of all nonspecific manifestations caused by various extra-strong stimuli of all kinds. Stress reactions, particularly neurohormonal influences, involve the production of „nonspecific resistance", such as homeostasis formation, the acceleration of recovery, etc., by the organism. The thorough study of extreme influences on the organism is important, not only for theoretical, but also for practical medicine, since this problem involves certain questions of the aetiology and pathogenesis of many diseases.

In the effects produced by stress, according to the work from Selye’s laboratory, the leading role is played by dystrophic lesions of some organs, in particular of the myocardium. As is known, Selye emphasized the reaction of the hypophyseal-adrenal system and considered the increased secretion of corticosteroids to be one of the main causes of the pathological processes produced.

The increase in the activity of hypophyseal-adrenal system produced by stimulation of both extra- and inter-receptors discovered by Selye, is confirmed by numerous authors and is an indisputable contribution to physiology. Not without reason is this system named after Selye. However, in analyzing the data obtained by Selye, and which reproduce his fundamental experiments, one can see that the reflexes caused by extreme stimulation are the basis of the described phenomena, in particular, of the excitation of the hypophyseal-adrenal system. Thus dystrophic lesions of various organs, produced by so-called stress, can be considered to be a type of reflex dystrophy.

Emotional stress, as is now known, plays one of the leading roles in the genesis of cardiovascular disease. Numerous clinical observations present evidence showing that stress, psychical overstrain, and negative emotions produce critical lesions of the myocardium and cause myocardial infarction (Lukomsky & Tareev, 1958; Minaev, 1961; Myasnikov, 1962; Gorizontov, 1974; Chazov, 1974; Shkhvatsabaya, 1974).

In experiments on animals, typical stress situations with the most powerful psychosomatic effects appear as the result of aggressive-defensive excitation and the arbitrary suppression of its motor effects. This, in principle, is close to the „non-responded (Lang, 1950), „fixed (Anokhin, 1965) emotions of a human being. For example, in experiments on monkeys for the purpose of simulating cardiovascular lesions, Startsev and Repin (1974) have produced emotional stress by immobilization of the monkeys on a bench. Such a stress situation resulted in the rise of negative emotions which finally caused the development of progressive ischaemia and a pre-infarction condition of the animals. It was also possible to cause emotional stress by means of direct electrical stimulation of the negative emotional centres of the hypothalamus (Sudakov, 1974). By continuous stimulation of these centres in the ventromedian and paramedian nuclei of the hypothalamus, marked changes in cardiac activity, namely, arrhythmia, extrasystoles, changes in ECG waves, ischaemia of the myocardium and cardiac arrest, were produced.

This model of the reproduction of myocardial infarction in monkeys under conditions of high strain, mental disturbance, insanity, and neurosis is interesting (Makagyan, Miminoshvili & Kogan, 1958). During the development of neurosis resulting in an alteration of the reactivity of the autonomic nervous system, the monkeys developed acute coronary failure. The negative T wave in the second and third lead together with the development of ventricular extrasystoles were observed in the ECG. At autopsy the animals showed muscular hypertrophy of the left ventricle, and septal infarction in the region of the apex cordis. Here it should be noted that no organic changes were observed in the aorta or coronary arteries, the lumen of which was free. Similar changes in the electrocardiogram of monkeys during the development of coronary failure, which showed the typical picture of myocardial infarction, were described by Cherkovich (1959). Here the stress was experimental neurosis caused by disturbance of the circadian cycle.

The widespread methods of the study of the development of neurogenic dystrophy of the internal organs, in particular of the cardiovascular system, include various kinds of disturbances of the „trophic" function of the nervous system. Excessive stimulation, damage and blocking of various parts of the nervous system, both central and peripheral, can cause neurodystrophic disorders. Some authors have observed morphological and functional changes in the myocardium produced by excessive stimulation of various parts of the central nervous system (Ostry et al., 1962; Myasnikov et al., 1963; Korteweg et al., 1957). Extensive clinical information resulting from neurosurgery shows that patients with organic diseases of the brain (tumours, hydrocephalus, epilepsy) showed abrupt changes in cardiac activity which, in relation to ECG characteristics, were similar to myocardial infarction. In some cases strong stimulation during an operation resulted in permanent damage to myocardial tissue in the form of extensive subendocardial haemorrhages and myocardial necrosis (Vichert, 1952).

Volynsky, Isakov and Kaizer (1950) described the symptoms of acute coronary failure caused by closed injury of a cat’s skull. These authors observed bradycardia, ventricular extrasystole, and disturbance in the conduction of the bundle of His. Decrease in the voltage of the P, R or Q waves, inversion of the T wave, and displacement of the S-T interval were observed in the ECG. Similar changes were observed in cats following electrical stimulation with bipolar electrodes implanted in various parts of the brain (Kenedi-Csanda, 1959).

At present the majority of authors recognize that, of all nervous structures of the brain, the most important role in nervous control of „trophic" processes is played by the hypothalamus. This is explained by the exceptional importance of the hypothalamus in the control of the vital processes of an organism. Karplus and Kreide (1909, 1910) have discussed the influence of the hypothalamus on the state of the cardiovascular system. They observed changes in blood pressure produced by stimulation of the anterior region. Similar data supporting the existence of hypothalamic vasomotor centres were obtained later by many investigators (Smetankin, 1961; Teplov, 1965; Tonkykh, 1965; Parin, 1966; Ranson, Kabata & Magoun, 1935; Melville et al., 1963; Gellhorn, 1964).

At present the interrelation between hypothalamic activity and the functional condition of the cardiovascular system has been studied thoroughly. However, the participation of the hypothalamus in the development of destructive lesions of the myocardium has received little attention.

In the clinical literature there are indications of a relation between the malfunction of the hypothalamus and organic lesions of the myocardium (Ivanov & Makarov, 1949; Kushelevsky & Reneva, 1951; Koreysha, 1956). More convincing evidence of the participation of the hypothalamus in the development of cardiovascular disease has been obtained experimentally. Functional and structural changes in the myocardium caused by application of experimental damage to the hypothalamus of cats and dogs has been described by Keller et al. (1933) and Watts et al. (1935). While producing electrocoagulation of hypothalamic nuclei of monkeys, the authors observed short-term cardiac arrest at the moment of coagulation. Moreover, the cavities of the hearts of two animals which died 30 minutes after the operation were filled with blood clots. Further, the