Wilhelm Raab

Key position of catecholamines in functional and degenerative cardiovascular pathology

Abstract The catecholamines, norepinephrine and epinephrine, occupy a prominent position in the dynamic, metabolic and structural pathogenic mechanisms of the most common functional and degenerative cardiovascular disorders, such as angina pectoris, myocardial degeneration and failure, arterial hypertension and atherogenesis. Although they are essential constituents of physiologic cardiovascular regulation, their potentially oxygen-wasting, efficiency-impairing, hypoxiating, necrotizing and vasoconstrictor properties become greatly accentuated by certain abnormal circumstances, such as: (1) excessive formation, liberation and local accumulation of catecholamines in cardiovascular tissues; (2) deterioration of sympatho-inhibitory and cholinergic counter-regulatory mechanisms; and (3) coexisting overactivity of other hormones (adrenal corticoids, thyroid hormone) which potentiate the injurious metabolic effects of the catecholamines on heart and blood vessels, in part possibly by way of derangements of the transmembrane cationic gradient. Many effective therapeutic measures are based on quantitative diminution and/or appropriate functional inactivation of the catecholamines.

Emotional and sensory stress factors in myocardial pathology: Neurogenic and hormonal mechanisms in pathogenesis, therapy, and prevention☆

Abstract In the complex but increasingly perceptible pluricausal pathogenesis of degenerative (so-called “coronary”) disease of the heart muscle, emotional and sensory stresses play a prominent, even though usually only contributory, role. Scrutiny of the pertinent contemporary transdisciplinary world literature provides abundant experimental and clinical evidence for a potentially cardiotoxic over-production of sympathogenic catecholamines and adrenocortical steroids, resulting from emotional and sensory stress-induced stimulations of the central nervous system and the pituitary gland. Fear, anger, and frustration, as well as, to a lesser extent, optical, acoustical, and thermal annoyances act as the most common potentially pathogenic stimuli. These stimuli disturb, via the sympatho-adrenomedullary system, the oxygen economy of the myocardium (particularly in conjunction with predisposing coronary atherosclerosis, and with the often associated additional adrenergic manifestations of physical inactivity and of nicotine). Intramyocardial electrolyte shifts, due to catecholamine-induced local hypoxia, and superimposed corticoid-induced depletion of myocardial potassium may be assumed to constitute the most fundamental metabolic derangements involved. There is only sparse evidence in favor of a significant contribution of emotional and sensory stimuli to coronary atherogenesis. However, stress-induced sympathetic and adrenal cortical overaction seems to affect the myocardium also indirectly by way of elevations of blood pressure and resulting hemodynamic strain. Prevention and counteraction of emotional and sensory detriments to the myocardium are feasible through psychotherapy, environmental adjustments, physical reconditioning, and tranquilizing and/or directly antiadrenergic medication.

Sympathogenic origin and antiadrenergic prevention of stress-induced myocardial lesions.

Abstract Moderate to nearly complete protection of the heart muscle against stress-induced necrotizing myocardial lesions in corticoid- or dihydrotachysterol-preconditioned rats was achieved through administration of drugs with direct or indirect antiadrenergic properties: reserpine, guanethidine (catecholamine depletion); mecamylamine (ganglionic blockade); chlorpromazine (inhibition of sympathetic-stimulating reflexes at the hypothalamic level), and Dibenamine (blockade of circulating catecholamines). In otherwise untreated animals, the norepinephrine content of the heart muscle was increased by injection of norepinephrine as well as by its liberation under stress. In corticoidpretreated rats, by contrast, both norepinephrine injection and stress were followed by losses of norepinephrine from the heart, presumably due to the extensive destruction of myocardial tissue under these conditions. Antiadrenergic drugs produced intermediary effects upon the cardiac content of norepinephrine by counteracting its accumulation as well as its depletion resulting from tissue necrosis. It is concluded that the stress-induced severe myocardial structural lesions in hormone-preconditioned animals are directly attributable to the reflex liberation of potentially cardiotoxic adrenosympathogenic catecholamines which accompanies all stressful situations.

THE NONVASCULAR METABOLIC MYOCARDIAL VULNERABILITY FACTOR IN "CORONARY HEART DISEASE". FUNDAMENTALS OF PATHOGENESIS, TREATMENT, AND PREVENTION.

Abstract Common use of the cliche “coronary heart disease” has created a disproportionately one-sided preoccupation with the vascular anatomic aspects of degenerative heart disease to the detriment of interest in those metabolic and neuroregulatory factors which determine the degree of myocardial vulnerability. Myocardial oxygen economy and health depend equally on vascular oxygen supply and myocardial oxygen consumption. The latter is dominated by sympathetic neurohormonal (catecholamine) activity. Myocardial cell vulnerability in the presence of an impaired compensatory dilatability of the coronary arteries (coronary sclerosis) is maximal in certain hemodynamically “handicapped” areas of the left ventricle. It is augmented by sympathogenic catecholamine action through (a) an increase in cardiac oxygen consumption, (b) shortening of diastolic coronary flow, (c) systolic compression of coronary ramifications, especially in the subendocardial layers, (d) presumable losses of potassium from anoxic myocardial cells. Adrenal corticoids and the thyroid hormone intensify catecholamine-induced myocardial vulnerability. The oxygen requirements of cardiac external work per se seem to be less responsible for the occurrence of myocardial anoxia than are the specifically oxygen-“wasting” and unfavorable microcirculatory effects of associated catecholamine liberation, e.g., during emotional excitement, exercise, and other stresses. Most of the procedures and agents designed for the treatment of the clinical manifestations of ischemic heart disease act by decreasing adrenergic metabolic myocardial vulnerability. Civilization-connected augmentation of primary myocardial vulnerability seems to be caused by emotional and environmental plus nicotine-mediated stimulations of the catecholamine-liberating sympatho-adrenal system, combined with a physical-inactivity-induced deterioration of sympathoinhibitory and vagal counterregulation. These pathogenic neurovegetative mechanisms are reversible and, therefore, of outstanding importance from the point of view of active prevention. Mass preventive cardiac-reconditioning systems, aimed at restoring the myocardial neuroregulatory equilibrium of fatigued, tense, and sedentary individuals, are organized abroad on a large scale by governments and private corporations. No such programs exist yet in the United States.

Catecholamine-induced myocardial hypoxia in the presence of impaired coronary dilatability independent of external cardiac work∗☆

Abstract Surface electrocardiograms were taken in vagotomized cats over areas of the left ventricle. An adjustable nonoccluding restriction device prevented part of the coronary arterial supply from dilating. Under these circumstances, brief stimulation of the cardiac sympathetic nerves or reflex stimulation of the adreno-sympathetic system through electrically induced muscular “exercise,” or intravenous injection of catecholamines (epinephrine, norepinephrine) caused regularly marked elevations of the S-T segment and the T wave, even if concomitant augmentation of cardiac mechanical work was only minimal. Identical electrocardiographic changes were elicited by exogenous anoxia (breathing 100 per cent nitrogen), and by more complete coronary constriction. By contrast, no S-T displacement occurred despite coronary restriction when heavy work loads were imposed upon the heart by noncatecholamine influences, namely, tachycardia produced by electrical stimulation of the right atrium, or high rises of the blood pressure produced by intravenous injection of angiotensin II , or both combined. Neurogenic and blood-borne catecholamines cause severe regional myocardial hypoxia when the normal compensatory coronary dilatation is impaired. Such catecholamine-induced myocardial hypoxia is not caused by the concomitant augmentation of cardiac mechanical work which these neurohormones usually elicit, but by their specific biochemical oxygen-wasting properties. Our findings agree with the clinical experience that in patients with coronary sclerosis attacks of angina pectoris are ordinarily triggered by sympathetic-stimulating, catecholamine-liberating conditions (exercise, emotions and other stresses), and prevented by various antiadrenergic measures. Contrary to traditional belief, it is suggested that anginal symptoms do not occur because “the heart works harder” but because certain areas of the myocardium whose coronary vessels have lost the ability for compensatory dilatation are exposed to the biochemical hypoxiating influence of acute catecholamine discharges accompanying various stresses. Except in cases of far advanced coronary sclerosis, the term “coronary insufficiency” is to be understood as meaning inability of the coronary circulation to compensate by adequate dilatation for sympathogenic (catecholamine-induced) excessive myocardial oxygen losses.

Effect of epinephrine and norepinephrine on the electrocardiogram of 100 normal subjects

Abstract Electrocardiograms were registered during infusions of epinephrine and norepinephrine, 0.2 to 0.3 μg. per kg. per minute, in 100 normal young adults. Epinephrine caused increase of heart rate (a decrease occurred when the hypertensive effect was great), lower voltage of the T wave, elevation and earlier appearance of the U wave, and depression of the S-T segment. Inversion of the T wave in lead II and sometimes also in leads V 4 to V 6 occurred in about 10 per cent of the subjects, while in about 10 per cent the elevated U waves showed fusion with the T waves, resulting in a combination wave which resembled a wide, elevated T wave. This effect is explained on the basis of change in repolarization velocity seen in ventricular action potentials. Norepinephrine infusion caused decrease of heart rate and usually elevation of the T wave, but after atropine was given its effect became similar to that of epinephrine. Ectopic rhythms appeared after norepinephrine administration only at high blood pressure levels and at low heart rates, while after epinephrine administration they appeared at all rates. The differences between the effects of these two substances are attributed largely to partial counteraction of the direct effect of norepinephrine on the heart by reflex vagal excitation and sympathetic inhibition originating in the pressoreceptor areas.

Cardiac adrenergic preponderance due to lack of physical exercise and its pathogenic implications

Abstract The influence of habitual vigorous exercise and of the lack of it, respectively, on the basic cardiac neurovegetative status at rest was studied in 360 healthy American and Austrian men (seventeen to fifty years of age), ranging from competitive athletes, mountaineers and Alpine soldiers to completely sedentary persons. Heart rate and the dynamic cardiac cycle (chronodynogram) at rest with special consideration of the isometric period of the left ventricle (total systole minus ejection period) were used as criteria of cholinergic, sympatho-inhibitory and adrenergic chronotropic and inotropic influences, respectively. In 216 subjects, the effects of vagal elimination (atropinization), in seventy-five the effects of infused epinephrine, and in sixty-four of norepinephrine, before and after atropinization, were recorded. The results, especially the basic resting values, reveal a linear increase of cardiac sympathetic tone and decline of cardiac neurovegetative counterregulatory effectiveness in proportion to decreasing degrees of habitual exercise. Physical training periods reversed the situation. Smoking habits (ranging from non-smoking to heavy smoking) seemed to leave the basic cardiac neurovegetative status unaltered despite the immediate adrenergic cardiac effects of tobacco smoking. The cardiovascular metabolic and functional hazards of physical inactivity-induced potentially oxygen-wasting, cardiac efficiency-impairing, myocardium-damaging and possibly atherogenesis-promoting adrenergic overactivity are discussed. Expanded epidemiological studies of primary neurovegetative factors together with other correlated pathogenic conditions (dietary, social, emotional), and the development of medically supervised, prophylactic mass reconditioning programs for degenerating sedentary populations are being urged.

Pressor Effects of Epinephrine, Norepinephrine and Desoxycorticosterone Acetate (DCA) Weakened by Sodium Withdrawal

Recent findings suggest an important role of the sodium ion, intracellularly deposited by the adrenal mineralocorticoids, as the physicochemical mediator between the pressor actions of the mineralocorticoids and of the adrenosympathogenic neurohormones. The following observations show that the pressor effectiveness of both the pressor neurohormones and desoxycorticosterone acetate depends on the availability of sodium. This supports the theory that vascular pressor responsiveness and tonus is determined jointly by the sodium-depositing corticoids as sensitizers and the adrenosympathogenic neurohormones as the physiologic stimulators of the vascular contractile elements.

The sympathogenic biochemical trigger mechanism of angina pectoris: Its therapeutic suppression and long-range prevention☆

Abstract Abundant clinical and experimental data indicate that attacks of anginal pain result from the coincidence of two fundamental factors: (1) impaired coronary dilatability (sclerosis) as the static predisposing element, and (2) the temporary influx into the heart of adrenosympathogenic catecholamines as the acutely oxygen-wasting and biochemically-hypoxiating cardiotoxic trigger. Simultaneous increase of the mechanical work of the heart muscle in itself seems to be of minor importance and may be completely absent. Exaggerated adrenosympathetic neurosecretory overexcitability commonly aggravates the anginal syndrome. Cardiac sympathectomy and practically all nonsurgical therapeutic procedures act on the basis of their antiadrenergic properties, such as drug-induced cardiac catecholamine depletion, ganglionic blockade, thyrostatic catecholamine inactivation, roentgen ray reduction of adrenal medullary epinephrine discharges, suppression of sympathotropic hypothalamic stimuli and reflexes, provocation of antagonistic sympathoinhibitory and cholinergic mechanisms. The various “coronary dilators” fail to dilate sclerotic coronary vessels. They seem to exert their beneficial influence mainly by way of general hemodynamic and cardiometabolic effects which are still poorly understood. The plurifunctional “monoamine oxidase inhibitors” antagonize catecholamine activity by a still unexplained antiadrenergic mode of action. Chronic cardiac adrenergic overactivity results from civilization-induced emotional factors (absolute adrenergic preponderance) and from lack of habitual physical exercise (relative adrenergic preponderance due to deficiency of cholinergic and sympathoinhibitory mechanisms). Both factors appear to contribute jointly to an increased metabolic vulnerability of the heart muscle, possibly also to atherogenesis, thus establishing an ultimately fatal vicious circle. Physical and psychological neurovegetative mass reconditioning programs for early prevention (instead of late rehabilitation) of degenerative heart disease are being sponsored by governments and social security agencies abroad on a large scale in thousands of rural reconditioning centers. No such organized attempt at mass cardiac health preservation has yet been undertaken in the United States. The establishment of a first American pilot reconditioning center is being planned.

Transmembrane gationic gradient and blood pressure regulation

Abstract Corticoid-induced potentiation of catecholamine pressor reactions, and the constant presence of catecholamines in arterial walls have been demonstrated. It has been proposed that the degree of vasoconstrictor effectiveness of intrinsic vascular catecholamines “is determined by the intra-extracellular electrolyte concentration difference, which, in turn, is influenced by the adrenal mineralocorticoids by virtue of their specific ability to deposit sodium intracellularly. ”129 A considerable amount of evidence has accumulated in support of this concept. Pending availability of methods for direct measurement of vascular transmembrane cationic gradients in vivo, it constitutes a plausible explanation of the primarily neurohormonal hypertension in cases of pheochromocytoma and of the primarily hormonal hypertension of hyperadrenocorticism and toxemia of pregnancy. It is consistent with the lowering of the blood pressure after procedures which reduce catecholamines and/or corticoids. The question of how dietary sodium restriction and natriuresis affect the transmembrane cationic gradient is still in need of exploration. Conditions in essential hypertension are complex due to the presumably frequent presence of nephrogenic pressor agents. However, here too, neural (catecholamine) and hormonal (corticoid) pathogenic elements are often discernible. Their abolition is believed to account for the therapeutic results of specific antiadrenergic treatments (sympathectomy, ganglionic blockade, reserpine), as well as of adrenalectomy, dietary sodium restriction, drug-induced natriuresis (chlorothiazide) and combinations of these. Although prevailingly renal hypertension proves most refractory to such measures, it nevertheless permits clinical amelioration in a minority of cases in which neurohormonalhormonal factors seem to coexist with renal mechanisms.