Gerald Glick

Relative Roles of the Sympathetic and Parasympathetic Nervous Systems in the Reflex Control of Heart Rate

This study was designed to define the relative roles of the sympathetic and parasympathetic nervous systems in the reflex alterations of heart rate consequent to changes in arterial pressure. In 23 experiments carried out on 22 anesthetized dogs and in studies performed on four trained, unanesthetized dogs, acute changes in arterial pressure were produced by administering drugs acting on the peripheral vascular bed. The effects of acutely elevating systemic pressure were also investigated in four intact unanesthetized human subjects. Augmenting arterial pressure above control levels with graded doses of phenylephrine always slowed heart rate strikingly. Although complete sympathetic blockade with guanethidine or pronethalol did not significantly alter the degree of slowing, parasympathetic blockade with atropine or vagotomy essentially abolished this response. Conversely, lowering pressure with intravenous injections of nitroglycerin always raised heart rate in the control state, a response abolished by sympathetic blockade with guanethidine or nethalide, but not by parasympathetic blockade with vagotomy or atropine. Thus, when arterial pressure rises above control, the decrease in heart rate is mediated by the parasympathetic nervous system, withdrawal of sympathetic activity playing no detectable role; when pressure falls below control levels, the elevation of heart rate is mediated primarily by the sympathetic nervous system. These findings are not consonant with the traditional concept of control of heart rate which predicates simultaneous reciprocal changes in activity occurring in the two components of the autonomic nervous system.

Glucagon. Its enhancement of cardiac performance in the cat and dog and persistence of its inotropic action despite beta-receptor blockade with propranolol.

The action of glucagon on cardiac performance was studied in 21 isolated cat papillary muscle preparations, in 13 spontaneously beating cat atria, in 15 intact dog hearts, and in 4 isolated perfused dog hindlimbs. In each papillary muscle preparation, addition of glucagon produced marked increases in maximal developed tension, averaging 36±4.2% (SEM) (P < 0.01), and shifted the force-velocity curve upwards and to the right, indicating that contractility was augmented. Glucagon always increased the rate of the spontaneously beating atrium, the rise averaging 28.8±5.5 contractions/min (P < 0.01). In the dog, myocardial performance was markedly augmented by the administration of glucagon, 50 μg/kg iv, as indicated by an average increase of 72.2±18.4% (P < 0.01) in the left ventricular peak dP/dt and of 58.9±12.8% (P < 0.01) in force recorded by a strain gauge arch, despite an average decrease of 3.8±1.2 cm H2O (P < 0.02) in left ventricular end-diastolic pressure. Heart rate rose an average of 38.7±10.9 beats/min (P < 0.02). Small but significant decreases in peripheral vascular resistance were produced. Single intravenous injections produced effects lasting 15 to 20 minutes. Propranolol did not prevent the inotropic responses in either the cat or dog preparations but markedly decreased the chronotropic effects.

EFFECTS OF BETA ADRENERGIC BLOCKADE ON THE CIRCULATION WITH PARTICULAR REFERENCE TO OBSERVATIONS IN PATIENTS WITH HYPERTROPHIC SUBAORTIC STENOSIS.

The circulatory effects of blocking the beta adrenergic receptors with Nethalide were studied in 10 patients with hypertrophic subaortic stenosis and in five postoperative subjects undergoing right heart catheterization. In the resting state, the heart rate and the rate of pressure development in the right ventricle diminished slightly, but cardiac index was not altered by the administration of Nethalide. These observations suggest that tonic sympathetic activity is not of major importance in basal subjects in the supine position. Nethalide attenuated the increase in heart rate and right ventricular dp/dt associated with exercise, and abolished the response of these two variables to the administration of isoproterenol. In the patients with hypertrophic subaortic stenosis Nethalide had little effect on the severity of the obstruction at rest, but reduced the intensification of the obstruction produced by exercise or isoproterenol. The possible clinical benefits of blocking the beta adrenergic receptors in these patients were discussed.

Cardiovascular effects of glucagon in man.

Abstract Because glucagon in animals has positive inotropic and chronotropic effects in the presence of beta-adrenergic blockade, catecholamine depletion or full digitalization, its cardiovascular effects in man were studied during diagnostic cardiac catheterization. In 11 patients 3 to 5 mg intravenously significantly increased cardiac index, mean arterial pressure, heart rate and maximum rate of left ventricular pressure development, but left ventricular end-diastolic pressure and systemic vascular resistance did not change significantly. Action after a single dose began in one to three, reached a maximum in five to seven and lasted for 10 to 15 minutes. In six patients given only 1 mg the only significant changes were increased cardiac index and decreased systemic vascular resistance. Glucagon benefits cardiac performance in man, and with its demonstrated action in the absence of catecholamines and in the presence of full digitalization, may be useful to treat acute heart failure.

Studies on Cardiac Dimensions in Intact, Unanesthetized Man

A method is described which permits measurement of relative changes in the external dimensions of individual cardiac chambers throughout the cardiac cycle in intact, unanesthetized man. It consists of suturing multiple radiopaque silver-tantalum clips to the surface of the heart at the time of cardiac operations. In the postoperative period, cine-radiograms are obtained and the distances between clips are measured on each individual frame. This technique has been found to be safe and has been employed in 68 patients without any complications. As a result of studies in eight patients utilizing biplane serial exposures, the effects of rotation of the heart in the sagittal plane during the cardiac and respiratory cycles were determined precisely. If clips were properly placed on the heart, the possible errors resulting from such rotation were found to be quite small. During inspiration right ventricular dimensions increased, while the opposite occurred during expiration and during the Valsalva maneuver. Left ventricular dimensions exhibited little change during normal respiration. During deep, slow inspiration, the changes in dimensions of the left ventricle lagged behind those of the right ventricle by one to five (generally two or three) cardiac cycles; the magnitude of the changes in the dimensions of the left ventricle was smaller than that which occurred in the right ventricle. The effects on ventricular dimensions of light muscular exercise performed in the supine position were studied in nine patients. The end-diastolic dimensions decreased by an average of 6.0% of control in the right ventricle, and by an average of 5.1% in the left ventricle. End-systolic dimensions decreased by an average of 5.6% of control in the right ventricle and by an average of 6.5% in the left ventricle. These decreases are considered to approximate one-half of the resting stroke volume. In the four patients in whom the rate of right ventricular pressure rise was determined continuously, exercise resulted in an elevation of dp/dt while ventricular end-diastolic dimensions decreased. These data are interpreted to indicate that an increase in myocardial contractility occurs during muscular exercise in man.

Diagnosis of cardiac tamponade by echocardiography: changes in mitral valve motion and ventricular dimensions, with special reference to paradoxical pulse.

The echocardiographic findings in three patients who presented with pericardial effusion and cardiac tamponade are described. Cyclic respiratory changes affected the diastolic movement of the anterior mitral leaflet, viz., during inspiration its anterior excursion decreased in amplitude and the E-F slope diminished. This inspiratory alteration in mitral valve motion was accompanied by an increase in right ventricular dimensions and a reciprocal decrease in left ventricular dimensions. Pericardial paracentesis confirmed the presence of effusion and relieved cardiac tamponade in all the patients. Repeat echocardiography, performed in two of the patients immediately after the pericardial tap, showed that the E-F slope had become steeper and that phasic respiratory variations in the diastolic motion of the anterior mitral leaflet were no longer present. The compatibility of our observations with the theories which endeavor to explain the mechanism of the paradoxical pulse in pericardial effusion with cardiac tamponade is discussed. We suggest that the abnormalities in anterior mitral leaflet motion defined by echocardiography constitute a useful addition to the study of patients with suspected cardiac tamponade resulting from pericardial effusion.

Studies on Cardiac Dimensions in Intact Unanesthetized Man V. Effects of Nitroglycerin

The objective of this study was to determine the effects of nitroglycerin on ventricular dimensions. At the time of corrective cardiac operations, silver-tantalum markers were sutured to one or both ventricles of 11 patients without clinical evidence of coronary artery disease. Following recovery, cineradiograms were exposed at 30 frames per second and distances between markers were measured before and after 0.6 mg. of nitroglycerin. In all patients, end-diastolic and end-systolic dimensions decreased within 2 to 6 minutes. Right ventricular end-diastolic and end-systolic lengths decreased by an average of 5.0 per cent and 3.6 per cent of control values, respectively, while left ventricular end-diastolic and end-systolic dimensions declined by an average of 6.2 per cent and 5.9 per cent of control, respectively. The diminutions of end-diastolic ventricular dimensions approximated 30 per cent of the stroke volume. Systolic excursions decreased by an average of 13.3 per cent of control for the right ventricle, while left ventricular excursions decreased in four of the six patients. Systolic, mean, and diastolic arterial pressures decreased in each patient after nitroglycerin. Cardiac output fell from an average of 5.6 to 5.0 L./min., decreasing in each of the six patients in whom it was determined, while stroke volume fell from an average value of 65 ml./beat during the control period to 55 ml./beat after nitroglycerin.Thus, nitroglycerin reduces both arterial pressure and ventricular dimensions and in view of the relationship between ventricular size, myocardial tension, and oxygen consumption, this action tends to reduce cardiac oxygen requirements and may explain, at least in part, the effectiveness of the drug in angina pectoris.

Circulatory Effects of Electrical Stimulation of the Carotid Sinus Nerves in Man

The effects of carotid sinus nerve (CSN) stimulation were studied at rest and during a mild level of supine bicycle exercise in seven patients in whom CSN stimulators had been implanted for the treatment of angina pectoris. At rest, CSN stimulation produced a fall in mean arterial pressure (MAP) averaging 23% and an 8% decrease in cardiac output (CO). Total peripheral resistance (TPR) fell by 14% and forearm vascular resistance (FVR) by 16%. During exercise, MAP fell 16%, but no significant change occurred in CO. Thus, the fall in MAP could be attributed to a reflexly induced decrease in peripheral vascular resistance. Only small decreases occurred in heart rate. No changes in venous tone, central venous pressure, or the maximum transverse end-diastolic diameter of the heart were produced by stimulation either at rest or during exercise. Thus, at rest, CSN stimulation reduces MAP by reflexly decreasing both vascular resistance and CO; during exercise, the diminution in CO no longer occurs. Finally, the venous system does not appear to participate in reflexes activated by CSN stimulation.

Reflex Cardiovascular Depression Produced By Stimulation Of Pulmonary Stretch Receptors In The Dog

To study the possible reflex effects of stimulation of pulmonary stretch receptors on the cardiovascular system, experiments were designed that would allow separate assessment of the responses of the heart, the total peripheral vascular resistance, and the resistance of the innervated hindlimb that was perfused at a constant flow rate. In every experiment, inflation of the lungs to a positive pressure of 20 mm Hg produced significant negative inotropic and chronotropic effects. Heart rate fell an average of 22.3+/-3.8% (SEM) (P < 0.01), pressure recorded from within an isovolumic balloon in animals on total cardiopulmonary bypass fell an average of 14.3+/-4.6% (P < 0.05), dp/dt recorded from within the balloon declined an average of 31.4 +/- 6.0% (P < 0.01), and contractile force measured with a Walton-Brodie strain gauge arch fell an average of 18.6 +/-2.2% (P < 0.01). Similarly, a depressor response to inflation of the lungs was noted in the periphery as manifested by an average decrease in total peripheral vascular resistance of 21.9+/-2.5% in the animals on total cardiopulmonary bypass (P < 0.01), and by an average decrease in perfusion pressure in the isolated hindlimb of 26.0 +/-3.8% (P < 0.01). After bilateral cervical vagotomy, the cardiovascular responses to inflation of the lungs were either abolished or markedly lessened. Thus, sudden expansion of the lungs activates the afferent arm of a depressor reflex, which produces negative inotropic and chronotropic responses, in addition to arterial vasodilation. The receptors are sensitive to stretch and the afferent pathway runs predominantly in the vagus nerves.

Depression of cardiac function by streptomycin and other antimicrobial agents

Abstract Signs of toxicity of the eighth cranial nerve in a patient receiving streptomycin who also had persistent hypotension after cardiac surgery led to investigation of the effects of streptomycin and other antibiotic agents on cardiac function. In 18 open chest dogs, there was a dose-dependent depression of cardiovascular function as a result of the intravenous administration of streptomycin in doses of 2.5, 10 and 40 mg/kg. Similar depressions were demonstrated after administration of tetracycline, kanamycin, vancomycin, erythromycin and colymycin. In 4 intact dogs given streptomycin, 2 g intramuscularly, cardiac output decreased 26 percent and mean arterial pressure decreased 22 percent 1 hour after administration. The average level of streptomycin in the blood at 1 hour was 35 μg/ml, within the usual therapeutic range for patients. In the isolated perfused cat heart, streptomycin, tetracycline, kanamycin, vancomycin and chloramphenicol caused a profound decrease in contractile force. These data should not be extrapolated directly to clinical situations since most of the experiments did not parallel precisely the usual form of antibiotic administration. In the presence of infection, antibiotic drugs are among the most effective agents available. However, the physician must be aware of the potential for cardiac depression, especially in patients with an already compromised cardiac status or with impaired renal function.