Joseph P. Gilmore

Homeometric Autoregulation in the Heart

The effect of increasing the activity of the ventricle on its contractility was investigated. Several beats after the ventricle increases the amount of tension it develops per unit of time, it exhibits an increased contractility as shown by the increase in work and the more rapid development of pressure from a given end-diastolic pressure or fiber length. This has been termed homeometric autoregulation in contradistinction to the Frank-Starling or heterometric type of autoregulation. It was found that changes in coronary flow are not essential to the exhibition of this phenomenon. Possible mechanisms and the physiologic significance of the findings are discussed.

The transport function of the atrium: Factors influencing the relation between mean left atrial pressure and left ventricular end diastolic pressure∗

Abstract Mean left atrial pressure is higher for any given left ventricular end diastolic pressure, as the heart rate is progressively increased, for two reasons. First, by encroaching on ventricular diastole, the relative period during which inflow into the atrium continues while the egress of blood from the atrium is blocked is increased. Second, with more severe tachycardia, atrial systole can be seen to occur either partially or completely while the mitral valve is still closed from the previous ventricular systole. At a constant heart rate, mean left atrial pressure is higher for any given left ventricular end diastolic pressure during efferent vagal nerve stimulation than during control conditions. This is due to a negative inotropic effect on the atrium and not to a change in the performance characteristics of the ventricle. At a constant heart rate, mean left atrial pressure is lower for any given left ventricular end diastolic pressure during cardiac sympathetic nerve stimulation than during control conditions. This is due to a positive inotropic effect on both the atrium and the ventricle. The relation between left ventricular end diastolic pressure and stroke work is determined only by the performance characteristics of the ventricle; the relation between mean left atrial pressure and stroke work is determined by the performance characteristics not only of the ventricle but also to a substantial extent by those of the atrium. Atrial contractility and the changes therein induced by central nervous system activity are of importance to circulatory regulation both because of the influence of atrial systole on ventricular end diastolic pressure and because of the effect of such changes on central venous pressure at any given level of ventricular stroke work. The possibility is suggested that depressed atrial function, i.e., atrial failure, may be a significant contributory factor in the elevated venous pressure observed in congestive heart failure.

Regulation of Ventricular Contraction: Influence of Cardiac Sympathetic and Vagal Nerve Stimulation on Atrial and Ventricular Dynamics

At constant heart rates, efferent stimulation of the vagus nerve and of the left stellate ganglion revealed the following: 1. Vagal stimulation exerts a profound depressant effect on the strength of the atrial contraction and can thereby influence ventricular filling and ventricular stroke work; it elevates mean atrial pressure at any given level of ventricular stroke work. This occurs under experimental conditions wherein the vagal stimulation used does not produce an alteration in the performance characteristics of the ventricle. The effects of vagal stimulation are blocked by atropine. 2. Stellate ganglion stimulation or norepinephrine infusion augments the strength of atrial contraction and thus the atrial contribution to ventricular filling. The augmented atrial contraction takes place in a shorter period of time. 3. Stellate ganglion stimulation or norepinephrine infusion increases the external stroke work and power produced by the ventricle from any given mean atrial pressure and from any given end-diastolic pressure or fiber length.4. There is a family of curves representing the relation between end-diastolic fiber length and stroke work, as well as a family of curves representing the relation between mean atrial or end-diastolic pressure and stroke work.5. When taken together with the well-known sympathetic and parasympathetic effects on heart rate, the above data are believed to comprise a reasonably comprehensive description of the means available to the central nervous system for directly inducing acute changes in the activity of the heart.

Regulation of Ventricular Contraction by the Carotid Sinus Its Effect on Atrial and Ventricular Dynamics

A lowering of pressure in the carotid sinus reflexly increases the force of atrial systole by (a) increasing sympathetic activity to the heart (carotido-sympatho-atrial reflex) and(b) decreasing efferent vagal activity to the heart (carotido-vago-atrial reflex); an elevation of carotid pressure has the reverse effect. The carotid sinus can thereby vary ventricular end-diastolic pressure and fiber length. A change of pressure in the carotid sinus reflexly modifies the ventricles contractility such that from a given end-diastolic pressure or fiber length, with a low carotid pressure the ventricles contraction will be substantially augmented and from a high carotid pressure it will be diminished. The role of the carotid sinus in circulatory regulation has been likened to a voltage regulating element in an electronic system; i.e., it causes an appropriate variation of input into the system so as to maintain a constant voltage when the current requirements of the system it is supplying are changed.

Myocardial Extraction and Production of Catechol Amines

Stimulation of the cardiac sympathetic efferent nerves is accompanied by a release of catechol amines in coronary blood. This release is a function of stimulation intensity and occurs even when stroke volume and coronary outflow are maintained constant. Comparison between the ethylenediamine and the trihydroxyindole methods for the analysis of plasma catechol amines shows both quantitative and qualitative differences, with only the results with the latter method showing a consistent relationship to the hemodynamic changes observed during cardiac sympathetic stimulation. The acutely synipatheetomized heart extracts catechol amines from coronary blood in the absence of nervous stimulation. The patterns of extraction observed indicate that the quantity of catechol amines in the myocardium can modify the extent of extraction in the unstimulated state as well as the extent of release during stimulation. Continued stimulation of the cardiac sympathetics is accompanied by at least a partial depletion of the myoeardial catechol amine stores. These stores appear to be repleted by circulating catechol amines, since the response to any given intensity of stimulation can be potentiated by a prior norepinephrine infusion. Dichloroisoproterenol prevents neither the myocardial extraction of catechol amines in the unstimulated state nor the release of catechol amines during sympathetic stimulation; it does lessen or abolish the cardiody-namic effects of sympathetic stimulation. Data are presented which indicate that a direct coronary vasoconstriction is one of the consequences of cardiac sympathetic nerve stimulation, the vasodilatation usually observed being due, at least in part, to overriding metabolic factors.

Effect of acetyl strophanthidin therapy on cardiac dynamics, oxygen consumption and efficiency in the isolated heart with and without hypoxia

Abstract Experiments in the isolated, supported heart preparation were performed in which the influence of graded doses of acetyl strophanthidin on myocardial oxygen consumption and efficiency was determined. Aortic pressure, heart rate and stroke volume, hemodynamic variables which can influence oxygen consumption and efficiency independently of drug action, were held constant or almost so. Under such circumstances, treatment with acetyl strophanthidin produced a marked increase in myocardial contractility without a change of either oxygen consumption or efficiency. When acute left ventricular failure was induced by a maintained restriction of coronary blood flow, acetyl strophanthidin therapy also produced a marked contractility increase, again with no change in oxygen consumption or efficiency. The evidence supporting the position that the digitalis glycosides have a different pharmacologic effect on the normal and failing heart is discussed.

Contribution of Baroreceptors to the Control of Renal Function

Electrical stimulation of the left stellate ganglion of the dog is associated with an increase in urine flow, in electrolyte and total solute excretion, and in the renal clearance of inulin. These changes appear rapidly, are well maintained during prolonged stimulation, and stop soon after stimulation has ceased. The hemodynamic responses associated with these changes are an increase in arterial pulse pressure, an increase or no change in mean arterial blood pressure, and a decline in mean left atrial pressure. The diuretic response to stellate ganglion stimulation is diminished, but not abolished, by bilateral cervical vagotomy as are the changes in electrolyte excretion, total solute excretion, and the renal clearance of inulin. However, the hemodynamic responses are not greatly modified by cervical vagotomy. Vagotomy just above the diaphragm does not appear to modify these responses. The effect of vagotomy on the renal responses to stellate stimulation appears to be a result of sectioning baroreceptor afferent nerves which traverse the vagus nerves. The rapidity of the renal response to stellate stimulation, its temporal relation to the hemodynamic changes, and the effect of cervical vagotomy indicate that the diuresis is, to a large degree, secondary to withdrawal of renal sympathetic vasoconstrictor nerve discharge. The similarities between the renal responses to stellate stimulation and to intravenous infusions indicate that infusion diuresis may be mediated, at least in part, by the same mechanism. When renal blood flow is measured directly in the perfused kidney, carotid occlusion is associated with little change or with a decrease in renal blood flow at a time when renal arterial pressure increases. When renal blood flow is maintained constant in the perfused kidney, carotid artery occlusion is associated with an increase in renal arterial pressure. The intrarenal administration of the adrenergic blocking agent, phenoxybenzamine, can prevent the increase in renal vascular resistance during carotid occlusion indicating that it is due to an adrenergic mechanism. The renal pressure-flow curve is displaced down and to the right during carotid occlusion; autoregulation of renal blood flow is still observed, although at a lower level of blood flow. All these changes indicate that the primary renal response to carotid occlusion is vasoconstriction mediated by the renal sympathetic nerves. It is well-known that urine flow increases when renal arterial pressure is increased independent of a change in the activity of the renal vasoconstrictor nerves and independent of a change in renal blood flow. Consequently, the rise in arterial pressure associated with carotid occlusion can contribute directly to the response of the kidney to carotid occlusion. The variability of the changes in water and electrolyte excretion by the kidney during carotid occlusion may represent a varying contribution of direct and reflex mechanisms to the total response.

Potassium changes in the heart during homeometric autoregulation and acetyl strophanthidin

Abstract The ability of the heart to alter its basic contractility consequent upon an increase in its dynamic and metabolic activity should be considered a hemodynamic phenomenon of prime importance in understanding the hearts intrinsic adaptation to change. The experiments recorded herein demonstrate that, accompanying such contractility changes, an ionic alteration occurs and that a net potassium ion loss is at least a biochemical symptom of the altered state of the myocardium when either heart rate or systolic intraventricular pressure is increased independently. The fact that the amount of this potassium ion loss approximates that which is seen with a dose of digitalis which increases contractility suggests that the observed loss of potassium ion during homeometric autoregulation may turn out to be related importantly to the observed hemodynamic phenomena.

Influence of norepinephrine on myocardial oxygen consumption under controlled hemodynamic conditions

Abstract Studies were performed to ascertain the effect of norepinephrine on the contractility and myocardial oxygen consumption of the isolated, supported heart preparation with aortic pressure, heart rate and stroke volume held constant. Graded infusions of norepinephrine were given into the left main coronary artery and the fall of left ventricular end-diastolic pressure used as a measure of the increase in contractility obtained. Low doses of norepinephrine caused pronounced falls of left ventricular end-diastolic pressure with no change, a slight rise or a slight fall in myocardial oxygen consumption. Thereafter, increases in the infusion rate of norepinephrine had relatively little influence on left ventricular end-diastolic pressure but produced a marked increase in myocardial oxygen consumption. These data suggest that the concept of the so-called oxygen-wasting effect of norepinephrine may be attributable to either (1) the use of a dose which exceeds that required for a near maximal inotropic effect or (2) at low doses, an inadequate consideration of the influence of induced hemodynamic alterations (rise of heart rate and aortic pressure) on myocardial oxygen consumption.

Mechanism of the myocardial effects of bretylium.

The increased myocardial contractility resulting from the injection of bretylium has been shown to be accompanied by a myocardial release of catecholamines. Cardiac sympathetic nerve stimulation following bretylium is associated with neither an increased contractility nor a release of myocardial catecholamines. The failure to release catecholamines under these conditions does not result from depletion, but rather from a block of the nerve release mechanism.