Francis J. Klocke

Reduced regional myocardial perfusion in the presence of pharmacologic vasodilator reserve.

To determine whether reductions in regional myocardial perfusion at reduced coronary arterial pressures reliably indicate maximal vasodilation of the distal vasculature, coronary autoregulation was studied in open-chest dogs at heart rates of approximately 60 beats/min, a level at which metabolic demand, time-averaged systolic compressive forces, and transmural vasodilator reserve approximate those found under usual resting conditions. Circumflex pressure was controlled with a programmable pressure source. Regional circumflex inflow was 0.56 +/- 0.04(SEM) ml . min-1 . g-1 when circumflex pressure equaled spontaneous aortic pressure and fell to 0.34 +/- 0.02 ml . min-1 . g-1 when circumflex pressure was reduced to 35 mm Hg. Reductions were similar in each myocardial layer, with endocardial flow falling from 0.68 +/- 0.04 to 0.39 +/- 0.03 ml . min-1 . g-1. During adenosine-induced vasodilation at 35 mm Hg, full-thickness and endocardial flows rose to 0.92 +/- 0.08 and 1.07 +/- 0.10 ml . min-1 . g-1, respectively. When coronary pressure was reduced to 25 mm Hg and autoregulation was again operative, full-thickness and endocardial flows fell to 0.28 +/- 0.03 and 0.28 +/- 0.04 ml . min-1 . g-1. During adenosine vasodilation at 25 mm Hg endocardial flow did not increase significantly but epicardial reserve remained present. These results indicate that significant reductions in regional myocardial perfusion can occur before pharmacologic vasodilator reserve is exhausted. In the absence of tachycardia, endocardial vasodilator reserve can persist to coronary pressures less than 35 mm Hg, but is ordinarily exhausted before epicardial vasodilator reserve.

Coronary pressure-flow relationships. Controversial issues and probable implications.

On the basis of the material discussed, our current assessments of the controversial points mentioned at the beginning of this article may be summarized as follows: Pf = 0, the minimum back pressure to coronary flow associated with a measurable conductance, is indeed greater than coronary outflow pressure (and usually left ventricular diastolic pressure, as well). Pf = 0 needs to be taken into account in attempts to determine coronary driving pressure. In maximally vasodilated beds, Pf = 0 derived from diastolic pressure-flow relationships exceeds coronary outflow pressure by at least a few mm Hg. Pf = 0 varies with coronary outflow and/or diastolic ventricular cavity pressure. When left ventricular preload is elevated, Pf = 0 exceeds outflow pressure by increasing amounts. Pf = 0 appears to be systematically higher and pressure-dependent in beds in which vasomotor tone is operative. An improved understanding of the nature of, and basis for, time-dependent changes in resistance and/or Pf = 0 during long diastoles in nonvasodilated beds is needed. The contour of pressure-flow relationships which are free of reactive effects is curvilinear rather than linear. The degree of curvilinearity is substantial and can change with interventions. Curvilinearity is accentuated at lower pressures and may reflect changes in the number of perfused vascular channels as well as the caliber of individual channels. Capacitive effects need to be dealt with quantitatively in studies of pressure-flow relationships. Values of the capacitance which is involved in these effects vary with both pressure and tone. Capacitive flow also depends upon the instantaneous rate of change of pressure, which has not usually been defined in published studies. Although intramyocardial capacitance is large and plays an important role in systolic-diastolic flow interactions, a controlling role in diastolic coronary arterial pressure-flow relationships has not been established experimentally. In vasodilated beds, in-flow remains remarkably constant for several seconds after the brief transient associated with a step-change in the level of constant pressure perfusion during a long diastole. Calculations of coronary vascular resistance (by whatever method) remain of limited value, particularly when changes in response to an intervention are modest. Because of the curvilinear diastolic pressure-flow relationship, resistance is pressure-dependent and, at any given pressure, is probably best defined by establishing the slope of a diastolic pressure-flow curve which is free of reactive effects.(ABSTRACT TRUNCATED AT 400 WORDS)

An Intrinsic Adrenergic Vasodilator Mechanism in the Coronary Vascular Bed of the Dog

The question of whether the coronary blood vessels contain an intrinsic adrenergic mechanism for vasodilatation has been examined by studying the response of the coronary vessels of the dog to isoproterenol. Initially, coronary blood flow, coronary sinus PO2, mean arterial pressure, and heart rate were measured continuously in anesthetized, open-chest animals. When isoproterenol, 0.1 to 0.3 μg/kg/min, was given intravenously, coronary flow and coronary sinus PO2 always increased in spite of tachycardia and a reduced or unchanged arterial pressure. Although this response suggested a primary vasodilating effect of isoproterenol, a vasodilatation consequent to increased myocardial activity or an extracardiac factor could not be eliminated. Accordingly, additional studies were performed in an isolated heart arrested with potassium and perfused with whole blood at constant rates of flow. Isoproterenol was given by single injections and constant infusions and always produced a decrease of perfusion pressure. These decreases could be blocked by nethalide and, as indicated by measurements of myocardial oxygen uptake and coronary venous PO2, did not depend upon increased myocardial metabolism or decreased myocardial oxygenation. With injections of 0.01, 0.1, 1.0, and 10.0 μg of isoproterenol, the decreases averaged respectively 3, 8, 14, and 26% of the control pressures. It is concluded that the coronary vessels of the dog do contain an intrinsic adrenergic mechanism for vasodilatation.

Oxygen cost of electrical activation of the heart

The present study was undertaken to define the O2 requirements of electrical activation of the heart. Thirteen isolated canine hearts were perfused with whole blood from which calcium had been removed with an exchange resin and to which the disodium salt of ethylenediaminetetraacetic acid had been added. Spontaneous depolarizations were suppressed by raising the plasma potassium to an average concentration of 7.5 mEq/liter, and the right ventricle was stimulated electrically at controlled frequencies. Although the stimuli produced propagated depolarizations, neither high-sensitivity strain gauge arches sutured to both ventricles, nor careful visual observation, showed any evidence of associated contractile activity. Ten of the hearts were studied with repetitive single stimuli applied in the conventional fashion, while the remaining three hearts were subjected to paired electrical stimulation. Changes of myocardial O2 consumption (MV˙O2) were measured at a constant coronary blood flow and arterial O2 content by determining changes of venous O2 content from a continuous recording of venous PO2. Increases of the frequency of depolarization were uniformly accompanied by small increases of MV˙O2, averaging 0.40 ± 0.04 (SEM) μliter/activation/100 g. The increases were of the same order of magnitude in the hearts subjected to paired electrical stimulation as in the hearts studied with single stimulation, suggesting that the altered frequency and rhythm of depolarization in paired electrical stimulation cannot account for the marked increase of MV˙O2 which this intervention produces in the intact heart. It is concluded that the amount of O2 required for electrical activation of the heart is less than 1% of the total O2 consumption of the normally working heart.

Observations on the Role of Diminished Oxygen Tension in the Functional Hyperemia of Skeletal Muscle

The hypothesis that lowered tissue oxygen tension acting on vascular smooth muscle can explain functional hyperemia in skeletal muscle was examined in ten dogs. A comparison was made between the blood flow increment that accompanied rapid, rhythmic contraction of a gastrocnemius muscle and the flow change that occurred in the same muscle at rest during its perfusion with venous blood obtained from the resting or contracting gastrocnemius muscle of the opposite leg. Blood PO2, pH, and PCO2 were measured in samples of venous blood from the muscle. There was no evidence that the perfusion circuit traumatized the perfused blood. During functional hyperemia, the increases in blood flow averaged 173%, and the average venous PO2, was 25 mm Hg. During venous perfusion, the maximum increases in blood flow averaged 56%, and the average venous PO2, was 23 mm Hg. When the muscle was stimulated to contract during its perfusion with venous blood, increases in blood flow occurred which averaged 143%, despite additional falls in venous blood PO2 that averaged only 3 mm Hg. These studies suggest that the effect of lowered PO2 on vascular smooth muscle does not produce sufficient vasodilatation to explain functional hyperemia in skeletal muscle.

Impedance to coronary flow

Impedance to flow in the coronary circulation is time-varying, precluding the use of Fourier transforms of pressure and flow waveforms to determine impedance. perturbation techniques have been used to determine impedance in long diastoles. Using a hydraulic servovalve, sinusoidal and ramp pressure waveforms were applied to the left circumflex coronary artery of anesthetised, open chest dogs. The resulting flow perturbations were analyzed to determine impedance. A lumped parameter viscoelastic model with pressure dependent parameters was adequate to describe the impedance. At frequencies up to 5 Hz, viscoelastic effects were negligible and a simple resistive-capacitive model was adequate. For slow ramps, this model was used to construct capacitance-free pressure-flow curves which were in good agreement wth those obtained from constant-pressure diastoles. The capacitance affecting coronary inflow appears to be a small fraction of total coronary capacitance.

Modulation of coronary autoregulatory responses

A number of studies of the coronary circulation in anesthetized animals have established the general features of the autoregulatory relationship between mean coronary pressure and flow and have documented vulnerability of the subendocardium to ischemia as coronary pressure is reduced. Although reductions in subendocardial flow and inner-outer flow ratio have been interpreted to indicate maximal vasodilation of the subendocardial vascular bed, recent studies have confirmed that reductions in resting subendocardial perfusion can occur in the face of vasodilator reserve recruitable by infusion of pharmacologic agents. These findings suggest that factors other than local metabolic mechanisms importantly modulate or potentially limit coronary autoregulatory responses. Interactions among regional myocardial performance, metabolic demand and flow remain incompletely characterized. In addition, although various extrinsic factors influencing coronary flow have been studied at normal coronary artery pressures, their potential influence on coronary autoregulation and subendocardial flow at reduced coronary pressures has been difficult to define. This article reviews limitations of intrinsic coronary autoregulatory responses, modulation of these responses by extrinsic factors, and possible chronic adaptations to reduced coronary artery pressure.