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Biomedical subjects

E O Feigl

Publications and source records attributed to E O Feigl.

At least 19 recordsLinked to original sources
PubMed1995

A model of combined feedforward and feedback control of coronary blood flow.

Recent evidence shows that norepinephrine affects coronary blood flow not only by alpha-receptor-mediated vasoconstriction and by feedback metabolic vasodilation that occurs as a result of myocardial beta-receptor activation, but also by the direct activation of coronary vascular beta-receptors that increase flow in a feedforward manner. The implications of combined feedforward and feedback control in maintaining the balance between metabolism and flow were investigated in the present mass balance model. Feedback was represented by a closed loop and was based on the hypothesis that the regulated variables are myocardial PO2 and PCO2 and that divergence of these variables from their operating point values functions as the metabolic error signals that manipulate coronary vascular smooth muscle and flow to match metabolism. alpha-Receptor-mediated vasoconstriction and beta-receptor-mediated vasodilation are represented by feedforward open loops that are activated simultaneously with increases in metabolism. The postulated control schemes of 1) metabolic feedback control alone, 2) feedback plus alpha- and beta-adrenergic feedforward control, and 3) feedback plus beta-adrenergic feedforward control were able to simulate the steady-state increase in coronary flow and the decrease in coronary venous PO2 that occurs during comparable experimental conditions. The simulations demonstrate that 1) the speed and accuracy of the flow response improve as beta-adrenergic feedforward control is added and alpha-adrenergic feedforward control is removed from the control scheme, 2) high feedback gain also improves the accuracy of the flow response, but the penalty is instability, and 3) a lag in alpha-adrenergic feedforward control improves the stability of the coronary response.

Animals↗
PubMed1995

EDRF and norepinephrine-induced vasodilation in the canine coronary circulation.

Experiments were performed to characterize the role of endothelium-derived relaxing factor (EDRF) in coronary vasodilation caused by norepinephrine. The circumflex or left anterior descending coronary artery was cannulated and pump perfused with constant pressure or constant flow in closed-chest anesthetized dogs. Prostaglandin synthesis was blocked with ibuprofen. During constant-pressure perfusion, EDRF inhibition with intracoronary N omega-nitro-L-arginine (L-NNA) did not affect the vasodilation due to nitroglycerin (an endothelium-independent process). However, L-NNA did significantly inhibit (P < 0.001) the vasodilation due to acetylcholine (an endothelium-dependent process). In response to bolus injections of norepinephrine, EDRF inhibition with L-NNA significantly reduced coronary vasodilation (P < 0.001). This inhibition was partially reversed with L-arginine infusion. To determine whether an increase in shear stress due to an increase in flow was the stimulus for EDRF release, experiments were performed during constant-flow conditions. Vasodilation caused by nitroglycerin was not inhibited by L-NNA, but EDRF inhibition did blunt acetylcholine-induced vasodilation significantly (P < 0.001) during constant-flow perfusion. During EDRF inhibition with L-NNA, vasodilation due to norepinephrine was not significantly altered when coronary flow was held constant (P = 0.19). In conclusion, EDRF plays a role in norepinephrine-induced coronary vasodilation that is largely flow dependent.

Acetylcholine↗
PubMed1993

Adenosine coronary vasodilation during hypoxia depends on adrenergic receptor activation.

The adenosine hypothesis of coronary control was investigated during steady-state hypoxia by making measurements of coronary venous and epicardial well adenosine concentrations in adrenergically intact dogs and animals with alpha - and beta-receptor blockade. The unexpected result was that a role for adenosine coronary vasodilation during hypoxia could only be found when adrenergic receptors were intact, but not during adrenergic blockade.

Adenosine↗
PubMed1993

Feedforward control of coronary blood flow via coronary beta-receptor stimulation.

It is usually assumed that the increase in coronary blood flow observed with norepinephrine occurs through local metabolic vasodilation secondary to cardiac beta-receptor activation. However, direct feedforward beta-receptor-mediated coronary vasodilation is also a possibility. In dogs with alpha-receptor blockade, the left circumflex artery was perfused at constant pressure. The vasodilator effect of intracoronary norepinephrine injections was determined during prolonged diastoles to avoid the chronotropic and intropic effects of norepinephrine. Norepinephrine caused a dose-dependent increase in coronary blood flow that was attenuated by both the selective beta 1-antagonist practolol and the selective beta 2-antagonist ICI 118,551. These data indicate that norepinephrine activates beta 1- and beta 2-receptors in coronary resistance vessels to cause vasodilation independent of inotropic and chronotropic effects. The physiological significance of coronary beta-receptor-mediated vasodilation was investigated in the beating heart. The coronary blood flow response and coronary venous oxygen tension response were compared when myocardial oxygen consumption was increased over the same range by one of three positive inotropic interventions: (1) norepinephrine, (2) paired-pulse stimulation, or (3) norepinephrine after alpha-blockade. During norepinephrine infusion (intervention 1), coronary venous oxygen tension decreased, indicating that the match between myocardial oxygen consumption and oxygen delivery is not maintained when coronary blood flow is controlled by alpha- and beta-receptors in addition to local metabolic factors. Paired-pulse stimulation (intervention 2) also resulted in a decrease in coronary venous oxygen tension, demonstrating that the balance between oxygen consumption and delivery is not maintained when blood flow is controlled by local metabolic factors alone. However, when coronary beta-receptor-mediated vasodilation was unmasked by alpha-blockade, norepinephrine infusion (intervention 3) produced no change in coronary venous oxygen tension. Therefore, coronary beta-receptor vasodilation helps maintain the balance between flow and metabolism in a feedforward manner in the beating heart.

Animals↗
PubMed1992

Subtraction method for the high-performance liquid chromatographic measurement of plasma adenosine.

The measurement of plasma adenosine with traditional high-performance liquid chromatographic techniques is difficult because of its nanomolar concentration, its short half-life in blood, and because of the difficulty in isolating adenosine from interfering peaks in the chromatogram. To prevent loss of adenosine in the blood sample, a "stop solution" is used to prevent enzymatic degradation and cellular uptake. Peak-shifting techniques on fractionated samples to measure adenosine derivatives have been used in the past to avoid interfering peaks in the chromatogram. A new method has been developed by which nanomolar levels of plasma adenosine can be accurately measured despite co-eluting peaks in the chromatogram. In this method, plasma samples are collected with a stop solution, processed, and divided. Adenosine deaminase is added to part of the sample to form a blank. A computer program subtracts the blank chromatogram from the paired unknown, and the result is compared to adenosine standards prepared from the blank and subtracted in a similar fashion. With this subtraction method, the overall recovery of physiological concentrations of adenosine was 89% from dog blood, and the average coefficient of variation was 12%. In summary, the subtraction method of plasma adenosine measurement offers good recovery, reproducibility, and the ability to quantify low levels of adenosine despite interfering peaks in the chromatogram.

Adenosine↗
PubMed1992

Role of myocardial oxygen and carbon dioxide in coronary autoregulation.

Myocardial oxygen (PO2) and carbon dioxide tensions (PCO2) are likely mediators of the local control of coronary blood flow. A previous study demonstrated that myocardial PO2 and PCO2, estimated by coronary venous values, interact synergistically to determine coronary flow. This synergistic relation was used in a prospective study to test the hypothesis that myocardial PO2 and PCO2 mediate changes in coronary vascular conductance during autoregulation. The left main coronary artery was pump perfused at controlled pressures in closed-chest anesthetized dogs. Autoregulation curves were obtained by increasing coronary perfusion pressure from 80 to 160 mmHg in 20-mm increments. Steady-state measurements of coronary venous PO2 and PCO2 and coronary conductance were obtained at each perfusion pressure. The coronary venous PO2 and PCO2 were used in the previously determined synergistic relation to predict the coronary vascular conductance during autoregulation. The predicted changes in coronary vascular conductance were compared with the actual changes in coronary vascular conductance for the pressure range of 80-160 mmHg. The data indicate that the synergistic interaction of oxygen and carbon dioxide accounts for approximately 23% of the change in coronary vascular conductance during autoregulation. These results suggest that other factors are also involved in autoregulation.

Animals↗
PubMed1992

Role of endothelium-derived relaxing factor in parasympathetic coronary vasodilation.

Vasodilation following the infusion of acetylcholine is due to the release of endothelium-derived relaxing factor (EDRF). However, the role of EDRF in neurogenic coronary vasodilation, when acetylcholine is released outside the vessel at the adventitial-medial junction, has not been established. The action of EDRF in parasympathetic coronary vasodilation was tested in the present study using a specific inhibitor of EDRF synthesis, nitro-L-arginine methyl ester (L-NAME). Experiments were conducted on closed-chest, alpha-chloralose-anesthetized dogs with the heart paced at a constant rate. Phentolamine and propranolol were administered to block alpha- and beta-adrenergic receptors, and ibuprofen was given to inhibit prostaglandin synthesis. Intracoronary infusion of L-NAME decreased the coronary vasodilation in response to intracoronary acetylcholine or vagal stimulation. The coronary response to the endothelium-independent vasodilator nitroglycerin was unaffected by L-NAME. These data demonstrate that L-NAME specifically inhibits coronary vasodilation caused by acetylcholine and vagal stimulation, indicating that parasympathetic coronary vasodilation is dependent on EDRF.

Animals↗
PubMed1992

Adrenergic blockade blunts adenosine concentration and coronary vasodilation during hypoxia.

Myocardial hypoxia is thought to be an important stimulus for increasing interstitial adenosine concentration. The adenosine hypothesis of coronary control was investigated during steady-state hypoxia by making measurements of coronary venous and epicardial well adenosine concentrations in adrenergically intact dogs and in animals with alpha- and beta-receptor blockade. In the adrenergically intact group, hypoxia sufficient to lower coronary venous oxygen tension to 8 mm Hg increased coronary blood flow 243% from normoxic values. Both coronary venous and epicardial well adenosine concentrations were increased throughout the hypoxic period. In the adrenergically blocked group, hypoxia to a similar level of coronary venous oxygen tension produced an increase in coronary blood flow of only 75%, which was significantly less than in the adrenergically intact group (p less than 0.01). Coronary venous adenosine was only transiently elevated, and epicardial well adenosine was unchanged from control levels. In a separate group of alpha- and beta-receptor-blocked animals that received an infusion of L-homocysteine thiolactone during hypoxia, there was no difference in tissue S-adenosylhomocysteine levels compared with those of normoxic controls. It is concluded that much of the coronary vasodilation associated with systemic hypoxia is dependent on adrenergic activation and that adenosine may only play a role in sustained hypoxic vasodilation when adrenergic receptors are intact.

Adenosine↗
PubMed1991

Synergistic action of myocardial oxygen and carbon dioxide in controlling coronary blood flow.

A two-part experiment was designed to test the hypothesis that myocardial oxygen and carbon dioxide tensions, as measured by coronary venous oxygen and carbon dioxide tensions, determine coronary blood flow during increases in myocardial oxygen consumption. The left main coronary artery was pump-perfused at constant pressure in closed-chest, anesthetized dogs. Oxygenators in the perfusion circuit permitted control of coronary arterial gas tensions. The steady-state relation between coronary venous oxygen and carbon dioxide tensions and coronary flow at a constant myocardial oxygen consumption was determined by locally altering coronary arterial oxygen and carbon dioxide tensions. Values of coronary venous oxygen and carbon dioxide tensions and coronary flow were also obtained at normal coronary arterial gas tensions during pacing-induced increases in myocardial oxygen consumption. The data yielded a hyperbolic relation among coronary venous oxygen and carbon dioxide tension and coronary flow during constant myocardial metabolism, suggesting a synergistic interaction between myocardial oxygen and carbon dioxide tensions in determining coronary flow. This relation was then used to predict the coronary flow change during pacing-induced increases in myocardial metabolism. Approximately 40% of the flow response during pacing-induced increases in myocardial oxygen consumption was predicted. In conclusion, coronary venous oxygen and carbon dioxide tensions synergistically interact to produce steady-state changes in coronary flow at a constant myocardial oxygen consumption. Changes in myocardial oxygen and carbon dioxide tensions can account for about 40% of the change in coronary flow during moderate changes in myocardial oxygen consumption.

Animals↗
PubMed1990

Adrenergic control of transmural coronary blood flow.

Tachycardia and an increase in myocardial metabolism result from the sympathetic activation that occurs during baroreceptor reflexes, emotion, and exercise. Paradoxically, a concomitant adrenergic alpha-receptor-mediated coronary vasoconstriction competes with the local metabolic coronary vasodilation that occurs during these conditions, and thereby limits metabolic hyperemia. Measurements of transmural blood flow in alpha-receptor blocked and alpha-receptor intact regions of the left ventricle during exercise demonstrate that adrenergic vasoconstriction helps maintain blood flow to the vulnerable subendocardium during tachycardia. This may be the explanation as to why paradoxical adrenergic coronary vasoconstriction has evolved. During controlled conditions of constant coronary flow, an anti-transmural steal effect due to adrenergic vasoconstriction in the subepicardium can be demonstrated during ischemic conditions. These observations demonstrate unexpected beneficial effects of adrenergic coronary vasoconstriction during tachycardia and cardiovascular stress.

Animals↗
PubMed1990

Interrelations between coronary artery pressure, myocardial metabolism and coronary blood flow.

Characteristically, the coronary circulation has been studied in the time-honored way of varying a single experimental variable while attempting to hold other hemodynamic variables constant. This has produced two-dimensional descriptions of coronary physiology where coronary blood flow vs. coronary artery perfusion pressure, or coronary blood flow vs. myocardial oxygen consumption, are plotted. However, the physiology is more complicated than these plots can show, because coronary blood flow and myocardial metabolism interact. Accordingly, a three-dimensional analysis of coronary physiology has been made where coronary artery pressure and myocardial oxygen consumption are the primary determinants of coronary blood flow, but interactions among all three variables are included. Data on coronary autoregulation and myocardial oxygen consumption have been combined, while maintaining mass balance, to form a three-dimensional surface that describes local metabolic control of coronary blood flow. Using this description of state in three dimensions, simulations of coronary physiology with and without coronary artery stenosis were performed which provide insight into the simultaneous variations in coronary artery pressure, myocardial metabolism and coronary blood flow.

Animals↗
PubMed1990

Beta-receptor subtypes in the canine coronary circulation.

The principal difficulty in determining the subtype of coronary vascular beta-receptors in vivo is to avoid the local metabolic coronary vasodilation that occurs secondary to activation of myocardial beta-receptors. Therefore, a nonbeating cardiac preparation without chronotropic or inotropic effects is needed. In this study, the coronary circulation was perfused at constant pressure in closed-chest chloralose-anesthetized dogs. The increase in coronary blood flow due to intracoronary injections of the combined beta 1- and beta 2-agonist isoproterenol was determined during prolonged asystoles after the cessation of cardiac pacing in atrioventricular heart-blocked animals. Both beta 1-selective (practolol and L 650,744) and beta 2-selective (ICI 118,551) antagonists blocked isoproterenol-induced coronary vasodilation. In contrast, isoproterenol vasodilation in the femoral circulation was blocked by beta 2- but not by beta 1-selective antagonists. In conclusion, both beta 1- and beta 2-receptors in coronary resistance vessels are stimulated by isoproterenol to produce vasodilation during prolonged asystoles, when cardiac chronotropic and inotropic effects are absent.

Adrenergic beta-Antagonists↗
PubMed1990

Cholinergic vasodilatation of coronary resistance vessels in dogs, baboons and goats.

Intracoronary infusion of acetylcholine produces a prompt increase in coronary blood flow in dogs, but a paradoxical decrease has been reported in baboons and cattle. The action of acetylcholine was reexamined in anesthetized dogs, baboons and goats, with the coronary circulation pump perfused at constant pressure and the heart rate held constant with electrical pacing. Intracoronary infusions of low doses of acetylcholine produced coronary vasodilatation and an increase in coronary venous oxygen tension without a change in cardiac contractility (dP/dt) or myocardial oxygen consumption in all three species. High doses of acetylcholine produced coronary vasodilatation only in dogs, but resulted in a decrease in cardiac contractility and myocardial oxygen consumption accompanied by a decrease in coronary flow in baboons and goats. It is concluded that low doses of acetylcholine produce coronary vasodilatation in all three species, and that the decrease in coronary blood flow observed in baboons and goats at high doses is probably due to local metabolic vasoconstriction secondary to the negative inotropic effects of acetylcholine.

Acetylcholine↗
PubMed1989

Acetylcholine causes coronary vasodilation in dogs and baboons.

Intracoronary administration of acetylcholine or efferent vagal stimulation causes coronary vasodilation in dogs. However, in baboons it has been reported that intracoronary acetylcholine results in a fall in coronary blood flow and that stimulation of the vagi is without effect. The dose response of intracoronary acetylcholine and the effect of efferent vagal stimulation on the coronary circulation were reinvestigated in closed-chest, anesthetized dogs and baboons. The left main coronary artery was cannulated and perfused at constant pressure. alpha-Adrenergic and beta-adrenergic receptors were pharmacologically blocked with phenoxybenzamine and propranolol. Heart rate was held constant by right ventricular pacing. In dogs, intracoronary infusion of acetylcholine (1-300 micrograms/min) elicited a dose-dependent increase in steady-state coronary blood flow and coronary sinus oxygen tension, without a change in myocardial oxygen consumption. Vagal stimulation caused a coronary vasodilation that was attenuated by a metabolically mediated decrease in flow. In baboons, acetylcholine increased steady-state coronary blood flow in the dose range of 1-10 micrograms/min, caused little change at 30 micrograms/min, and decreased flow at 100-300 micrograms/min. Coronary sinus oxygen tension increased in a dose-dependent manner up to 10 micrograms/min. Myocardial oxygen consumption was unchanged in the dose range of 1-10 micrograms/min and declined between 30 and 300 micrograms/min. Efferent stimulation of the vagi resulted in coronary dilation obscured by a metabolic reduction of flow. It is concluded that 1) low doses of acetylcholine elicit a primary coronary vasodilation in both species, but in baboons high doses of acetylcholine cause a reduction of both myocardial oxygen consumption and coronary blood flow below control values and 2) vagal stimulation causes a competition between coronary vasodilation and metabolic reduction of flow in dogs and baboons.

Acetylcholine↗
PubMed1989

Coronary autoregulation.

Autoregulation of coronary blood flow is complicated because the heart provides the blood flow and pressure for its own perfusion. Aortic pressure is not only the perfusion pressure for the coronary circulation, but is also the afterload for the left ventricle. Coronary autoregulation has therefore been studied when the coronary circulation is cannulated and perfused separately from the aorta. Even then, changes in coronary artery pressure result in alterations in myocardial metabolism due to the Gregg effect. Local metabolic vascular control appears to be the dominant factor in coronary autoregulation. If myocardial metabolism is enhanced, coronary autoregulation occurs at a higher level of flow. The balance between myocardial oxygen supply and demand is critical for coronary autoregulation, since good autoregulation is only observed when the coronary venous oxygen tension is near the normal value of about 20 mmHg. At present there is little evidence for a myogenic mechanism of coronary autoregulation, and adenosine also does not seem to be involved. It is concluded that coronary autoregulation is predominantly due to a local metabolic mechanism, but the substance that mediates the control is unknown.

Adenosine↗
PubMed1988

Blood oxygen content estimated from PO2, PCO2, and pH.

Oxygen content of blood (265 samples, 25 dogs) from two experimental groups was estimated from measurements of blood PO2, PCO2, pH, hemoglobin, and body temperature with the computational subroutines of Olszowka and Farhi (6). Each computed value was compared with the corresponding oxygen content measured directly by a galvanometric oxygen fuel cell (Lex-O2-Con analyzer). The computed values had consistent errors when compared with the corresponding fuel cell determinations. Linear regression of fuel cell determinations on the corresponding computed values was used to obtain a corrected estimate of oxygen content. When the linear regression correction procedure was performed within each of 25 dogs, the resultant estimates were substantially improved over a lumped correction. The mean absolute value of the difference between the corrected calculated value within an individual dog and the corresponding oxygen fuel cell content determination was 0.38 +/- 0.28 (6 anesthetized dogs, 76 samples) and 0.17 +/- 0.15 (19 awake dogs, 189 samples) (SD) vol% for the two experimental groups. It is concluded that blood oxygen content may be accurately estimated from PO2, PCO2, and pH when appropriately corrected. The advantage is that only a small subset of the total number of blood samples needs to be analyzed with the oxygen fuel cell.

Animals↗
PubMed1988

Adrenergic coronary vasoconstriction helps maintain uniform transmural blood flow distribution during exercise.

The hypothesis that alpha-adrenergic coronary vasoconstriction helps maintain a uniform transmural distribution of myocardial blood flow during exercise was tested in dogs. Carotid artery loops were surgically constructed and a splenectomy performed three weeks prior to study. On the day of study, the dog was anesthetized briefly (fentanyl and nitrous oxide) for percutaneous catheterization, and alpha-receptors in one myocardial region were blocked with phenoxybenzamine (0.25 mg/kg) infused selectively into the left circumflex coronary artery. Recirculation of phenoxybenzamine was minimized by drainage of coronary sinus outflow during the infusion. After the dog recovered from the anesthesia, regional blood flow was measured at rest and during graded treadmill exercise with the microsphere technique calibrated by reference blood samples. Average transmural flow was limited by alpha-vasoconstriction and was less in the region where alpha-receptors were intact than in the region where they were blocked, as has been described by others. The ratio of inner layer myocardial blood flow to outer layer flow was better maintained in the region with alpha-receptors intact than in the region with alpha-receptors blocked when myocardial oxygen consumption was 150 microliter/min/g or greater (p less than 0.001). Even though average transmural flow was limited by alpha-receptor activation, inner layer myocardial blood flow was greater in the region with alpha-receptors intact than in the region with alpha-receptors blocked when myocardial oxygen consumption was 500 microliter/min/g or more (p less than 0.05). In conclusion, adrenergic coronary vasoconstriction mediated by alpha-receptors helps to maintain a uniform transmural distribution of myocardial blood flow during exercise in spite of limiting average transmural flow.

Animals↗