John L. McNay

Direct Renal Vasodilatation Produced by Dopamine in the Dog

The effects on directly measured renal blood flow, mean blood pressure, and calculated renal vascular resistance of intravenous infusions of dopamine, isoproterenol, and norepinephrine were compared. Dopamine, at doses not affecting mean blood pressure, decreased renal vascular resistance and increased renal blood flow. In contrast, isoproterenol decreased both blood pressure and renal vascular resistance but did not consistently increase renal blood flow. Renal artery injection of dopamine produced vasodilatation at doses ranging from 0.75 to 12 μg and biphasic flow responses including transient vasoconstriction at higher doses. It is concluded that the probable basis for the effect of intravenous dopamine infusion on renal blood flow is its direct renal vasodilating action. The direct effect of dopamine on the femoral vascular bed is vasoconstriction. The combination of renal vasodilating, and femoral vasoconstricting, effects is unique and is interpreted as evidence for a renal vasodilating effect of dopamine distinct from the conventional beta-adrenergic mechanism. A possible physiological role for dopamine other than as a precursor to norepinephrine may be related to this property. It is also suggested that the ability of dopamine to alter the distribution of cardiac output in favor of visceral organs may find useful clinical applications.

Pressure-Dependent Heterogeneity of Renal Cortical Blood Flow in Dogs

We determined the effect of perfusion pressure on the distribution of blood flow within the renal cortex of the anesthetized dog. Total blood flow to the denervated kidney was measured by an electromagnetic flowmeter and perfusion pressure was manipulated over the autoregulatory range (136 to 81 mm Hg) by an aortic clamp. Distribution of cortical blood flow was determined by the radioactive microsphere technique. Tissue perfusion rates of four cortical zones of equal thickness differed significantly from each other at normal arterial pressure. In sequence from superficial to deep, perfusion of the cortex zones averaged 4.18, 6.80, 3.07, and 1.68 ml. g−1. min−1. Aortic constriction significantly reduced perfusion of the outer cortical zone and augmented perfusion of the inner two cortex zones. Twelve percent of total renal blood flow was redistributed by pressure reduction. Atropine, 1 mg/kg, had no effect on cortical perfusion rates at either pressure. The influence of microsphere diameter and density on cortex perfusion rates was systematically studied and found to be minor. This observation implies that the microsphere method is valid for measuring distribution of blood flow within the renal cortex. We conclude that zones of the renal cortex are perfused at different rates and respond differently to changes in arterial pressure.

Evaluation of the pre-ejection period as an estimate of myocardial contractility in dogs

Abstract The pre-ejection period, measured externally by subtracting the left ventricular ejection time from the total systolic time, was evaluated in dogs under a variety of experimental conditions in order to determine the effect of various levels of inotropic stimuli, changes of heart rate, aortic diastolic pressure and left ventricular end-diastolic pressure. In addition, the pre-ejection period was systematically compared to 2 more completely evaluated internal indexes of myocardial contractility: the time to maximal dp/dt (first derivative of left ventricular pressure) and the maximal dp/dt divided by instantaneous left ventricular pressure. No effect of heart rate on the pre-ejection period was noted when left ventricular end-diastolic pressure, aortic diastolic pressure and contractile indexes were held constant. Increases in aortic diastolic pressure caused significant but small increases in the pre-ejection period during constancy of end-diastolic pressure, heart rate and contractile indexes. Increases in left ventricular end-diastolic pressure were found to alter markedly the pre-ejection period in an inverse fashion at fixed levels of aortic diastolic pressure, heart rate and contractile indexes. There was, however, a significant correlation between the pre-ejection period and the internal indexes of contractility over a wide range of inotropic stimuli in experiments in which left ventricular end-diastolic pressure was shown to vary in a random manner. These studies indicate that the pre-ejection period may be used as an index of myocardial contractile state in situations in which the left ventricular end-diastolic pressure is constant or proved not to vary systematically under the conditions being studied. During all studies, internal and external measurements of the preejection period were found to correlate well at levels of left ventricular end-diastolic pressure below 12 mm Hg, but they were increasingly divergent at higher levels of end-diastolic pressure.

In Vivo Analysis of Adrenergic Receptor Activity of Dobutamine

Studies were performed in anesthetized dogs to evaluate the cardiac and systemic effects of intravenously administered dobutamine and to determine its direct effects on the renal and femoral vascular beds. The results demonstrated that dobutamine possessed an inotropic efficacy similar to that of isoproterenol and norepinephrine; its chronotropic effect was similar to or greater than that of norepinephrine. In contrast to norepinephrine, dobutamine increased cardiac output and reduced total peripheral resistance with minimal effects on mean aortic pressure. Studies on the denervated hind limb demonstrated that dobutamine stimulated both alpha and beta receptors. The dose of dobutamine which produced a 50% increase in femoral blood flow was 180 times the required dose of isoproterenol and the dose which produced a 50% increase in contractile force was 43 times the required dose of isoproterenol. Studies on the renal vasculature demonstrated that dobutamine caused no dopamine-like renal vasodilator activity and only minor vasodilation mediated by beta receptors. We concluded that dobutamine is more cardioselective than is isoproterenol. The dobutamine-induced decrease in peripheral resistance observed in the whole dog was presumably due to increased myocardial contractility coupled with a greater net effect of beta-adrenergic vasodilation than alpha-adrenergic vasoconstriction. Studies with reserpine-treated dogs showed that all dobutamine-induced effects were due to a direct action on receptors.

A Hemodynamic Comparison of Dopamine and Isoproterenol in Patients in Shock

The hemodynamic responses to isoproterenol and dopamine were investigated in 22 patients with the shock syndrome from various etiologies. Dopamine was superior to isoproterenol in seven patients with normal or low peripheral resistance. In this group of patients administration of isoproterenol was associated with unacceptably low blood pressure. Isoproterenol was superior in three patients in whom dopamine did not increase cardiac output. Both amines produced adequate clinical response in four patients, and a combination of isoproterenol and dopamine was necessary for adequate therapy in two patients. Six patients did not respond hemodynamically or clinically to either dopamine or isoproterenol. This investigation has demonstrated that optimal sympathomimetic amine therapy of shock is facilitated by an analysis of hemodynamic status and responses to drug administration.

Control plasma renin activity and changes in sympathetic tone as determinants of minoxidil-induced increase in plasma renin activity.

A study was made of the possible mechanism(s) underlying minoxidil-induced increase in plasma renin activity (PRA). 10 patients with essential hypertension were treated with minoxidil and subsequently with a combination of minoxidil plus propranolol. Minoxidil lowered mean arterial pressure 31.6 plus or minus 3.3 mm Hg, mean plus or minus SEM. There was an associated increase in both PRA, 6.26 plus or minus 2.43 NG/ML/H, and heart rate, 21.4 plus or minus 2.7 beats/min. The changes in PRA and heart rate were positively correlated, r, 0.79. Addition of propranolol reduced mean arterial pressure by a further 10.1 plus or minus 1.5 mm Hg and returned heart rate to control levels. Propranolol reduced PRA significantly but not to control levels. Control PRA positively correlated with PRA on minoxidil, r, 0.97, and with PRA on minoxidil plus propranolol, r, 0.98. We conclude that control PRA is a major determinant of change in PRA with minoxidil. Minoxidil increased PRA by at least two mechanisms: (a) an adrenergic mechanism closely related to change in heart rate and blocked by propranolol, and (b) a mechanism(s) not sensitive to propranolol and possibly related to decrease in renal perfusion pressure.

Redistribution of Cortical Blood Flow during Renal VasodNatation in Dogs

We studied the distribution of cortical blood flow during renal vasodilation induced by four maneuvers; reduction of perfusion pressure, intraarterial infusion of acetylcholine, and diuresis induced by ethacrynic acid or mannitol. Dogs were anesthetized with pentobarbital and urinary losses replaced. Bloodflow of the denervated kidney was measured by an electromagnetic flowmeter, and distribution of renal cortical blood flow analyzed by the radioactive microsphere technique. Acetylcholine caused progressively greater proportional vasodilation from superficial to deep cortex. The resulting pattern of flow redistribution was nearly identical to that observed in response to reduced perfusion pressure (autoregulation). Since the same pattern of heterogeneous cortical response was elicited by two qualitatively different stimuli, we propose that it reflects differential responsiveness of individual cortex zones. Ethacrynic acid redistributed flow in a different pattern, augmenting the proportion to the middle, but not the juxtamedullary cortex. High urine flow was excluded as a nonspecific basis for this difference, since acetylcholine produced its usual pattern of redistribution during the ethacrynic acid-induced diuresis. Additionally, ethacrynic acid-induced flow redistribution was not secondary to high urine flow per se, since mannitol diuresis did not significantly alter distribution of flow.

Possible predisposition of diabetic patients to hyperkalemia following administration of potassium-retaining diuretic, amiloride (MK 870)☆☆☆

Abstract We have observed two cases of hyperkalemia during short-term administration of the potassium-retaining diuretic, amiloride, to four diabetic patients. The response of serum potassium to intravenous glucose was also significantly modified by amiloride supporting a close association between carbohydrate and potassium metabolism. The hyperkalemia was not clearly associated with impaired renal function or excessive potassium retention and developed over a short time period at doses which are usually safe. There is evidence suggesting that both amiloride and triamterene share this toxic effect. Spironolactone should be considered suspect as a contributory agent since it has been co-administered in several fatal cases including one in this series. Attention is drawn to reciprocal decreases in serum sodium which occurred simultaneously with the development of hyperkalemia in our patients. The electrocardiogram was unreliable in assessing the clinical significance of the hyperkalemia. We suggest that diabetic patients may have an abnormality of electrolyte homeostasis which predisposes them to hyperkalemia during administration of potassium-retaining diuretics.

Differential effects of propranolol on heart rate and plasma renin activity in patients treated with minoxidil

The relationship between PPC and its effect on minoxidil‐induced increases in PHA and heart rate was examined in 9 patients with essential hypertension. Concomitant with the minoxidil‐induced depression of mean arterial pressure (30.7 ± 3.5 mm Hg, mean ± SEM), heart rate increased from 79.1 ± 3.0 to 100.4 ± 4.6 BPM, and PHA increased from 1.12 ± 0.28 to 8.58 ± 2.83 nglmllhr. Addition of propranolol to minoxidil caused a decrease in heart rate in proportion to log PPC:

Antihypertensive effect of a dopamine beta hydroxylase inhibitor, bupicomide: a comparison with hydralazine.

The cardiovascular effects of a new antihypertensive drug, bupicomide, were compared with those of hydralazine in 6 patients with mild to moderate hypertension. The mean supine arterial pressure of patients was reduced 15.2 mm Hg by bupicomide (900 to 2,000 mg/day) and 15.7 mm Hg by hydralaslne (300 to 600 mg/day). Heart rate increased an average of 11.3 bpm during bupicomide and 14.5 bpm by hydralaine. Neither drug was associated with a postural decrease in mean arterial pressure. The heart rate response during maximum tolerated treadmill exercise was not diminished by either drug. Cardiac index was increased during administration of both drugs. Bupicomide and hydralazine reduced forearm vascular resistance, while renal blood flow and renal vascular resistance were not significantly modified. Evidence of equivalent augmentation of sympathetic nervous activity during administration of both drugs consisted of equal and significant increases in heart rate and urinary norepinephrine excretion, and decreases in duration of the pre‐ejection period. The absolute values of these parameters were correlated with mean arterial pressure, which may indicate that the increase in sympathetic nervous activity was mediated by baroreceptor reflexes. Although bupicomide inhibits dopamine ß‐hydroxylase, our results suggest that it is acting as a direct vasodilator.