Allen W. Cowley

Role of the Baroreceptor Reflex in Daily Control of Arterial Blood Pressure and Other Variables in Dogs

Normal and sinoaortic baroreceptor–denervated dogs were monitored continuously (24 hours a day) to quantify the role of the baroreceptors in determining the average level and the variability of arterial blood pressure, heart rate, cardiac output, and total peripheral resistance. The frequency of occurrence over 24-hour periods was obtained for each variable using a fiber optic curve-scanning system to read the variables from continuously recorded charts and a digital computer system to plot curves. The results indicate that the degree of hypertension previously reported for this preparation has been highly exaggerated, presumably due to the methods of study. The average 24-hour mean arterial blood pressure was 101.6 mm Hg in normal dogs and only 112.7 mm Hg in baroreceptor-denervated dogs. The normal dogs exhibited narrowly distributed 24-hour frequency distribution curves for blood pressure; in contrast the denervated dogs exhibited curves with twice the 24-hour standard deviation. Similar analysis indicated that the baroreceptors exerted less influence on the daily stabilization of heart rate than they did on arterial blood pressure and that they had very little if any influence on the daily stabilization of cardiac output and total peripheral resistance. Hemodynamic variables during postural changes were studied along with diurnal rhythms. We concluded that the primary function of the baroreceptor reflex is not to set the chronic level of arterial blood pressure but, instead, to minimize variations in systemic arterial blood pressure, whether these variations are caused by postural changes of the animal, excitement, diurnal rhythm, or even spontaneous fluctuations of unknown origin.

Interaction of Vasopressin and the Baroreceptor Reflex System in the Regulation of Arterial Blood Pressure in the Dog

The hemodynamic effects of 1-hour intravenous infusions of vasopressin were evaluated in trained, unanesthetized dogs in the normal state and following sinoaortic baroreceptor denervation. Pressor sensitivity to vasopressin was greatly enhanced following baroreceptor denervation; threshold sensitivity was increased 11-fold and sensitivity at higher dose levels was increased 60–100-fold. Infusion of physiological levels of vasopressin caused an average increase in arterial blood pressure of 33 mm Hg in conscious, baroreceptor-denervated dogs compared with an increase of 5 mm Hg in normal dogs. In contrast, similar intravenous infusions of norepinephrine at physiological levels resulted in a 3-fold increase in pressor sensitivity with no change in threshold dose. Hy-pophysectomy of baroreceptor-denervated dogs did not significantly alter their pressor sensitivity to vasopressin in the conscious state. The arterial blood pressure response to intravenous vasopressin infusions was greatly depressed when a high background level of circulating vasopressin was present. Decapitated, spinal, anesthetized dogs maintained with a small continuous infusion of norepinephrine exhibited the greatest sensitivity to vasopressin; the threshold dose for a pressor response was similar to that in conscious baroreceptor-denervated dogs, but pressor sensitivity at physiological dose levels was increased nearly 8, 000-fold. The elevations in arterial blood pressure resulting from vasopressin infusions of less than 1.0 munits/kg min−1 were large enough to implicate the direct pressor effect of vasopressin in the normal control of arterial blood pressure.

Renin, Aldosterone, Body Fluid Volumes, and the Baroreceptor Reflex in the Development and Reversal of Goldblatt Hypertension in Conscious Dogs

The renal artery to a sole remaining kidney was constricted in unanesthetized dogs while renal arterial pressure was recorded distal to the occluder. Following the constriction, mean arterial blood pressure, which was continuously monitored 24 hours a day for 1 week, exhibited a biphasic increase. The first peak in pressure correlated with a large increase in plasma renin activity; the second peak correlated with an increase in plasma volume brought about by positive sodium and water balances. Renin activity was returning to normal when the second peak occurred. Increased drinking played a major role in the positive water balance. Plasma aldosterone concentration was moderately and transiently increased for only a few hours following the constriction. The experiment was repeated in sinoaortic baroreceptor-denervated dogs; apparently, the baroreceptor reflex significantly slows the time course of the arterial blood pressure increase during the first few days of constriction but does not alter the magnitude of the pressure increase after 1 week. After release of renal artery constriction, mean arterial blood pressure decreased progressively over a 3-day period, during which time significant negative sodium and fluid balance occurred. The slow return of the pressure back to normal correlated highly with a decrease in plasma volume. In the baroreceptor-denervated dogs, the initial fall in arterial blood pressure apparently also resulted at least partly from a decrease in plasma renin activity, but this effect was not observed in the intact dogs because the renin activities in these dogs had already decreased to normal prior to constrictor release. The effects of the baroreceptor reflex on the time course of the pressure decrease did not seem to be as significant as those on the time course of the pressure increase.

Subpressor angiotensin infusion, renal sodium handling, and salt-induced hypertension in the dog.

We studied the combined effect of subpressor amounts of angiotensin and long-term sodium chloride infusion on arterial pressure in 16 dogs for periods of 2-8 weeks. In dogs receiving 3.5 liters of isotonic NaCl daily, but no angiotensin, the arterial pressure increased an average of only 3 mm Hg. When angiotensin was infused continuously at a rate of 5 ng/kg per min (a rate too small to cause an observable immediate increase in pressure), subsequent infusion of 3.5 liters of saline daily then increased the pressure by 39 mm Hg. The urinary output of sodium increased to the same extent in both instances, that is, there was no extra sodium loss because of the elevated pressure. This suggests that the angiotensin significantly blocked the normal ‘pressure natriuresis’ usually seen with such large increases in pressure. However, the plasma aldosterone levels during angiotensin infusion were not found to be different from those in the absence of angiotensin. Therefore, we have suggested that the tendency of the kidneys to retain sodium under the influence of angiotensin was probably caused mainly by a direct effect of angiotensin on the kidney itself. Such a direct renal sodium-retaining effect also could be a contributing factor in the marked hypertension that results from salt administration in the presence of small amounts of angiotensin.

The concept of autoregulation of total blood flow and its role in hypertension

Arterial vascular resistance to blood flow is increased in every known form of established hypertension. The proposed mechanisms responsible for these alterations in vascular resistance include humoral factors, the nervous system and local autoregulatory events. This study focuses on the potential importance of the phenomenon of tissue autoregulation as a factor in vascular resistance. Nearly all individual organ systems can locally adjust their vascular resistance (autoregulate) to maintain appropriate blood flow, so that the sum of all the tissue resistances determines the total blood flow through the circulation (cardiac output). The extent to which these local autoregulatory mechanisms can influence hemodynamic events associated with various types of hypertension is evaulated. It is concluded that even slight fluid retention over periods of weeks and months enables autoregulatory mechanisms to sustain a 50 per cent increase in arterial pressure with only a 5 per cent observed increase in cardiac output. In some forms of hypertension, these mechanisms appear to explain the observed hemodynamic changes (i.e., low renin essential hypertension or primary aldosteronism). In other forms, there may be no reason for autoregulation to occur, so the mechanism might be of no consequence in determining the vascular resistance. The evidence indicates that regulation of cardiac output cannot explain the cause of hypertension, but local autoregulation of flow must be carefully considered if we are to understand fully the hemodynamic events associated with various forms of hypertension.

Influence of Acute Stimuli on Plasma Aldosterone Concentration in Anephric Man and Kidney Allograft Recipients

The response of plasma aldosterone concentration to postural variation, adrenocorticotropic hormone (ACTH), and angiotensin II was studied in five kidney allograft recipients and compared with the response observed in the same five subjects during the anephric period. Normal subjects acted as intact controls. After 2 hours of normal ambulation, plasma aldosterone levels increased in normal subjects (6.7 ± 1.6 to 22.9 ± 2.7 ng/100 ml plasma), remained unchanged in anephric patients (4.5 ± 1.0 to 5.2 ± 1.1 ng/100 ml plasma), and increased in kidney allograft recipients (6.8 ± 1.5. to 25.6 ± 1.9 ng/100 ml plasma). After ACTH administration, plasma aldosterone levels increased in normal subjects (7.5 ± 1.8 to 24.3 ± 2.5 ng/100 ml plasma), anephric subjects studied immediately after hemodialysis (16.6 ± 1.6 to 30.0 ± 2.6 ng/100 ml plasma), and kidney allograft recipients (5.0 ± 1.6 to 22.3 ± 1.4 ng/100 ml plasma). After angiotensin II infusion, plasma aldosterone levels increased in normal subjects (7.2 ± 1.8 to 42.5 ± 3.6 ng/100 ml plasma), remained unchanged in anephric subjects (8.6 ± 2.1 to 7.4 ± 1.6 ng/100 ml plasma), and increased in kidney allograft recipients (6.3 ± 1.5 to 40.2 ± 3.1 ng/100 ml plasma). In anephric man after prolonged absence of the renal renin-angiotensin system ACTH increased the rate of aldosterone secretion but angiotensin II had little effect. An intact renal renin-angiotensin system was necessary for increased aldosterone secretion in response to postural variation.

RENAL RESPONSES TO SLIGHT ELEVATIONS OF RENAL ARTERIAL PLASMA ANGIOTENSIN II CONCENTRATION IN DOGS

1. Angiotensin II was infused into the renal artery of intact kidneys of slightly volume expanded anaesthetized dogs at rates of 125, 250, 500, and 1000 pg/kg body weight per min, resulting in elevations of the calculated renal arterial plasma angiotensin II concentration of 16·9 (s.e.m. = 2·1), 35·0 (s.e.m. = 4·3), 73·3 (s.e.m. = 8·8), and 159·8 (s.e.m. = 20·4) pg/ml.

Heart Rate as a Determinant of Cardiac Output in Dogs with Arteriovenous Fistula

Abstract The importance of heart rate in the control of cardiac output under conditions of a high level of venous return was studied in a series of 17 anesthetized open chest dogs with the atrioventricular bundle cut. The results show that high heart rates do not increase cardiac output under conditions of normal venous return. On the other hand, when venous return is markedly increased above normal by opening large arteriovenous fistulas, maximal cardiac output is achieved only at very high heart rates. As venous return increases, the heart rates at which maximal values of cardiac output are obtained are progressively increased. Norepinephrine or sympathetic stimulation further elevates the heart rate required for maximal cardiac output. These observations help to explain why tachycardia and the other cardiostimulant actions of the sympathetic nervous system play an important role in the regulation of cardiac output.

Quantification of Intermediate Steps in the Renin-Anglotensin-Vasoconstrictor Feedback Loop in the Dog

The major intermediate steps in the renin-angiotensin-vasoconstrictor feedback loop have been experimentally determined. The quantitative relationships between renal perfusion pressure, renin secretion, arterial renin activity, and systemic arterial blood pressure were determined in dogs in which the cardiovascular control loops of the central nervous system were eliminated by spinal cord destruction and decapitation. Step-decreases in renal perfusion pressure to a single kidney were introduced and maintained constant to open the feedback loop of arterial pressure. Renin activity was measured by radioimmunoassay of angiotensin I. Each decrease of 15 mm Hg in renal perfusion pressure between pressures of 100 and 50 mm Hg elevated the net secretion of renin nearly 20 ng min−1 g−1 kidney an d the arterial renin activity nearly 7.0 ng ml−1 hour−1. Renin secretion and arterial renin activity decreased at perfusion pressures below 50 mm Hg. A bioassay procedure for estimating the rate of angiotensin II formation at various increments of arterial renin activity showed that an increase in renin activity of 10 ng ml−1 hour−1 resulted in an increase in the net production of angiotensin II of 5.0 ng kg−1 min−1. The results of these experiments are useful in predicting alterations in the system that follow a decrease in renal artery pressure, and they clarify interactions of the renin-angiotensin system with other homeostatic pressure-regulating systems.

Failure of chronic aldosterone infusion to increase arterial pressure in dogs with angiotensin-induced hypertension.

To generate quantitative data relating to the hypertensive activity of aldosterone, 9 μg/kg per day (4 times normal) aldosterone (4-ALDO) were infused chronically in both adrenalectomized and intact dogs until steady state conditions were achieved. Mean arterial pressure (MAP) was monitored continuously, 24 hours per day, and daily steady state values for MAP based on approximately 600 sample points per day were determined by employing computerized data analysis. In some studies, angiotensin II (A II) was also infused chronically (5 ng/kg per min) prior to and during 4-ALDO administration to maintain plasma levels of A II constant. 4-ALDO infusion in intact dogs maintained on 75 mEq sodium per day increased MAP by only 13 mm Hg compared to a greater than 30 mm Hg rise observed with A II infusion alone, even though plasma aldosterone concentration rose in these experiments only two-thirds as much as when 4-ALDO was infused. When A II was infused chronically, a fall in plasma A II concentration could not compensate for the hypertensive effects of superimposed 4-ALDO infusion; therefore, maximal aldosterone-induced hypertension was expected. However, in both adrenalectomized and intact dogs, the further addition of 4-ALDO failed to increase the degree of A II-induced hypertension and failed to promote sodium retention. Chronic A II infusion in intact dogs maintained on 75 and 190 mEq sodium per day produced a sustained increase in plasma aldosterone concentration (2.7 and 1.6 times control, respectively) as well as kaliuresis and hypokalemia. Infusion of A II in adrenalectomized dogs produced hyperkalemia, not hypokalemia. The data indicate that high plasma levels of aldosterone, at least over a period of several weeks, have only weak hypertensive effects in the dog, particularly in instances in which the aldosteronism is associated with a primary increase in A II.