Arterial baroreceptor input contributes to long-term control of blood pressure

A little more than three decades ago, there was little doubt that baroreceptors were crucial for both the short-term and long-term control of mean arterial blood pressure (MAP). Then, in 1970 it was reported that baroreceptors reset completely within 48 hours in hypertensive rats. Three years later, it was reported that MAP was near normal in dogs with both aortic and carotid baroreceptors denervated based on continuous measurements, thus discrediting numerous reports of denervation-induced hypertension. These two observations quickly led to a reevaluation of the importance of baroreceptor input in long-term control mechanisms. Finally, a consensus emerged that baroreceptor input could not be involved in long-term control of MAP, and this conclusion can be found in all modern textbooks of physiology used in the instruction of medical students. However, recent experimental observations have challenged the conclusion that baroreceptor input plays no role in the long-term control of MAP. In this article, the principal arguments against baroreceptor involvement in long-term control of MAP are summarized, and the new findings that suggest that a reappraisal of our current concept is required are reviewed.     

Physiology of the renal baroreceptor mechanism of renin release and its role in congestive heart failure

The function of the renal baroreceptor can be quantitatively described by a stimulus-response curve showing a flat section in the high pressure range, a steep slope in the low pressure range, and a well-defined threshold pressure slightly below resting systemic pressure. This stimulus-response curve shows a close functional relation to autoregulation of renal blood flow, glomerular filtration rate and sodium excretion. Threshold pressure and slope are subject to different physiologic control mechanisms: The slope is increased by a low sodium diet, whereas threshold pressure is elevated by an increased renal sympathetic nerve discharge or by circulating catecholamines. Sympathetic influences also reset renal autoregulation. Recent studies have provided evidence for an important role of the renal baroreceptor in the long-term control of arterial blood pressure. The sympathetic modulation of threshold pressure can induce sodium retention in early heart failure, and the sympathetic effects on autoregulation may help to explain clinical reports on a deterioration of renal function during converting-enzyme therapy.     

Elevated level of erythropoietin in congestive heart failure Relationship to renal perfusion and plasma renin

Abstract. Background. In animal experiments reduction of renal perfusion can stimulate erythropoietin production. The relationship between renal haemodynamics and erythropoietin production is unknown in congestive heart failure. Objective. The aim was to study the relationship between serum erythropoietin and renal haemodynamics, plasma renin activity and haematocrit in patients with congestive heart failure and in healthy control subjects. Patients and methods. Serum erythropoietin, renal plasma flow, glomerular filtration rate and plasma renin activity were determined in 14 patients with acyanotic congestive heart failure, and 36 healthy controls. Results. Serum erythropoietin was significantly elevated in congestive heart failure 26.6 U l^?1 (median) compared with controls 17.0 U l^?1 despite a normal haematocrit, and increased with the severity of congestive heart failure (New York Heart Association class II: 17 U l^?1 [n = 4]; class III: 30 U l^?1 [n = 5]; class IV: 45 U l^?1 [n = 5]). Significant inverse correlations between serum erythropoietin and renal plasma flow (r = ?0.60, P < 0.03), and between serum erythropoietin and glomerular filtration rate, were found in congestive heart failure but not in the control subjects. A significant positive correlation (r = 0.71, P < 0.03) was demonstrated between serum erythropoietin and plasma renin activity in congestive heart failure. Conclusion. A severe reduction in renal perfusion in congestive heart failure appears to cause an increase in serum erythropoietin.     

Effect of sodium depletion on plasma renin concentration before and during adrenergic beta-receptor blockade with propranolol in normotensive man.

Plasma renin levels have been used to discriminate between different forms of hypertension, but how to define the normal range of plasma renin levels has not been agreed upon. Sodium depletion stimulates renin release. Evaluation of plasma renin would, therefore seem possible only in relation to sodium balance. Plasma renin concentration and concurrent daily sodium excretion were determined in 33 healthy normotensive subjects (control group) ingesting high, normal and low sodium diets. A well-defined hyperbolic relationship was found between the two variables indicating that the physiologic level of plasma renin concentration depends on the state of sodium balance. An increase in plasma potassium concentration may reduce plasma renin concentration, but this appeared to be overruled by the stimulating effect of sodium depletion. To examine whether beta-adrenergic stimulation contributes to the increase in plasma renin concentration during sodium depletion, the relationship between plasma renin concentration and concurrent sodium excretion was studied during beta-receptor blockade with propranolol. In 20 healthy normotensive subjects in whom beta-receptor blockade was verified by a significant reduction in pulse rate, the same hyperbolic relationship was found between plasma renin concentration and sodium excretion as in the control group showing that sodium depletion stimulates renin release independent of sympathetic nervous activity.     

The role of renal prostaglandins in the renin response to isoproterenol in the rat in vitro

Renal prostaglandins (PGs) have been considered to be important mediators of renin release. However, the mechanism and the site of action have not been clarified. To investigate the role of PGs in the control of isoproterenol-induced renin release, we studied the effect of two inhibitors of PG synthesis, indomethacin and meclofenamate, on the renin release stimulated by isoproterenol and dibutyryl cAMP. We used an in vitro superfusion system of rat renal cortical slices. Neither indomethacin nor meclofenamate affected basal renin release. Isoproterenol (8 x 10(-7) M) increased renin and PGE2 release which was blocked by indomethacin (10(-4) M) and meclofenamate (10(-4) M). Dibutyryl cAMP stimulated renin release significantly, and this effect was not blocked by indomethacin (10(-4) M). Moreover, dibutyryl cAMP did not stimulate PGE2 release. In view of the fact that we have previously shown that PG-stimulated renin release is not blocked by propranolol and is enhanced by phosphodiesterase inhibitors, our present experiments suggest that the site of action of PGs on renin release is located between the beta-adrenergic receptor and the generation of cAMP.     

Effects of altering the interval between the stimulus and the reflex response in the analysis of the baroreceptor control of the sinus and atrioventricular nodes in man

Baroreceptor control of the sinus node may be determined by raising or lowering blood pressure with intravenous bolus injections of phenylephrine or glyceryl trinitrate and calculating the slope of the linear regression between the drug induced changes in systolic blood pressure and RR interval using shift 1 coupling--namely, coupling of each systolic blood pressure value with the interval of the following cardiac cycle. To assess whether shift 1 coupling provides the best linear fit and the highest regression slope nine subjects received phenylephrine and glyceryl trinitrate injections both during spontaneous sinus rhythm and during atrial pacing to evaluate baroreflex control of the sinus and of the atrioventricular node respectively. In regression analysis of the data, for each drug injection nine different shifts (from 0 to 8) were used to couple systolic blood pressure with RR or StQ intervals. When the mean results from all subjects were compared the use of shift 1 was equal or superior to the use of any other shift for both the RR and the StQ interval responses evoked by either phenylephrine or glyceryl trinitrate. In many instances, however, the shift that provided the highest correlation and regression coefficient was different from shift 1, and the use of these best individual shifts provided results considerably different from those obtained with the standard shift 1. It is concluded that in the regression analysis of baroreflex cardiac responses to vasoactive drugs the regular use of shift 1 does not invariably provide the best estimation of baroreflex sensitivity. This is better achieved by calculating the best shift in individual responses.     

Role of renal nerves in the stimulation of the renin system by reduced renal arterial pressure

The aim of this study was to determine the role of renal innervation in the prolonged stimulation of renin secretion and renin synthesis accompanying renal artery stenosis. Male Sprague-Dawley rats, in which the left kidney had been denervated or sham denervated 4 days earlier, received a left renal artery clip (ID 0.2 mm). Plasma renin activity and renin mRNA were assayed 1, 2, or 4 days after clipping. The stimulation of both plasma renin activity and renin mRNA was blunted markedly in the rats with the denervated clipped kidney. The typical suppression of renin mRNA in the intact right kidney, however, was not different between rats with sham-denervated or denervated left kidneys, nor was the increase of blood pressure in response to renal artery clipping different between the experimental groups. To test whether the suppression of renin mRNA in the contralateral kidney was related to the increase of blood pressure, another group of rats with denervated clipped left kidneys was treated additionally with the T-type calcium channel blocker mibefradil (15 mg. kg(-1). d(-1)). Despite blood pressure normalization by mibefradil, plasma renin activities and renin mRNA levels in the clipped denervated kidneys and in the intact right kidneys remained unchanged. These findings suggest that renal nerves are responsible for marked background stimulation of both renin secretion and renin mRNA expression, which is normally masked by the inhibitory effect of renal perfusion pressure on the renin system. Renal nerve activity is therefore an important determinant of the gain of renin stimulation during reduced renal arterial pressure.     

The transient ventilatory response to carbon dioxide at rest and in exercise in man

A new technique has been developed to measure the transient response to inhaled CO2 using 30 sec pulses at constant inflow. Multiple experiments are ensemble-averaged in order to define the resulting small signals. We measured the peak changes in ventilation (delta V') and in PCO2 (delta PCO2), taking the ratio (delta V'/delta PCO2) as an index of response. Six healthy volunteers performed experiments at rest, 50 W and 100 W exercise. Three runs, each containing three pulses, were performed at each workload and subsequently averaged. Analysis of variance showed no significant difference between successive pulses or among subjects. delta V' did not differ significantly with workload, but delta PCO2 was progressively smaller as workload increased, and hence the response, delta V'/delta PCO2, greater. The delay between the rise in PCO2 and the rise in ventilation was also progressively shorter as workload increased, being 16-18 sec at rest, 7-13 sec at 50 W, and 3-6 sec at 100 W. Our results suggest that there is increased sensitivity to CO2 in exercise, which may be due to progressive activation of the peripheral chemoreceptors as work load increases. The delay at rest is too long for the peripheral chemoreceptor. Therefore, with these small stimuli, the central chemoreceptor must account for the CO2 response at rest.