The circadian rhythm of plasma renin activity during continuous recumbency was determined fifty-one times in thirty subjects who either slept at night or remained awake for 24 h. Both groups had maximum values between 2400 and 0800 h, despite absence of the expected early morning fall in blood pressure, pulse, and glomerular filtration rate in the awake subjects. Infusion of normal saline between 2300 and 0300 h initially suppressed renin, but did not prevent its subsequent rise regardless of the amount of sodium appearing in the urine. Of thirteen patients tested two to five times, twelve had recurrence of the zenith within a single 4 h period on retesting, despite differences in sodium intake, basal blood pressure, and mean plasma renin activity. Peaks of lesser magnitude were also frequently noted, most commonly at 1000 h and 1800-2000 h. Minimum PRA values were not restricted to a particular time of day and did not generally recur at the same time upon retesting. The mean ratio of maximum to minimum PRA in each study was 246% +/- 18.3% (+/- 1 SEM). The circadian rhythm of renin appears to be independent of known renal mechanisms responsible for regulating renin release. It is possible that this rhythm is controlled by the central nervous system.

Previous work from this laboratory indicated significant elevations of cortisol after the administration of tryptophan. The current investigation was designed to confirm this observation and study the effect of this agent on ACTH. Cortisol rose 12.4 +/- 5.2 microgram/dl (mean +/- SD) in 10 of 12 tests (P less than 0.02). Responding patients had rises of ACTH averaging 101.8 +/- 45.8% (range, 40-159 pg/ml) above baseline. The time course of the ACTH change closely paralleled that of cortisol, and there were significant correlations between the rises of the two substances (r = 0.81; P less than 0.01). The current data strongly suggest that tryptophan administration stimulates ACTH release, possibly through activation of the central serotonergic nervous system. Review of the literature suggests the possibility that ACTH stimulation only occurs at high plasma tryptophan (and presumably brain serotonin) concentrations, with ACTH inhibition occuring at lower levels.

Tryptophan administration was used to evaluate the possibility that serotonergic neurons are involved in regulating the release of cortisol, renin, and aldosterone. Eleven studies were undertaken using 2 or 10 g tryptophan administered to fasting patients in continued supine posture. Aldosterone rose significantly to 208% (range, 128-329%) of baseline in all seven studies using 10 g and in one of the four studies using 2 g. Renin rose significantly to 189% (range, 116-340%) of baseline in four of the seven studies using 10 g and in two of the four studies using 2 g. Cortisol rose from 10.1 +/- 3.3 to 20.0 +/- 3.7 micrograms/100 ml (P less than 0.001 by t test) in six of the seven studies using 10 g and three of the four studies using 2 g. In eight studies, there was a significant rise of more than one substance after tryptophan administration. In six of these, peak values of the responding hormones occurred at the same time or within a single 30-min sampling interval despite the absence of a constant relationship between their rises. The results suggest participation of the central serotonergic nervous system in the control of renin and aldosterone in addition to its previously postulated role in cortisol release.

The circadian periodicity of plasma renin activity (PRA) during continuous recumbency was determined five times in a patient with primary hyperaldosteronism. All curves were parallel with one another. There were significant elevations of PRA at 1600-2000 h, falls at 2400 h, and peaks at 0200-0800 h. This periodicity was uninfluenced by changes in baseline PRA, serum potassium concentration, salt intake, plasma volume, blood pressure, or mineralocorticoid effect. It persisted despite inability of the patient to sleep on two nights. It is suggested that the observed periodicity of renin is a true endogenous diurnal rhythm of possible central nervous system origin.

Plasma renin activity (PRA) was measured every 4 h during a 24-h period of continuous recumbency in 10 patients with essential hypertension. All had maximum values at 12 midnight, 4 AM or 8 AM. Analysis of our date and that of others indicates that in some patients with "low renin" hypertension (LRH) these noctural peaks are of normal magnitude, occasionally exceeding values obtained after four hours of erect posture. Sleep-induced renin release in these patients is not suppressed despite blunted responses to other stimuli. This suggests that the ability to synthesize and release renin may be normal in these patients. Such peaks were not obserived in all LRH subjects, however. The area enclosed by the recumbent PRA curve was also normal in some, but not all patients with LRH. Low renin hypertension may not be a homogeneous disorder.

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Intravenous hydralazine, 0.15, 0.30 or 0.60 mg/kg, was administered to 11 supine hypertensives on two occasions: once after pretreatment with intravenous propranolol, 0.1 mg/kg, and once after pretreatment with intravenous placebo. The average fall in mean arterial pressure for each dosage of hydralazine was no different with or without propranolol, even though propranolol inhibited rises in plasma renin activity and pulse due to hydralazine. However, in each of four patients who had high supine baseline plasma renin activity, propranolol enhanced the fall in blood pressure caused by hydralazine. A second group of patients was given an infusion of 0.01 or 0.02 mg/kg per minute phentolamine, which did not change baseline blood pressure. Subsequent administration of intravenous hydralazine, 0.15 mg/kg, resulted in a fall in blood pressure which was larger than previously observed with intravenous hydralazine alone, regardless of supine baseline plasma renin activity. These data are consistent with the hypothesis that reflex catecholamine release interferes with the hypotensive effect of intravenous hydralazine. Pretreating with propranolol weakens homeostatic defenses against hydralazine such as rises in pulse rate and plasma renin activity. However, propranolol appears to enhance the alpha-adrenergic effect of released catecholamines, and the antihypertensive response to hydralazine is unaltered. In patients with high supine plasma renin activity, propranolol potentiates the fall in blood pressure induced by hydralazine, perhaps because the hypertension in such patients is renin dependent.