MethodsAtrial natriuretic factor (ANF), a recently sequenced cardiac peptide, has been shown to have potent natriuretic, diuretic, and vasodilating effects in several species. We have developed a radioimmunoassay to measure the levels of immunoreactive ANF in human plasma. Plasma levels of ANF in healthy volunteers on a low sodium diet were 9.8±1.4 pmol/liter and increased to 21.9±3.0 on a high sodium diet. The levels of atrial natriuretic factor correlated directly with urinary sodium and inversely with plasma renin activity and plasma aldosterone levels. Patients with marked edema due to congestive heart failure had plasma levels of atrial natriuretic factor five times higher than normal (P < 0.05), whereas patients with cirrhosis and edema had levels that were not different from normal. These results suggest that atrial natriuretic factor plays an important role in the adaptation to increased sodium intake.

To study the hemodynamic and metabolic effects of chronic inhibition of endothelium-derived nitric oxide, we treated conscious rats with an oral solution of TV'-nitro-L-arginine (LNA), an inhibitor of nitric oxide production by endothelial cells. After 3 days of treatment with 2.74 mM LNA, rats had higher blood pressures (136±5 versus 113±3 mm Hg, p<0.0005) than did the control animals. This effect was maintained through 7 days of treatment (142±6 versus 109±4 mm Hg,p<0.0005) and in three animals for 35 days (167±7 mm Hg). The blood pressure rise was dose dependent. The hypertensive effect of oral LNA was not enhanced by the administration of 20 mg intraperitoneal LNA and was prevented by pretreatment with L-arginine, although L-arginine also caused a transient but significant increase in urinary sodium excretion. When LNA treatment was discontinued, blood pressure fell gradually, with an effective biological half-life of 4.2 days. Metabolic balance studies did not identify differences in sodium or potassium balance between treated and control animals. Plasma renin activity was lower in LNA-treated animals, and aldosterone concentrations tended to be lower. In contrast, atrial natriuretic factor levels and serum electrolyte concentrations were unchanged after 7 days of treatment with LNA. These data support the premise that endothelium-derived nitric oxide plays an important role in basal hemodynamic homeostasis. Oral administration of LNA may serve as a model of chronic nitric oxide-deficient hypertension and allow for the future study of endothelium dependence in hypertension. (Hypertension 1993^1:359-363) KEY WORDS • nitric oxide • arginine • endothelium-derived relaxing factor N itric oxide (NO) generation by endothelial cells appears to account for a major component of endothelium-dependent relaxing factor activity. NO synthase, the enzyme responsible for NO generation, has recently been cloned from brain tissue.' The enzyme uses arginine as its sole substrate, 2 and several analogues of arginine have been shown to be specific competitive inhibitors of NO production. Supported in part by grant HL-18575 from the National Heart, Lung, and Blood Institute and by grants from the American Heart Association and its Indiana Affiliate. J.D. performed this work during the tenure of a Clinician-Scientist Award from the American Heart Association.Address for correspondence: Jamie Dananberg, MD, Division of Endocrinology, University of Michigan Medical Center, 5570 MSRB-II Box 0678, Ann Arbor, MI 48109-0678.Received January 10,1992; accepted in revised form November 9, 1992. nine (LNA), when administered intravenously, is more potent then L-NMMA in raising blood pressure in the anesthetized rat. 8No studies to date have investigated the effects of NO synthase inhibitors on the intact, conscious animal. Furthermore, all prior work has examined only the intravenous administration of these compounds. In this study, we sought to determine the endocrine, hemodynamic, and metabolic effects of LNA when given orally to other...

Intact and hypophysectomized male rats on low and high sodium diets were treated with sc infused ACTH and alpha MSH, and the levels of aldosterone and corticosterone were determined in truncal blood. Plasma aldosterone levels were lower in hypophysectomized animals on the low sodium diet than in intact animals on the low sodium diet. Alpha MSH (8 micrograms/day) restored plasma levels of aldosterone to normal in hypophysectomized rats on the low sodium diet. ACTH (6 micrograms/day) did not cause significant changes in plasma levels of aldosterone in hypophysectomized animals. ACTH restored plasma corticosterone to normal in hypophysectomized rats, whereas alpha MSH had no effect on corticosterone. Alpha MSH did not increase plasma aldosterone levels in intact rats. These data suggest that alpha MSH may be important in the regulation of aldosterone secretion in the rat and that zona glomerulosa responsiveness to alpha MSH in vivo is increased by hypophysectomy. The mechanisms of alpha MSH action on glomerulosa cells are different from those of ACTH.

Increased visceral fat accumulation is a strong predictor of arterial hypertension. In this study, we explored the hypothesis that increased hepatic portal venous free fatty acid delivery results in increased blood pressure. Such an effect might explain the link between visceral obesity and hypertension. In nine conscious, instrumented rats, we studied the effects of 1-hour infusions of sodium oleate solution into the portal and femoral veins and infusions of sodium caprylate solution into the portal vein on 3 separate days. Basal blood pressure was not significantly different on the 3 study days. Mean arterial pressure increased 29 +/- 4 mm Hg during portal oleate infusion and 13 +/- 2 mm Hg during femoral oleate infusion (both significant increases over basal, P < .001). Mean arterial pressure did not change during portal caprylate infusion. The increase during portal oleate infusion was greater than that during femoral oleate infusion (P = .028). Heart rate rose during all three infusions; the increase was greatest during portal oleate infusion (334 +/- 4 to 412 +/- 2 beats per minute). During portal venous oleate infusion in five rats, plasma norepinephrine rose from 2.17 +/- 0.34 to 3.58 +/- 0.50 nmol/L, epinephrine rose from 0.79 +/- 0.28 to 1.84 +/- 0.44 nmol/L, and corticosterone rose from 147 +/- 55 to 1130 +/- 289 nmol/L. Three rats given portal venous oleate infusions for 1 week had increased blood pressure compared with baseline (mean increase, 16 +/- 4 mm Hg). These studies indicate that increases in portal venous fatty acid concentrations have significant pressor effects, perhaps mediated by increased sympathetic tone.(ABSTRACT TRUNCATED AT 250 WORDS)