Renal hemodynamic and excretory responses to renin inhibition induced by A-64662.

Experiments were conducted in sodium-depleted anesthetized monkeys to determine the effects of the primate-selective renin inhibitor A-64662 on renal function. Five groups of monkeys were examined with each group receiving an i.v.

Intraocular pressure lowering effects of the renin inhibitor ABBOTT-64662 diacetate in animals.

Corneal application of enalkiren (ABBOTT-64662), [N-(3-amino-3-methyl-1- oxobutyl)-4-methoxy-L-phenylalanyl]-N-[1S,2R,3S)-1-(cyclohexylmethyl+ ++)-2,3- dihydroxy-5-methylhexyl]-L-histidinamide], a renin inhibitor compound, lowered intraocular pressure (IOP) in unanesthetized rabbits and anesthetized monkeys. IOP was significantly decreased for at least 60 minutes after administration of a 0.3% solution of enalkiren in monkeys and for at least 90 minutes after the administration of 0.

Effects of chronic infusion of renin inhibitor A-64662 in sodium-depleted monkeys.

The potent and primate-selective renin inhibitor A-64662 (n = 8) or vehicle (n = 6) was administered intravenously for 7 days to sodium-depleted cynomolgus monkeys to investigate the chronic effects on arterial pressure, sodium excretion, and the renin-angiotensin-aldosterone system. A 0.1-mg/kg i.

Cardiovascular actions of the primate-selective renin inhibitor, A-62198.

A-62198 [dimethylacetyl-Phe-His-NHCH(cyclohexylmethyl)CH-(OH)C H(OH)CH2N3] is a potent, selective inhibitor of primate renin. This compound induced a dose-dependent fall in mean arterial blood pressure (MAP) when administered as an i.v.

Effects of the renin inhibitor A-64662 in monkeys and rats with varying baseline plasma renin activity.

The efficacy of the potent, primate selective renin inhibitor A-64662 was studied in monkeys and rats with varying baseline plasma renin activity (PRA) to elucidate the relationship between PRA and the hypotensive response induced by this compound. The effect of a single bolus of vehicle or A-64662 at 0.001, 0.

Regulation of renal Na+-K+-ATPase in the rat: role of increased potassium transport.

The purpose of this study was to characterize the alterations in collecting tubule Na+-K+-ATPase activity produced by sustained increments in dietary potassium in the rat and to evaluate the role of aldosterone in their generation. In adrenal-intact animals, feeding a high-potassium diet (10-fold that of control) or administration of a high physiological dose of aldosterone (5 micrograms X 100 g-1 X day-1), which simulates the delivery rate of this hormone during potassium loading (both for 7 days), caused marked increments in Na+-K+-ATPase activity in the cortical collecting tubule (CCT) but had no effect on the enzyme in the inner stripe of the medullary collecting tubule (MCT). A significant increase in enzyme activity was also observed after smaller dietary potassium increments (2.

Modulation of renal sodium-potassium-adenosine triphosphatase by aldosterone. Effect of high physiologic levels on enzyme activity in isolated rat and rabbit tubules.

The purpose of this study was to determine the nephron site, time course, and mechanism of mineralocorticoid action on renal tubular Na-K-ATPase in rats and rabbits, without dietary manipulation and by using the natural mineralocorticoid aldosterone. Sustained, high physiologic levels of circulating aldosterone mimicking those produced endogenously during potassium loading or sodium deprivation were provided by constant delivery of the hormone in doses of 5 or 50 micrograms/100 g body wt per 24 h, respectively, from osmotic minipumps implanted subcutaneously. In adrenal-intact rats receiving the 5-microgram dose, aldosterone levels were similar to those seen in animals fed a high K diet and produced a time-dependent increase in Na-K-ATPase activity in the cortical-collecting tubule (CCT) to a level 103% higher than in controls after 7 d (2,007 +/- 178 vs.

Relationship between adrenal steroids and renal Na-K-ATPase. Effect of short-term hormone administration on the rat cortical collecting tubule.

Mineralo- and glucocorticoids stimulate renal Na-K-ATPase activity if given over a few days, but their immediate effect on the enzyme (i.e. within the time period required to alter electrolyte transport) remains controversial.

Regulation of renal Na-K-ATPase in the rat. Role of the natural mineralo- and glucocorticoid hormones.

Both mineralo- and glucocorticoids stimulate renal Na-K-ATPase, but their relative role in the regulation of the enzyme remains controversial. In this study we measured Na-K-ATPase activity in the cortical collecting tubule (CCT) of adrenalectomized rats replaced with either the native mineralocorticoid (aldosterone) or glucocorticoid (corticosterone) in doses calculated to yield previously determined physiologic concentrations of these hormones (5 ng X dl-1 and 5 micrograms X dl-1, respectively). This was achieved by continuous delivery of aldosterone (1 microgram X 100 g-1 X d-1) from an osmotic minipump or of corticosterone (2 pellets of 20 mg each), implanted subcutaneously either at adrenalectomy or 7 d later, when Na-K-ATPase activity reached its nadir.

Corticosterone binding sites along the rat nephron.

Glucocorticoids influence numerous kidney functions but the precise location of glucocorticoid receptors in the nephron is not known. To identify the renal binding sites of corticosterone, the natural glucocorticoid in the rat, we measured the binding of [3H]corticosterone to discrete nephron segments microdissected from adrenalectomized rats. Highest specific binding capacity at 25 degrees C (expressed as fmol X cm-1 +/- SE) was found in the cortical collecting tubule (9.