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This study investigated the ability of the selective angiotensin II (AII)-type (AT)1 receptor antagonist losartan to reverse the fast (< 30 sec) pressor effect of AII, and the hypertension produced by chronic (2 weeks) i.v. infusion of AII (AII hypertension). We hypothesized the following: if AII hypertension is caused solely by stimulation of AT1 receptors mediating the fast pressor effect, then the time course of the antihypertensive effect of losartan in AII hypertension should parallel the time course of losartan inhibition of pressor responses to acute, bolus injection of AII. Thus, in one group of rats, pressor responses to bolus injections of AII (10 ng, n = 10) were measured before and subsequently at numerous time points after losartan administration (3 mg.kg-1 i.v.). Other groups of rats received continuous infusions of AII i.v. for 15 days at 2 ng.min-1 (n = 8), 4 ng.min-1 (n = 8) or 10 ng.min-1 (n = 6). On days 2, 7 and 12 of the AII infusion, rats received a bolus injection of losartan (3 mg.kg-1, i.a.). Mean arterial pressure (MAP) was then measured at numerous time points after losartan administration. Within 5 min of administration, losartan caused almost complete inhibition of fast pressor responses to acute injections of AII, and the magnitude of this inhibition did not change for over 24 hr. On the other hand, in AII hypertension, losartan lowered MAP significantly within 5 min only in rats receiving 10 ng.min-1 AII, but in all three groups caused a slower decline in MAP that peaked around 2 hr after losartan injection.(ABSTRACT TRUNCATED AT 250 WORDS)

The authors recently reported that renovascular hypertension (RVH) in rats is associated with enhanced responsiveness to the slow pressor effect of angiotensin II (AngII). It was concluded that the contribution of AngII to the development of hypertension could not be inferred solely from measurements of plasma peptide concentrations. This experiment was performed to test the corollary hypothesis that the antihypertensive efficacy of angiotensin-converting enzyme inhibitors in established RVH could be caused in part by inhibition of the slow pressor effect. After five control days of measurement of mean arterial pressure (MAP) and other variables, RVH rats were given the angiotensin-converting enzyme inhibitor enalapril in their drinking water. Half of these rats also received a continuous infusion of AngII, 4 ng/min i.v., an infusion rate previously shown to restore normal MAP in normal rats rendered hypotensive by chronic treatment with enalapril. Other RVH rats were given the potent vasodilator minoxidil in their drinking water, and half of these received AngII. Treatments lasted 7 days and were followed by 5 days without intervention. Enalapril significantly reduced MAP, but concurrent AngII infusion overcame this effect; MAP remained at control hypertensive levels. AngII did not affect the antihypertensive response to minoxidil. These results confirm that addition of relatively modest amounts of AngII to the circulation is able to maintain elevated blood pressure in RVH. Thus, inhibition of the slow pressor effect of AngII may partially explain the antihypertensive effect of angiotensin-converting enzyme inhibitors in RVH.

The effects of dl-propranolol, d-propranolol, butoxamine or practolol on erythropoietin (ESF) production in rabbits exposed to hypoxia (0.42 atmosphere) for 18 hours were investigated. Rabbits treated with dl-propranolol (4 or 8 mg/kg i.p.) or butoxamine (15 or 30 mg/kg i.p.) produced significantly less ESF in response to hypoxia than did saline-treated control animals. ESF production in rabbits given d-propranolol or practolol during hypoxia was not significantly different from that of control animals exposed to hypoxia. Based on the proposed selectivity of butoxamine for beta2 adrenergic receptors and of practolol for beta1 adrenergic receptors, it is suggested that ESF production in rabbits exposed to hypoxia may involve the activation of beta2 adrenergic receptors.

The erythropoietic effects of the renal prostaglandins were investigated in exhypoxic polycythemic mice and in isolated perfused dog kidneys. Prostaglandins A2 and E2 in a dose range of 100 to 800 mug/kg b.wt. were found to produce a dose-related increase in radioactive iron incorporation in red cells. Prostaglandin F2 alpha was devoid of an erythropoietic effect in polycythemic mice. In that PGE2 is the principal renal prostaglandin, PGE2 (0.5 mug/min) or saline was infused into isolated perfused dog kidneys that had been programmed by prior exposure to hypoxia (0.42 atm) for 4 hours. PGE2-infused kidneys during 5 hours of perfusion with blood from nonhypoxic donor dogs produced significant increases in perfusate titers of erythropoietin when compared with that of saline infusion controls at the same time intervals. These data suggest an involvement of the renal prostaglandin PGE2 in erythropoietin production by the kidney.

Circulating angiotensin II (ANG II) has several physiological effects that result from interaction of the peptide with AT1 receptors in the brain. Our purpose was to determine if selective pharmacological blockade of brain AT1 receptors would reverse chronic low-dose ANG II-induced hypertension. Male Sprague-Dawley rats were instrumented with chronic indwelling arterial and venous catheters and a lateral intracerebroventricular (i.c.v.) cannula. All rats received ANG II i.v. for 15 days at a dose of 4 ng.min-1. On days 2, 7 and 12 of the ANG II infusion a bolus of an AT1 receptor antagonist, the active metabolite of losartan, EXP 3174 (1 microgram in 2 microliters of saline, i.c.v.; n = 5) or vehicle (2 microliters of saline; n = 2) was administered into the cerebrospinal fluid. Mean arterial pressure and heart rate were measured at numerous time points after this injection. Although the dose of EXP 3174 used in preliminary experiments was shown to block the responses to i.c.v. ANG II this treatment did not lower MAP in chronic ANG II-hypertension. These results suggested that either ANG II-hypertension does not involve brain AT1 receptors, or that i.c.v. EXP 3174 may not gain access to brain sites at which circulating ANG II acts to produce hypertension. To test this latter possibility ANG II was microinjected into the area postrema of anesthetized rats. The area postrema is one of several circumventricular organs at which circulating ANG II may act to influence arterial pressure regulation.(ABSTRACT TRUNCATED AT 250 WORDS)

A reduction in functioning renal mass through surgical ablation leads to the development of hypertension and chronic renal failure in rats. Reduced renal mass (RRM) hypertension is more severe and develops more quickly if rats are on high salt intake. It has previously been shown that hypertension in these rats can be prevented by treatment with angiotensin-converting enzyme inhibitors. The current experiment examined the effect of losartan, an angiotensin II antagonist, on blood pressure in RRM and intact rats after a 3-fold increase in salt intake. It was found that chronic treatment with i.v. losartan (3 mg/kg/day) completely prevented sodium-induced hypertension in the RRM rats, whereas neither increased salt intake nor losartan treatment affected blood pressure in the intact rats. The antihypertensive effect of losartan was associated with an apparent renoprotective effect in RRM rats (blood urea nitrogen concentration rose in untreated animals, but remained stable in treated animals), but was not accompanied by chronic changes in water or sodium balance. The ability of losartan to prevent RRM hypertension suggests that angiotensin II is necessary for the development of this model of hypertension.