Protective effects of valsartan and benazeprilat in salt-loaded stroke-prone spontaneously hypertensive rats.

These experiments examined the effectiveness of chronic blockade of the renin angiotensin system with either valsartan or benazeprilat on survival, blood pressure and end-organ damage in salt-loaded stroke-prone SHR. Valsartan or benazeprilat given continuously by subcutaneous osmotic minipump beginning at 10.5 weeks of age lowered blood pressure, as determined by radiotelemetry, prevented proteinuria, prolonged survival and decreased the severity of histopathological changes in the heart and kidney. These results indicate that angiotensin receptor blockade affords a similar degree of protection as inhibition of angiotensin converting enzyme in salt-loaded stroke-prone SHR. Furthermore, our results are consistent with a primary contribution of angiotensin II to the maintenance of blood pressure and support a principal role for angiotensin II-dependent mechanisms in the development of end-organ damage in the salt-loaded stroke-prone SHR.

Cardiovascular effects of adenosine A2 agonists in the conscious spontaneously hypertensive rat: a comparative study of three structurally distinct ligands.

The hemodynamic responses to 5'-N-ethylcarboxamide adenosine (NECA), a nonselective adenosine agonist, were compared to those elicited by the sodium salt of 2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamido adenosine (CGS 21680C) and N6-2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)-ethyl adenosine (CGS 24012), two structurally dissimilar selective A2 agonists in conscious spontaneously hypertensive rats (SHR). Dose-related reductions in mean arterial pressure occurred after bolus administration of NECA, CGS 21680C and CGS 24012. Dose-dependent tachycardia was seen with both CGS 21680C and CGS 24012, whereas NECA produced a biphasic response on heart rate. At high doses (3 and 10 micrograms/kg), NECA evoked an immediate and dramatic fall in heart rate, followed by a more gradual and long-lasting tachycardia. At equihypotensive doses, both CGS 21680C and CGS 24012 produced significant increases in cardiac output, but NECA had no effect. Although each of the adenosine agonists reduced total peripheral resistance, the greatest change was produced by CGS 21680C. Hindquarter, renal and mesenteric vascular resistances were significantly reduced by both CGS 21680C and CGS 24012, whereas only mesenteric vascular resistance was reduced with NECA. CGS 24012 reduced renal vascular resistance to the greatest extent and produced a concomitant significant increase in renal blood flow. Marked elevation in plasma renin activity occurred with CGS 24012 and CGS 21680C, whereas no change was seen after NECA. The hemodynamic responses to NECA, CGS 21680C and CGS 24012 were significantly reduced by the adenosine antagonist, 8-(p-sulfophenyl) theophylline, suggesting that these agents act through stimulation of adenosine receptors in the conscious SHR. Furthermore, blockade of the beta adrenergic receptor with metoprolol (1 mg/kg, i.v.) significantly attenuated the increase in heart rate produced by NECA, CGS 21680C and CGS 24012. The cardiovascular pattern of responses to the two selective A2 agonists, CGS 21680C and CGS 24012, are distinct from those of NECA, the nonselective adenosine agonist. The responses to both CGS 21680C and CGS 24012 indicate that systemic vasodilation, with resultant cardioexcitation and stimulation of renin release, are the predominant hemodynamic effects of selective A2 agonists in the conscious SHR. In contrast, the cardiovascular effects produced by NECA are mediated by activation of both A1 and A2 receptors.

Hemodynamic effects of adenosine agonists in the conscious spontaneously hypertensive rat.

The present studies examined the underlying hemodynamic mechanisms contributing to the reduction in blood pressure observed in conscious spontaneously hypertensive rats after systemic administration of adenosine agonists. The effects produced by i.v. and i.a. injections of 2-phenylaminoadenosine [CV-1808, adenosine (A2) selective agonist], 5'-N-ethylcarboxamide adenosine (NECA, nonselective agonist), 2-chloroadenosine (2-CADO, A1 selective agonist) and cyclopentyladenosine (CPA, A1 selective agonist) were evaluated and compared to those of hydralazine. All agents produced hypotensive effects after bolus i.v. injection. Although CPA, NECA and 2-CADO elicited dose-dependent bradycardia, CV-1808 and hydralazine increased heart rate. These effects, with the exception of the hydralazine-evoked responses, were attenuated by prior treatment with 8-(p-sulfophenyl)theophylline (2 mg/kg/min), whereas both CV-1808 and hydralazine produced regional vasodilation, significant increases in blood flow occurred only after CV-1808 (3-30 micrograms/kg). The regional hemodynamic responses to NECA were more complex; low doses (0.1-1 microgram/kg) produced consistent reductions in regional vascular resistance, whereas at the highest dose renal vasoconstriction occurred. Although regional vasodilation occurred after 2-CADO, mesenteric vasoconstriction was observed subsequent to CPA administration. Whereas a significant increase in renin release was evident in animals treated with CV-1808 and hydralazine, no change occurred in response to the NECA-, 2-CADO- or CPA-induced hypotension. We conclude that the predominant hemodynamic response after selective activation of A2 receptors is one of regional vasodilation and hypotension leading to a reflex increase in heart rate and renin release.(ABSTRACT TRUNCATED AT 250 WORDS)

Central and peripheral inhibition of angiotensin converting enzyme (ACE) in the SHR: correlation with the antihypertensive activity of ACE inhibitors.

A series of five structurally distinct ACE inhibitors were evaluated for their ability to inhibit tissue ACE activity in the SHR after oral administration. In the first series of experiments, the ACE inhibitors captopril, enalapril, pentopril, CGS 14824A and CGS 16617 were given to groups of SHR at doses that produced a 15 to 20 mm Hg reduction in blood pressure within 1 hour. Under these conditions of dose and time, only captopril significantly inhibited brain ACE activity (43%), whereas inhibition of serum ACE activity ranged from 72% to 99% with these agents. Inhibition of aortic ACE activity ranged from 54% to 87%, and lung ACE inhibition varied from 50% to 83%. In the second series of experiments, SHR were administered higher doses of each ACE inhibitor such that these compounds produced peak reductions in blood pressure (-25 mm Hg to -33 mm Hg) within a range of 2 to 6 hours. When tissue ACE activity was measured at the time corresponding to peak reduction in blood pressure, all five ACE inhibitors produced a significant inhibition of brain ACE activity ranging from 21% to 76%. Serum ACE activity was almost completely inhibited by these agents, with the exception of captopril (62% inhibition). The inhibition of aortic ACE activity ranged from 79% to 99%, while the inhibition of lung ACE activity did not increase under these conditions. These data suggest that ACE inhibitors may exert their maximal antihypertensive effects by inhibiting ACE in vascular tissues and brain.