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.

Synergistic effects of combined converting enzyme inhibition and angiotensin II antagonism on blood pressure in conscious telemetered spontaneously hypertensive rats.

OBJECTIVE: To investigate the chronic effects of combined administration of an angiotensin II receptor antagonist (valsartan) and an angiotensin converting enzyme inhibitor (benazeprilat) on blood pressure and heart rate in conscious telemetered spontaneously hypertensive rats. METHODS: Blood pressure and heart rate were monitored (by radiotelemetry) during 2-week infusions of 0.5-10 mg/kg valsartan per day and 0.5-10 mg/kg benazeprilat per day, alone or in combination, into conscious spontaneously hypertensive rats. Also, responses of blood pressure in conscious spontaneously hypertensive rats to exogenous angiotensin I and II were determined. RESULTS: Synergistic antihypertensive effects were observed when valsartan and benazeprilat were coadministered at submaximal monotherapy doses in the range 0.5-1.5 mg/kg per day. For all combination groups, the area over the curve (mmHg x days) for lowering of blood pressure was significantly greater (synergy) than that predicted from the sum of the monotherapy responses. Combination therapy abrogated pressor responses to angiotensin I more effectively than did comparable doses of the monotherapies. CONCLUSIONS: These results demonstrate that combination therapy aimed at interrupting operation of the renin-angiotensin system simultaneously at multiple sites can prevent the partial escape which occurs during chronic angiotensin converting enzyme inhibitor monotherapy. Furthermore, multiple-site intervention results in a more efficacious antihypertensive response than that achieved with high doses of the individual monotherapies.

Effects of valsartan and hydrochlorothiazide alone and in combination on blood pressure and heart rate in conscious-telemetered spontaneously hypertensive rats (SHR).

The purpose of this study was to examine the effectiveness of combined administration of the angiotensin AT1 receptor antagonist valsartan, with the diuretic hydrochlorothiazide (HCTZ), on blood pressure in conscious spontaneously hypertensive rats (SHR). Both drugs were administered continuously via subcutaneously implanted osmotic minipumps alone or in combination for a period of 2 weeks. Mean arterial pressure and heart rate were monitored throughout the infusion interval by means of chronically-implanted radiotransmitters. Coadministration of a diuretic with valsartan potentiated the blood pressure lowering effect in conscious SHR. Responses varied in magnitude from additive (valsartan at 1 mg/kg/day + hydrochlorothiazide at 3 and 10 mg/kg/day) to synergistic (valsartan at 3 mg/kg/day + hydrochlorothiazide at 10 mg/kg/day). The greater blood pressure lowering seen in SHR receiving combination therapy was associated with only a transient increase in heart rate. A similar potentiation of the antihypertensive effect was seen during coadministration of hydrochlorothiazide (HCTZ) with the angiotensin converting enzyme inhibitor benazeprilat. Additivity was noted with benazeprilat at 1 mg/kg/day + hydrochlorothiazide at 3 mg/kg/day, whereas a higher dose of HCTZ resulted in a synergistic response. These findings suggest that the similar results obtained with angiotensin converting enzyme inhibitors and AT1 receptor antagonists are due to the capacity to which diuretic-induced activation of the renin angiotensin system occurs.

Effects of the ETB-selective antagonist IRL 2500 in conscious spontaneously hypertensive and Wistar-Kyoto rats.

The pharmacologic profile of a novel and selective ETB antagonist, IRL 2500 (N-(3,5-dimethylbenzoyl)-N-methyl-(D)-(4-phenylphenyl)-alany l-L-tryptophan) was examined in conscious spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) rats. The initial vasodepressor response to endothelin-1 (ET-1) and IRL 1620 (0.5 nmol/kg, i.v.) was significantly reduced in conscious WKY rats pretreated with IRL 2500 (10 mg/kg, i.v.). The secondary and sustained pressor response to these agonists, however, was not altered by IRL 2500. The linear peptide antagonist BQ 788, although also inhibiting the initial depressor responses, attenuated the secondary pressor response to IRL 1620 and potentiated the pressor response to ET-1. IRL 2500, administered alone to naive conscious SHRs produced a -37 +/- 8 mm Hg reduction in blood pressure, followed by a secondary pressor response (+38 +/- 7 mm Hg) with a duration exceeding 90 min. Pretreatment with either the ETA-selective antagonist BQ 123 or with the nonselective ETA/ETB antagonist SB 209670 resulted in marked potentiation of the depressor response and significant attenuation of the secondary rise in pressure. These results indicate that in the conscious rat, IRL 2500 acts as an ETB1-selective antagonist. In addition, ETA receptor activation contributes to the sustained pressore response to IRL 2500 in the conscious SHR. Furthermore, IRL 2500 may also exert a non-ET receptor-mediated vasodilation in the SHR.