benazeprilat and Body-Weight

Changes in microcirculation play an important role in the pathogenesis and maintenance of hypertension. The changes can be due to an alteration in vessel diameter or in the number of small blood vessels. In this study, the effects of prolonged administration of different blockers of the renin angiotensin system on the microcirculation of the cutaneous maximus muscle of young spontaneously hypertensive rats were determined by using the dorsal microcirculatory chamber model. Animals were treated with the angiotensin-converting enzyme inhibitor (ACE inhibitor) benazeprilat (3 mg/kg/d) or the specific angiotensin II AT1 receptor antagonist valsartan (3 mg/kg/d) for 4 weeks. Blood pressure was significantly lowered by 22 to 33% and to a similar extent in both treatment groups, whereas blood pressure in the control group continued to rise. Microvascular diameters and density were measured before and during the drug treatment and compared with those in the control group. There was no significant effect of either of the drug treatments on vascular diameters when compared with the control group for any vessel type (arterioles or venules). In contrast, there was a significant decrease in small arteriolar and venular density and in large venular density after treatment with the ACE inhibitor, whereas the angiotensin II AT1 receptor antagonist had no significant effect. The data do not suggest a role for angiotensin II in the long-term control of striated muscle microvascular tone. However, angiotensin II may be involved in microvascular growth via a non-AT1 receptor-mediated mechanism, or other vasoactive peptides degraded by ACE may contribute to the effects of the ACE inhibitor.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Benzazepines; Body Weight; Hemodynamics; Hypertension; Male; Microcirculation; Muscle, Skeletal; Rats; Rats, Inbred SHR; Renin-Angiotensin System; Tetrazoles; Time Factors; Valine; Valsartan

The present study examines the effects of prolonged angiotensin II antagonism in spontaneously hypertensive rats by using an angiotensin II receptor antagonist (DuP 753) that is devoid of agonistic properties and selective for the subtype 1 of the angiotensin II (AT1) receptor. The antihypertensive effects of DuP 753 and its effects on circulating parameters of the renin-angiotensin system were compared with those of a converting enzyme inhibitor (benazeprilat). To minimize any influence of differences in the pharmacokinetic properties of the two blockers, administration was by continuous intravenous infusion. The experiments were performed in conscious, freely moving rats with continuous 24-hour monitoring of blood pressure. DuP 753 (10 or 30 mg/kg/day) lowered mean arterial pressure to the same extent as benazeprilat (3 or 10 mg/kg/day) during a 48-hour period. The antihypertensive effect was sustained when the treatment was extended to 7 days (DuP 753, 10 mg/kg/day; benazeprilat, 3 mg/kg/day). Neither of the compounds affected the baseline or diurnal rhythm of heart rate. Plasma concentrations of renin and angiotensin II were increased sevenfold and 10-fold, respectively, in the rats treated with DuP 753. In rats treated with benazeprilat, plasma renin concentration increased threefold, whereas angiotensin II was unchanged. Heart weights were significantly reduced to a similar extent by DuP 753 and benazeprilat. Both compounds also induced a smaller but significant decrease in blood pressure in Wistar-Kyoto rats. Our results indicate that the antihypertensive effects of converting enzyme inhibitors in spontaneously hypertensive rats are mainly due to the blockade of the renin-angiotensin system. In this rat model, angiotensin II appears to play an important role in the maintenance of hypertension that is mediated via the AT1 receptor.

Topics: Angiotensin I; Angiotensin II; Animals; Antihypertensive Agents; Benzazepines; Biphenyl Compounds; Blood Pressure; Body Weight; Dose-Response Relationship, Drug; Hemodynamics; Imidazoles; Losartan; Male; Myocardium; Nephrectomy; Organ Size; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Tetrazoles; Time Factors