Effects of YM358, an angiotensin II type 1 (AT(1)) receptor antagonist, and enalapril on blood pressure and vasoconstriction in two renal hypertension models

The effects of the angiotensin II type 1 receptor antagonist YM358 on blood pressure were compared to those of the angiotensin converting enzyme inhib itor enalapril in one-kidney, one-clip renal hypertensive rats (1K1C RHR), two-kidney, one-clip renal hypertensive rats (2K1C RHR) and normotensive ra ts (NTR). Additionally, the local drug actions in peripheral tissues were i nvestigated using isolated mesenteric arteries from these rats. In 2K1C RHR , YM358 and enalapril produced a long-lasting hypotensive effect in a dose- dependent manner. In 1K1C RHR. YM358 (30 mg/kg) also produced an antihypert ensive effect., whereas enalapril (30 mg/kg) had no effect. Administration of YM358, but not enalapril, to 1K1C RHR, 2K1C RHR and NSR did not affect h eart rate. In isolated mesenteric arteries from 1K1C RHR and 2K1C RHR, angi otensin II (Ang II), angiotensin I (Ang I) and tetradecapeptide (TDP), a ph ysiologically active renin substrate, produced concentration-dependent vaso constriction. YM358 (10(-7) M) inhibited the vasoconstricting responses to Ang II, Ang I and TDP in isolated mesenteric arteries. In contrast, enalapr ilat (10(-7) M), an active metabolite of enalapril, did not completely inhi bit the response to Ang 1 and TDP. These results indicate that YM358 has hi gher efficacy than enalapril for the treatment of hypertension.