The neurogenic origin of hypertension in SHR may be mediated by angiotensin II through a receptor different from AT 1 and AT 2

Abstract

In spontaneously hypertensive rats (SHR) 15–18 weeks old, the intracerebroventricular (icv) administration of peptide angiotensin II (Ang) antagonists results in a short (30–60 min) decrease (15–25 mmHg) of blood pressure (BP). Both EXP-3174, a known metabolite of Losartan and AT 1 selective, and PD-123177, a receptor AT 2 specific compound, do not affect SHR BP following icv administration. The recoptor AT 1 selective non-peptide Ang antagonists, Losartan and L-158809, induce long-lived (days) significant BP reductions (≤ 40 mmHg) in SHR, but only 18 h after icv injection. The slow development of BP reduction and its persistence might be due to the formation of an active metabolite, different from EXP-3174, a Losartan metabolite. In older SHR (25–28 weeks), the hypotensive effect of Losartan and L-158809 is not significant. These results suggest that in the CNS of the young SHR, an active Renin-Ang-System is implicated in the establishment of the hypertensive state, and that the receptor for this function is different from AT 1 and AT 2, since it has a selectivity profile different from AT 1 and AT 2 receptor types.