The neurogenic origin of hypertension in SHR may be mediated by angiotensin II through a receptor different from AT1 and AT2.

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 AT1 selective, and PD-123177, a receptor AT2 specific compound, do not affect SHR BP following icv administration. The receptor AT1 selective non-peptide Ang antagonists, Losartan and L-158809, induce long-lived (days) significant BP reductions (< or = 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 AT1 and AT2, since it has a selectivity profile different from AT1 and AT2 receptor types.