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.
Paré
M C
MC
Department of Pharmacology, Faculty of Medicine, University of Sherbrooke, Canada.
Maltais
S
S
Escher
E
E
D000804:Angiotensin II / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D006973:Hypertension / Q000209:etiology* / Q000378:metabolism; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology; D007276:Injections, Intraventricular; D019808:Losartan; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D011945:Receptors, Angiotensin / Q000378:metabolism*; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology
D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D007093:Imidazoles; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000804:Angiotensin II; D019808:Losartan