3h-imidazo(4-5-b)pyridine--2-butyl-3-((2--(1h-tetrazol-5-yl)(1-1--biphenyl)-4-yl)methyl)---sodium-salt and Hypertension

To clarify the precise mechanisms involved in the reduced coronary flow reserve in hypertension, we compared the effects of the angiotensin II type 1 (AT1) receptor antagonist FK-739 with those of the angiotensin-converting enzyme (ACE) inhibitor enalapril for 6 weeks on the smooth muscle (SM) cell phenotype in intramyocardial arteries from male Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Compared with WKY, SHR showed a significant increase in left ventricular (LV) hypertrophy and fibrosis, blood pressure (BP), and vascular remodeling of the intramyocardial arteries, and a significant decrease in endothelial NO synthase and the contractile-type myosin heavy chain isoform SM2 of the intramyocardial arteries as well as calponin 1 and GATA-6. In the hearts of SHR, both drugs equivalently and significantly reduced BP, which was still significantly higher than that in the WKY groups, and also reduced LV hypertrophy and fibrosis, whereas endothelial NO synthase was significantly restored. Although both drugs showed little effect on the vascular remodeling of the intramyocardial arteries in the SHR hearts, FK-739, but not enalapril, significantly restored SM2 and GATA-6 in the SHR hearts to the same levels as those of the vehicle WKY group. The effects of the two drugs on these indices were not observed in the three WKY hearts. Thus, the AT1 receptor antagonist may modulate the SM cell phenotype toward the contractile-type more effectively than the ACE inhibitor before the morphological changes occur in the intramyocardial arteries of the SHR hearts.

Topics: Actins; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Body Weight; Calcium-Binding Proteins; Calponins; Coronary Vessels; DNA-Binding Proteins; Enalapril; GATA6 Transcription Factor; Heart Rate; Hypertension; Imidazoles; Immunoblotting; Male; Microfilament Proteins; Muscle, Smooth, Vascular; Myosin Heavy Chains; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Pyridines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Transcription Factors

The pharmacological properties of FK 739, a new angiotensin II-receptor antagonist, were examined. FK 739 inhibited the specific binding of [125I]-angiotensin II to rat aortic smooth muscle cell membrane with an IC50 value of 8.6 nM, but did not displace the specific binding of [125I]-angiotensin II to bovine cerebellum membrane. In isolated helical strips of rabbit aorta, FK 739 shifted the concentration-response curve of angiotensin II-induced contraction in parallel to the right, and the values of the slope and pA2 were 1.06 and 8.45, respectively. In in vivo studies, oral administration of FK 739 at 10 mg/kg significantly inhibited the angiotensin I-induced pressor response in normotensive rats and dogs, and it caused a fall of mean blood pressure in renal hypertensive rats and dogs. In spontaneously hypertensive rats, FK 739 at 32 and 100 mg/kg significantly decreased the mean blood pressure in a dose-dependent manner. Additionally, we studied whether FK 739 would cause side effects such as dry cough, like other ACE inhibitors did. Oral administration of FK 739 (10 and 32 mg/kg) did not affect the capsaicin-induced bronchial edema. On the other hand, captopril (10 mg/kg) significantly enhanced capsaicin-induced bronchial edema. These results indicate that FK 739 is a potent and competitive antagonist for AT1-type receptors, and suggest that FK 739 might be a safe and useful agent for the treatment of hypertension in clinical trials.

Topics: Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Blood Pressure; Bronchial Diseases; Cattle; Cell Membrane; Cerebellum; Dogs; Edema; Guinea Pigs; Hypertension; Hypertension, Renovascular; Imidazoles; In Vitro Techniques; Male; Muscle Contraction; Muscle, Smooth, Vascular; Pyridines; Rabbits; Rats; Rats, Inbred SHR; Rats, Wistar