FK-739

We compared the cardiac effects of the selective angiotensin II type 1 (AT1)-receptor blockade, FK-739, with an angiotensin-converting-enzyme (ACE) inhibitor, enalapril, on left ventricular (LV) distensibility and collagen metabolism in spontaneously hypertensive rats (SHRs). We treated 14-week-old SHRs with FK-739 (30 mg/kg/day) or enalapril (10 mg/kg/day) for 6 weeks. Both FK-739 and enalapril induced a significant decrease in blood pressure (p < 0.001) and regression of LV hypertrophy (p < 0.001) compared with vehicle, with no differences between the treated groups. Furthermore, FK-739 caused a greater decrease in LV collagen content than did enalapril (FK-739-treated group, 3.06 +/- 0.11 mg/g; enalapril-treated group, 3.47 +/- 0.05 mg/g; p = 0.015) with no change in collagen phenotypes. Hearts taken from rats treated with FK-739 also showed greater LV distensibility than those taken from enalapril-treated rats (FK-739-treated group vs. enalapril-treated group at > or = 15 mm Hg, p < 0.001). These results suggest that, compared with ACE inhibition, AT1-receptor blockade may have additional effects on LV distensibility and collagen metabolism in the regression of LV hypertrophy induced by pressure overload.

Angiotensin AT1 receptor antagonists are divided into two types, surmountable and insurmountable, based on the way they inhibit angiotensin II-induced vasoconstriction. To elucidate what causes the difference, we studied how antagonists associate with and dissociate from AT1 receptor sites in rat liver membranes. Three antagonists, 6-propyl-7-oxo-4[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-4,7- dihydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid (SRL1080227), 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H- benzimidazole-7-carboxylic acid (CV-11974) and 2-butyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-3H-imidazo- [4,5-b]pyridine (FK739), showed competitive antagonism when they were added simultaneously with [125I]angiotensin II, but CV11974 and SRL1080227 showed apparently noncompetitive antagonism when membranes were preincubated with each antagonist. The longer the preincubation time with CV11974 or SRL1080227 was, the more effectively the antagonist inhibited [125I]angiotensin II binding, while the inhibition by FK739 did not change with the preincubation time. To estimate their dissociation rate from the receptor binding site, we studied [125I]angiotensin II binding to membranes which had been preincubated with each antagonist and washed twice. Membranes pretreated with FK739 completely recovered the ability to bind [125I]angiotensin II with a period of 60 min, while membranes preincubated with CV11974 did not read this level of recovery. [125I]angiotensin II binding to membranes preincubated with SRL1080227 increased gradually, but did not reach the control level during the experiment. The kinetic properties of SRL1080227, CV11974 and FK739 were consistent with their characteristic modes in inhibiting angiotensin II-induced contraction of isolated rabbit aorta and decreasing blood pressure of spontaneously hypertensive rats.(ABSTRACT TRUNCATED AT 250 WORDS)