ANGIOTENSIN-II-INDUCED RESPONSES IN VASCULAR SMOOTH-MUSCLE CELLS - INHIBITION BY NONPEPTIDE RECEPTOR ANTAGONISTS

The present study investigates the effect of angiotensin II and LR-B/081 (-methyl 2-[[4-butyl-2-methyl-6-oxo-5-[[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl] methyl]-1(6H)pyrimidinyl] methyl]-3-thiophenecarboxylate), a novel non-peptide angiotensin II receptor antagonist, on both early and late responses in rat vascular smooth muscle cells. Angiotensin II induced a rapid and transient elevation of inositol trisphosphate intracellular levels, triggered the release of both prostaglandin E(2) and prostaglandin I-2 (EC(50) = 21 +/- 3 and 16 +/- 2 nM, respectively), and, in long-term studies, increased leucine and thymidine incorporation. All angiotensin II effects were antagonized by LR-B/081 and losartan, the reference non-peptide angiotensin AT(1)-selective receptor antagonist, whereas they were unaffected by PD123177 (1-(4-amino-3-methylphenyl)methyl-5-diphenylacetyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine carboxylic acid), a non-peptide angiotensin AT(2)-selective receptor antagonist. LR-B/081 displayed a much higher potency than losartan in inhibiting angiotensin II-induced prostaglandin E(2) (IC50 = 0.15 +/- 0.02 and 39 +/- 9 nM, respectively) and prostaglandin I-2 release (IC50 = 0.18 +/- 0.04 and 134 +/- 30 nM, respectively) and was also more potent in blocking the increase in protein synthesis (IC50 = 242 +/- 119 nM and 1221 +/- 687 nM, respectively). Moreover, LR-B/081 and losartan blocked the response to angiotensin III but failed to inhibit the prostaglandin release stimulated by vasopressin or the mitogenic effect of serum. LR-B/081 and losartan were devoid of intrinsinc agonistic properties in the experimental conditions employed. The present results describe LR-B/081 as a novel, highly specific and potent, non-peptide angiotensin AT(1)-selective receptor antagonist, that is capable of blocking angiotensin II-proliferative responses, which may be of relevance for cardiovascular diseases.