Angiotensin II-induced responses in vascular smooth muscle cells: inhibition by non-peptide receptor antagonists

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The present study investigates the effect of angiotensin II and LR-B/081 (-methyl 2-[[4-butyl-2-methyl-6-oxo-5-[[2′-(1 H-tetra-zol-5-yl) [1,1′-biphenyl]-4-yl] methyl]-1(6 H)-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-1 H-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 (IC 50 = 0.15 ± 0.02 and 39 ± 9 nM, respectively) and prostaglandin I 2 release (IC 50 = 0.18 ± 0.04 and 134 ± 40 nM, respectively) and was also more potent in blocking the increase in protein synthesis (IC 50 = 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.