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/0 81 (-methyl [[4-butyl-2-methyl-6-oxo-5-[[2'-(1H-tetrazol-5-yl) [1,1'-b iphenyl]-4-yl] methyl]-1(6H)pyrimidinyl] methyl]-3-thiophenecarboxylat e), a novel non-peptide angiotensin II receptor antagonist, on both ea rly and late responses in rat vascular smooth muscle cells. Angiotensi n 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, respective ly), and, in long-term studies, increased leucine and thymidine incorp oration. All angiotensin II effects were antagonized by LR-B/081 and l osartan, the reference non-peptide angiotensin AT(1)-selective recepto r antagonist, whereas they were unaffected by PD123177 cetyl-4,5,6,7-t etrahydro-1H-imidazo[4,5-c]pyridine carboxylic acid), a non-peptide an giotensin AT(2)-selective receptor antagonist. LR-B/081 displayed a mu ch higher potency than losartan in inhibiting angiotensin II-induced p rostaglandin 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 p rotein synthesis (IC50 = 242 +/- 119 nM and 1221 +/- 687 nM, respectiv ely). Moreover, LR-B/081 and losartan blocked the response to angioten sin III but failed to inhibit the prostaglandin release stimulated by vasopressin or the mitogenic effect of serum. LR-B/081 and losartan we re devoid of intrinsinc agonistic properties in the experimental condi tions employed. The present results describe LR-B/081 as a novel, high ly specific and potent, non-peptide angiotensin AT(1)-selective recept or antagonist, that is capable of blocking angiotensin II-proliferativ e responses, which may be of relevance for cardiovascular diseases.