Angiotensin II-induced responses in vascular smooth muscle cells: inhibition by non-peptide 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-tetra-zol-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 E2 and prostaglandin I2 (EC50 = 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 AT1-selective receptor antagonist, whereas they were unaffected by PD123177 (1-(4-amino-3-methylphenyl)methyl-5-diphenylacetyl-4,5,6,7-tetr ahy dro-1H- imidazo[4,5-c]pyridine carboxylic acid), a non-peptide angiotensin AT2-selective receptor antagonist. LR-B/081 displayed a much higher potency than losartan in inhibiting angiotensin II-induced prostaglandin E2 (IC50 = 0.15 +/- 0.02 and 39 +/- 9 nM, respectively) and prostaglandin I2 release (IC50 = 0.18 +/- 0.04 and 134 +/- 40 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 intrinsic properties in the experimental conditions employed.(ABSTRACT TRUNCATED AT 250 WORDS)
Catalioto
R M
RM
Department of Pharmacology, Laboratori Guidotti, San Piero a Grado, Pisa, Italy.
Porchia
R
R
Renzetti
A R
AR
Criscuoli
M
M
Subissi
A
A
Giachetti
A
A
D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D001713:Biphenyl Compounds / Q000494:pharmacology; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D015232:Dinoprostone / Q000378:metabolism; D011464:Epoprostenol / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D007930:Leucine / Q000378:metabolism; D019808:Losartan; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D014176:Protein Biosynthesis; D011725:Pyridines / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology*; D013936:Thymidine / Q000378:metabolism
D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D007093:Imidazoles; C094835:LR B-081; D011725:Pyridines; D011744:Pyrimidinones; D013777:Tetrazoles; D013876:Thiophenes; D000804:Angiotensin II; C066253:PD 123177; D015544:Inositol 1,4,5-Trisphosphate; D004247:DNA; D011464:Epoprostenol; D007930:Leucine; D019808:Losartan; D015232:Dinoprostone; D013936:Thymidine