A long-term receptor stimulation is requisite for angiotensin II-dependent DNA synthesis in vascular smooth muscle cells from spontaneously hypertensive rats.
Angiotensin II stimulates DNA synthesis in aortic smooth muscle cells prepared from spontaneously hypertensive rats, with maximal levels detected 20 h after stimulation. Angiotensin II receptor antagonists inhibited the angiotensin II-induced DNA synthesis. In particular, the noncompetitive antagonist 2-ethoxy-1-[[2'(1 H-tetrazol-5-yl) biphenyl-4-yl]methyl]-1 H-benzimidazole-7-carboxylic acid (CV11974) was more effective than expected from its affinity for the angiotensin II receptor and its potency for inhibiting angiotensin II-induced increase in cytosolic free Ca2+ concentration 2-n-Butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1 H-tetrazol-5-yl)biphenyl-4-yl) methyl]imidazole, potassium salt (losartan), one of the antagonists, inhibited angiotensin II-induced DNA synthesis by 92% and 79%, even when added 2 and 4 h after angiotensin II stimulation, respectively. Angiotensin II also increases the mRNA of platelet-derived growth factor-A chain and basic fibroblast growth factor. The increase was observed within 4 h after angiotensin II stimulation. In this case, the addition of losartan at 4 h after angiotensin II stimulation hardly influenced the time course of the mRNA level of growth factors. Also, conditioned media of cells stimulated with angiotensin II did not influence DNA synthesis in the presence of CV11974. These results suggest that sustained receptor stimulation with angiotensin II is required for DNA synthesis in addition to the early intracellular signaling following phospholipase C activation in a manner independent of the induction of growth factors such as platelet-derived growth factor-AA and basic fibroblast growth factor.
Itazaki
K
K
Shionogi Research Laboratories, Shionogi and Co. Ltd., Osaka, Japan.
Hara
M
M
Itoh
N
N
Fujimoto
M
M
D000804:Angiotensin II / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001011:Aorta / Q000187:drug effects; D001483:Base Sequence; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004261:DNA Replication / Q000187:drug effects*; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D019808:Losartan; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000096:biosynthesis / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D017479:Receptors, Platelet-Derived Growth Factor / Q000235:genetics; D013777:Tetrazoles / Q000494:pharmacology
C085920:2-butyl-3-((2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-3H-imidazo(4,5-b)pyridine; D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D007093:Imidazoles; D010982:Platelet-Derived Growth Factor; D011725:Pyridines; D013777:Tetrazoles; D016222:Fibroblast Growth Factor 2; D000804:Angiotensin II; D017479:Receptors, Platelet-Derived Growth Factor; D019808:Losartan; C081643:candesartan; D002118:Calcium