[Ca2+]i and PKC-alpha are involved in the inhibitory effects of Ib, a novel nonpeptide AngiotensinII subtype AT1 receptor antagonist, on AngiotensinII-induced vascular contraction in vitro.
The vasoactive peptide AngiotensinII (AngII) is an important factor in the cardiovascular system, exerting most of its effects through AngII receptor type 1 (AT1). Ib, a new nonpeptide AT1 receptor antagonist, has been observed to play a positive role in the treatment of hypertension in preclinical tests. In this study, the inhibitory effects of Ib on AngII-induced vascular contraction in vitro were investigated, and its molecular mechanisms were further explored. In endothelium-denuded aortic rings from rabbits, Ib produced a rightward shift in the concentration-response curve for AngII with a decrease in the maximal contractile response and the pD2' was 7.29. In vascular smooth muscle cells (VSMCs), the specific binding of [125I]AngII to AT1 receptors was inhibited by Ib in a concentration-dependent manner with IC50 value of 0.96nM. Ib could inhibit both AngII-induced Ca2+ mobilization from internal stores and Ca2+ influx. Moreover, the translocation of PKC-alpha stimulated by AngII was inhibited by Ib. Thus, the inhibitory effects of Ib might be related with the depression on AngII-induced increase in [Ca2+]i and translocation of PKC-alpha through blocking AT1 receptors.
Wang
Yu
Y
Department of Physiology, College of Pharmacy, China Pharmaceutical University, No. 24, Tong Jia Xiang Street, Nanjing 210009, China.
Wang
Wei
W
Wang
Qiujuan
Q
Wu
Jinhui
J
Xu
Jinyi
J
Wu
Xiaoming
X
D000804:Angiotensin II / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000502:physiology*; D019808:Losartan / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D051571:Protein Kinase C-alpha / Q000502:physiology*; D011817:Rabbits; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D013777:Tetrazoles / Q000378:metabolism / Q000494:pharmacology*; D014230:Triazoles / Q000378:metabolism / Q000494:pharmacology*
C524079:5-n-butyl-4-(4-(2-(1H-tetrazol-5-yl)-1H-pyrrol-1-yl)phenylmethyl)-2,4-dihydro-2-(2,6-dichlorophenyl)-3H-1,2,4-triazol-3-one; D047228:Angiotensin II Type 1 Receptor Blockers; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D014230:Triazoles; D000804:Angiotensin II; D051571:Protein Kinase C-alpha; D019808:Losartan; D002118:Calcium