1. Pitavastatin inhibits upregulation of intermediate conductance calcium-activated potassium channels and coronary arteriolar remodeling induced by long-term blockade of nitric oxide synthesis.
- Author
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Terata Y, Saito T, Fujiwara Y, Hasegawa H, Miura H, Watanabe H, Chiba Y, Kibira S, and Miura M
- Subjects
- Animals, Arterioles drug effects, Arterioles pathology, Blood Pressure drug effects, Coronary Vessels pathology, Fibrosis, In Situ Hybridization, Lipids blood, Male, Myocardium metabolism, NG-Nitroarginine Methyl Ester pharmacology, Nitric Oxide biosynthesis, RNA, Messenger metabolism, Rats, Rats, Inbred WKY, Reverse Transcriptase Polymerase Chain Reaction, Up-Regulation, Coronary Vessels drug effects, Hydroxymethylglutaryl-CoA Reductase Inhibitors pharmacology, Nitric Oxide antagonists & inhibitors, Potassium Channels, Calcium-Activated antagonists & inhibitors, Quinolines pharmacology
- Abstract
Unlabelled: We have reported that intermediate conductance Ca(2+)-activated K(+) channels (ImK) showed augmented expression in angiotensin II (AII) type 1 receptor-dependent manner in post-ischemic rat heart. ImK has tyrosine phosphorylation sequence in the C-terminus and motifs for NFkappaB and AP1 in the promoter. While statin inhibits AII-mediated vascular remodeling via anti-inflammatory effect independent of cholesterol lowering. To test the possible effect of statin on expression of ImK, Wistar-Kyoto rats received L-nitro-arginine methyl ester (LNAME: 1 mg/ml in drinking water) for 4 weeks in group L. While in L+P group, rats received both LNAME and pitavastatin (PTV: 1 mg/kg/day in drinking water). Temporal profile of ImK mRNA was examined by RT-PCR using specific primers for ImK., Results: Long-term LNAME administration produced significant hypertension and resulted in marked microvascular remodeling characterized by medial thickening and perivascular fibrosis of coronary arterioles (100-200 microm in diameter). RT-PCR revealed significant up-regulation of ImK mRNA with two distinct peaks in L group in the early phase (days 3-7) and the late phase (4 weeks). PTV partially inhibited a rise in systolic blood pressure, but completely abolished the first peak of ImK upregulation (0.76 +/- 0.04 vs. 3.96 +/- 1.43 folds at day 7, p < 0.001). Co-treatments with PTV also significantly inhibited medial thickening and perivascular fibrosis. These findings indicate that statin inhibits microvascular remodeling induced by chronic inhibition of NO synthesis through the action independent of cholesterol lowering., (Copyright 2003 S. Karger AG, Basel)
- Published
- 2003
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