Role of BKCa Channels in NO‐Induced Relaxation of Control and Nitrate Tolerant Isolated Mesenteric Arteries

Abstract

The clinical efficacy of nitroglycerin (NTG) is limited by the development of tolerance. The present study was designed to identify the role of BKCa channels in NO‐induced relaxation of control and tolerant arteries. Rats were treated with or without NTG (0.6 mg/hr) patches for 3 days. Isometric tension was recorded in isolated mesenteric arteries and relaxation responses to NTG and sodium nitroprusside (SNP; 10−9 to 10−5 M) were obtained. Nitrate tolerance was evident by marked impairment in responses to NTG and SNP in tissues from rats treated with NTG patches. Iberiotoxin (10−7 M), a selective BKCa‐blocker, inhibited NTG‐ and SNP‐induced relaxations in rings from nontolerant rats; residual responses to NTG and SNP were abolished in rings from tolerant rats. The selective BKCa‐opener, NS1619 (10−9 to 10−6 M), caused relaxation of tolerant and nontolerant arteries; however, tolerant rings were more sensitive than nontolerant rings to relaxation by NS1619. Immunoblot analysis indicated increased BKCa expression in arteries from tolerant animals. The data suggest that NO‐induced relaxation is dependent on BKCa activation in control and tolerant mesenteric arteries. Although BKCa expression is increased in tolerant arteries, responses to NO‐donors, but not BKCa‐openers, are markedly impaired, consistent with defective coupling between NO donors and BKCa activation (Supported by NIH HL098896).