Nitroglycerin‐Induced Relaxation is Mediated by BKCa Channels in Nitrate Tolerant Arteries

Abstract

Numerous studies have examined the cause(s) of nitrate tolerance, but remarkably little is known about possible adaptive processes that may occur in nitrate-tolerant blood vessels. We tested the hypothesis that nitrate tolerance induces a compensatory response involving K channels in nitroglycerin-induced smooth muscle relaxation. Rats were treated with placebo or NTG (0.6 mg/hr) patches for 3 days. Thoracic aortae were removed, cut into rings, and suspended in organ baths. Relaxation responses to NTG (10−9 to 10−5 M) were obtained in the absence and presence of several K channel blockers. Nitrate tolerance was evident by a >7-fold rightward shift in the NTG concentration-response curve in tissues from rats treated with NTG patches as compared with placebo. Iberiotoxin (10−7 M), a selective blocker of BKCa, had no effect on NTG-induced relaxation of rings from nontolerant rats, but caused a further rightward shift (>7-fold) in the concentration-response curve to NTG in rings from tolerant rats. Selective blockers of other K channels, including glyburide (10−6 M), apamin (10−6 M), and 4-aminopyridine (10−3 M) had no effect on responses to NTG in either nontolerant or tolerant rings. Whole cell voltage-clamp studies from placebo and NTG-treated rat aortic myocytes indicated that NTG (10 μM) significantly increased BKCa current density in tolerant aortic myocytes at +80 mV (22.6 ± 3.02 and 52.5 ± 5.52 pA/pF, control and tolerant respectively). The data suggests that in nontolerant arteries, NTG-induced relaxation is independent of BKCa channel activation. By contrast, prolonged in vivo treatment with NTG results in a major role for BKCa in NTG-induced relaxation of nitrate tolerant arteries.