K-ATP CHANNEL ACTIVATION MEDIATES NICORANDIL-INDUCED RELAXATION OF NITRATE-TOLERANT CORONARY-ARTERIES

We compared the tolerance-inducing effects of nitroglycerin (NTG) and nicorandil (NIC) in porcine isolated coronary arteries and assessed th e role of K-ATP channels in the response to NIC in nitrate-tolerant an d nontolerant preparations. In coronary arteries contracted with U4661 9 (1 - 3 x 10(-9) M), NTG, NIC, sodium nitro-prusside (SNP), and croma kalim produced concentration-dependent relaxations. The rank order of potency was NTG greater than or equal to SNP > cromakalim > nicorandil . Exposure of the rings to NTG (10(-4) M) for 90 min, followed by repe ated rinsing for 1 h, produced a parallel, rightward shift of the subs equent concentration-response curves to NTG and SNP; a slight but sign ificant reduction in the maximal response to NTG was also observed. Pr evious exposure to NTG had no effect on the NIC or cromakalim concentr ation-response curves. When the tissues were exposed to NIC (3 x 10(-4 ) M) for 90 min, followed by repeated rinsing for 1 h, there was no ef fect on the subsequent concentration-response curves to NTG, NIC, SNP, or cromakalim. In both nitrate-tolerant and nontolerant coronary arte ries, glibenclamide (GLI 10(-6) M), a selective K-ATP channel blocker, caused a parallel rightward shift in the concentration-response curve to cromakalim, but had no effect on responses to NTG or SNP. In nonto lerant coronary arteries, GLI had no effect on NIC-induced relaxation, but in nitrate-tolerant preparations, GLI produced a significant righ tward shift in the NIC concentration-response curve. The results demon strate that prolonged exposure to NTG, but not NIC, causes tolerance i n isolated porcine coronary arteries and that the response to NIC is n ot affected by nitrate tolerance. The data also suggest that NIC-induc ed relaxation of nitrate-tolerant, but not nontolerant, coronary arter ies is mediated by activation of K-ATP channels.