CORONARY VASORELAXATION BY NITROGLYCERIN - INVOLVEMENT OF PLASMALEMMAL CALCIUM-ACTIVATED K+ CHANNELS AND INTRACELLULAR CA++ STORES

This study investigated nitroglygerin (NTG) relaxations in isolated do g coronary artery in comparison with other vascular preparations. Unde r maximal PNU-46619 precontraction, the coronary artery was significan tly more sensitive to NTG than mesenteric artery, mesenteric vein and saphenous vein. In the coronary artery, NTG (1-100 nM) produced relaxa tions with EC50 = 9.4 nM. In KCl-contracted arteries (20-80 mM KCl), r elaxation by NTG was progressively reduced. Relaxation responses to NT G also were inhibited significantly by potent calcium-activated K+ (BK ) channel blockers, charybdotoxin (100 nM) and iberiotoxin (200 nM), b ut not by K-ATP, blockers such as PNU-37883A (10 mu M) or PNU-99963 (1 00 nM). Nitric oxide (0.1-30 nM) and acetylcholine (3300 nM) also prod uced relaxations which were significantly attenuated by the BK blocker s, In further experiments, NTG (1-100 nM) produced inhibition of PNU-4 6619-induced SR [Ca++](i) release, with an IC50 of 8.5 nM, which was n ot affected by charybdotoxin, Furthermore, P1075 (50 nM), a K-ATP open er, did not inhibit agonist-stimulated SR [Ca++](i) release. Ryanodine (10 mu M), which acts on SR Ca++ release channels, did not alter NTG relaxations, whereas thapsigargin (0.1 mu M), a selective inhibitor of SR Ca++-ATPase pump, produced pronounced inhibition of NTG relaxation s. These results suggest that NTG, in the therapeutic concentration ra nge, produces coronary relaxation primarily via two cellular mechanism s: plasmalemmal BK channel activation and stimulation of SR Ca++-ATPas e to produce increased SR Ca++ accumulation. These two mechanisms appa rently are equally important and act together to produce a unique vaso relaxation profile demonstrated by NTG-type coronary vasodilators.