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Vol. 284, Issue 3, 838-846, March 1998

Coronary Vasorelaxation by Nitroglycerin: Involvement of Plasmalemmal Calcium-Activated K+ Channels and Intracellular Ca++ Stores

Sajida A. Khan, Nicole R. Higdon and Kaushik D. Meisheri

Cardiovascular Pharmacology, Pharmacia & Upjohn, Inc., Kalamazoo, Michigan

This study investigated nitroglygerin (NTG) relaxations in isolated dog coronary artery in comparison with other vascular preparations. Under maximal PNU-46619 precontraction, the coronary artery was significantly more sensitive to NTG than mesenteric artery, mesenteric vein and saphenous vein. In the coronary artery, NTG (1-100 nM) produced relaxations with EC50 = 9.4 nM. In KCl-contracted arteries (20-80 mM KCl), relaxation by NTG was progressively reduced. Relaxation responses to NTG also were inhibited significantly by potent calcium-activated K+ (BK) channel blockers, charybdotoxin (100 nM) and iberiotoxin (200 nM), but not by KATP blockers such as PNU-37883A (10 µM) or PNU-99963 (100 nM). Nitric oxide (0.1-30 nM) and acetylcholine (3-300 nM) also produced relaxations which were significantly attenuated by the BK blockers. In further experiments, NTG (1-100 nM) produced inhibition of PNU-46619-induced SR [Ca++]i release, with an IC50 of 8.5 nM, which was not affected by charybdotoxin. Furthermore, P1075 (50 nM), a KATP opener, did not inhibit agonist-stimulated SR [Ca++]i release. Ryanodine (10 µM), which acts on SR Ca++ release channels, did not alter NTG relaxations, whereas thapsigargin (0.1 µM), a selective inhibitor of SR Ca++-ATPase pump, produced pronounced inhibition of NTG relaxations. These results suggest that NTG, in the therapeutic concentration range, produces coronary relaxation primarily via two cellular mechanisms: plasmalemmal BK channel activation and stimulation of SR Ca++-ATPase to produce increased SR Ca++ accumulation. These two mechanisms apparently are equally important and act together to produce a unique vasorelaxation profile demonstrated by NTG-type coronary vasodilators.

0022-3565/98/2843-0838$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics


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