Coronary vasorelaxation by nitroglycerin: involvement of plasmalemmal calcium-activated K+ channels and intracellular Ca++ stores.
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 microM) 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 microM), which acts on SR Ca++ release channels, did not alter NTG relaxations, whereas thapsigargin (0.1 microM), 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.
Khan
S A
SA
Pharmacia & Upjohn, Inc., Kalamazoo, Michigan, USA. sakhan@am.pnu.com
Higdon
N R
NR
Meisheri
K D
KD
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D018999:Charybdotoxin / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D008297:Male; D005996:Nitroglycerin / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000187:drug effects*; D012433:Ryanodine / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
D010455:Peptides; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D014665:Vasodilator Agents; D018999:Charybdotoxin; D012433:Ryanodine; D019284:Thapsigargin; C064719:iberiotoxin; D005996:Nitroglycerin; D011188:Potassium; D002118:Calcium