Role of calcium-activated K+ channels in vasodilation induced by nitroglycerine, acetylcholine and nitric oxide

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 267; no. 3; pp. 1327 - 1335
• Main Authors: KHAN, S. A, MATHEWS, W. R, MEISHERI, K. D
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01.12.1993
• Subjects: Acetylcholine - pharmacology; Adenosine Triphosphate - physiology; Animals; Biological and medical sciences; Calcium - physiology; Cardiovascular system; Charybdotoxin; Colforsin - pharmacology; Drug Interactions; Glyburide - pharmacology; Guanidines - pharmacology; Medical sciences; Mesenteric Arteries - drug effects; Muscle Relaxation - drug effects; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - physiology; Nitric Oxide - pharmacology; Nitroglycerin - pharmacology; Norepinephrine - pharmacology; Peptides - pharmacology; Pharmacology. Drug treatments; Pinacidil; Potassium - pharmacology; Potassium Channels - drug effects; Potassium Channels - physiology; Rabbits; Scorpion Venoms - pharmacology; Vasodilation - drug effects; Vasodilation - physiology; Vasodilator Agents - pharmacology; Vasodilator agents. Cerebral vasodilators; Vasodilator agent; Calcium; Rabbit; Smooth muscle; Ionic channel; Lagomorpha; Muscle contraction; In vitro; Vasodilation; Vertebrata; Mesenteric artery; Mammalia; Animal; Nitrogen monoxide; Acetylcholine; Circulatory system; Mechanism of action; Potassium
• ISSN: 0022-3565; 1521-0103

A comparative analysis was carried out of the sensitivities of in vitro vasorelaxations by nitroglycerine (NTG), acetylcholine (ACh) and nitric oxide (NO) to blockade by glyburide, a blocker of ATP-sensitive K+ channels (KATP), as well as to blockade by charybdotoxin (ChTX) and iberiotoxin (lbTX), potent blockers of calcium-activated K+ channels (KCa). In the isolated rabbit mesenteric artery (RMA) precontracted with 5 microM norepinephrine (NE), ACh (0.01-1 microM), NTG (0.01-5 microM) and NO (0.075-2.7 microM) produced a dose-dependent vasodilation. Glyburide (0.5 microM) had no significant effect on relaxation dose-response curves (DRCs) to ACh, NTG or NO. In contrast, glyburide completely abolished the relaxation DRC by pinacidil, a known KATP opener. ChTX (10 or 100 nM) caused an inhibition of relaxation DRCs to ACh, NTG and NO. In all cases, ChTX shifted the relaxation DRC to the right and depressed the maximal response. Another potent KCa blocker, lbTX (20 nM) also significantly inhibited relaxation DRCs to NTG, ACh and NO and inhibited maximal relaxation response to SNP. The effects of ChTX and lbTX were selective; they did not inhibit relaxations by pinacidil and forskolin. Finally, it was observed that the use of 80 mM K+ as a contractile stimulus inhibited NTG relaxations in a manner similar to the KCa blockers. Collectively, these data provide strong support for the hypothesis that the activation of KCa plays an important role in mediating the vasorelaxation caused by NTG, SNP, ACh and NO.