Potassium channel activation and relaxation by nicorandil in rat small mesenteric arteries.
1. We used whole-cell patch clamp to investigate the currents activated by nicorandil in smooth muscle cells isolated from rat small mesenteric arteries, and studied the relaxant effect of nicorandil using myography. 2. Nicorandil (300 microM) activated currents with near-linear current-voltage relationships and reversal potentials near to the equilibrium potential for K+. 3. The nicorandil-activated current was blocked by glibenclamide (10 microM), but unaffected by iberiotoxin (100 nM) and the guanylyl cyclase inhibitor LY 83583 (1 microM). During current activation by nicorandil, openings of channels with a unitary conductance of 31 pS were detected. 4. One hundred microM nicorandil had no effect on currents through Ca2+ channels recorded in response to depolarizing voltage steps using 10 mM Ba2+ as a charge carrier. A small reduction in current amplitude was seen in 300 microM nicorandil, though this was not statistically significant. 5. In arterial rings contracted with 20 mM K+ Krebs solution containing 200 nM BAYK 8644, nicorandil produced a concentration-dependent relaxation with mean pD2 = 4.77+/-0.06. Glibenclamide (10 microM) shifted the curve to the right (pD2 = 4.32+/-0.05), as did 60 mM K+. LY 83583 caused a dose-dependent inhibition of the relaxant effect of nicorandil, while LY 83583 and glibenclamide together produced greater inhibition than either alone. 6. Metabolic inhibition with carbonyl cyanide m-chlorophenyl hydrazone (30 nM), or by reduction of extracellular glucose to 0.5 mM, increased the potency of nicorandil. 7. We conclude that nicorandil activates KATP channels in these vessels and also acts through guanylyl cyclase to cause vasorelaxation, and that the potency of nicorandil is increased during metabolic inhibition.
Davie
C S
CS
Department of Cell Physiology and Pharmacology, University of Leicester.
Kubo
M
M
Standen
N B
NB
D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000502:physiology; D009126:Muscle Relaxation / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D020108:Nicorandil / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014475:Uncoupling Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology*
D000634:Aminoquinolines; D015220:Calcium Channels; D004791:Enzyme Inhibitors; D010455:Peptides; D015221:Potassium Channels; D014475:Uncoupling Agents; D014665:Vasodilator Agents; D020108:Nicorandil; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; C064719:iberiotoxin; C041715:6-anilino-5,8-quinolinedione; D006162:Guanylate Cyclase; D005905:Glyburide