4-Aminopyridine antagonizes the acute relaxant action of metformin on adrenergic contraction in the ventral tail artery of the rat.
The ability of metformin (MF) to acutely relax phenylephrine (PE)-induced contraction in the isolated rat tail artery is reported to be accompanied by repolarization of the arterial smooth muscle cell (SMC) membranes. These membranes contain potassium (K) channels which if opened could mediate such repolarization and resultant relaxation. We have shown that the acute relaxation of rat tail arterial tissue rings by graded levels of MF > or = 0.24 mmol/L is markedly antagonized by a high concentration of tetraethylammonium (TEA; 10 mmol/L) which nonselectively inhibits nearly all K channels. Thus, we tested effects of more selective inhibitors of K channels in the same tissue. We also tested MF for relaxation of contractions induced by high levels of extracellular K. To avoid confounding variables, we also conducted these tests in arterial rings in which endothelium and sympathetic nerve endings had been removed. In the absence of K channel inhibition, half-maximal PE-induced contractions were rapidly relaxed by all levels of MF with an EC50 of 1.7+/-0.2 mmol/L (n=8 rings). 1 mmol/L 4-aminopyridine (4AP) which only inhibits voltage-operated and ATP-sensitive K channels markedly antagonized this relaxation, shifting the EC50 for MF to 7.5+/-0.7 mmol/L (n=8; p < 0.05). TEA at 1 mmol/L (which only inhibits calcium-activated K channels), barium at 20 micromol/L (which only inhibits inward rectifier K channels) and glyburide at 5 micromol/L (which only inhibits ATP-sensitive K channels) did not alter this relaxation. Finally, MF failed to relax contractions produced by elevations of extracellular K to levels high enough to abolish the K gradient across arterial SMC membranes. Thus, acute relaxation of rat tail arterial smooth muscle by MF may be dependent on the transmembrane K gradient and mediated at least in part by specific activation of K efflux through 4AP-sensitive voltage-dependent K channels in arterial SMC membranes.
Peuler
J D
JD
Department of Pharmacology, Midwestern University, Downers Grove, IL 60515, USA. JPEULE@Midwestern.edu
Lee
J M
JM
Smith
J M
JM
D015761:4-Aminopyridine / Q000494:pharmacology*; D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000294:innervation / Q000378:metabolism / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D007004:Hypoglycemic Agents / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D066298:In Vitro Techniques; D008687:Metformin / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000294:innervation / Q000378:metabolism / Q000502:physiology; D010656:Phenylephrine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013623:Tail / Q000098:blood supply*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D007004:Hypoglycemic Agents; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D014662:Vasoconstrictor Agents; D010656:Phenylephrine; D008687:Metformin; D015761:4-Aminopyridine