title: Attenuation by 4-aminopyridine of delayed vasorelaxation by troglitazone.
abstract: Troglitazone and other thiazolidinediones (TZDs) are thought to relax arterial smooth muscle by directly inhibiting calcium channels in smooth muscle cell membranes. However, until recently such inhibition was only examined acutely, ie, within only seconds or minutes after administration of these agents to arterial smooth muscle preparations. Recently, a novel experiment was reported in which troglitazone caused a 2-phase relaxation of perfused resistance arteries, namely, an acute relaxation (within the first 20 minutes of treatment), which was blocked by a nonselective calcium channel blocker and a delayed relaxation (after 2 hours), which was not. We sought to determine if any of the 4 major potassium (K) channels in vascular smooth muscle play a role in the delayed relaxation. We incubated vascular contractile rings prepared from ventral tail arteries of rats with physiological buffer containing either 0 or 4 micromol/L troglitazone for 3 hours (4 micromol/L is typical of plasma levels from diabetic patients). Different K channel inhibitors (1 mmol/L 4-aminopyridine [4AP]; 1 mmol/L tetraethylammonium [TEA]; 5 micromol/L glyburide; 20 micromol/L barium) were coadministered with each level of troglitazone in additional preparations. Then these arterial rings were contracted with either norepinephrine (NE), arginine vasopressin (AVP), or high-K buffer. All contractions were significantly relaxed by troglitazone (P <.05). Only 4AP significantly attenuated troglitazone's relaxation of NE and AVP contractions (P <.05), though not high-K-induced contractions. TEA, glyburide, and barium had no such influence. Thus, for both adrenergic (NE) and nonadrenergic (AVP) contractions, the delayed arterial vasorelaxation by troglitazone may be mediated at least in part by activation of 4AP-sensitive K channels. Furthermore, the specific subtype of the channels involved is most likely those bound in the outer cell membrane where their effectiveness in terms of mediating relaxation would depend on an intact transmembrane K ion gradient.
authors.affiliation: Department of Pharmacology, Midwestern University, Downers Grove, IL, USA.
authors.forename: Jacob D
authors.initials: JD
authors.lastname: Peuler
authors.forename: R K N
authors.initials: RK
authors.lastname: Warfield
authors.forename: Laura E
authors.initials: LE
authors.lastname: Phelps
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology*; D000818:Animals; D001127:Arginine Vasopressin / Q000494:pharmacology; D001158:Arteries / Q000187:drug effects; D002839:Chromans / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007004:Hypoglycemic Agents / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009638:Norepinephrine / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D045162:Thiazolidinediones / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D000077288:Troglitazone; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D002839:Chromans; D007004:Hypoglycemic Agents; D026902:Potassium Channel Blockers; D045162:Thiazolidinediones; D014662:Vasoconstrictor Agents; D001127:Arginine Vasopressin; D015761:4-Aminopyridine; D000077288:Troglitazone; D011188:Potassium; D009638:Norepinephrine