Differential effects of lidocaine and mexiletine on relaxations to ATP-sensitive K+ channel openers in rat aortas.
BACKGROUND
In cardiac myocytes, lidocaine reduces but mexiletine increases adenosine triphosphate (ATP)-sensitive K+ currents, suggesting that these class Ib antiarrhythmic drugs may differentially modify the activity of ATP-sensitive K+ channels. The effects of lidocaine and mexiletine on arterial relaxations induced by K+ channel openers have not been studied. Therefore, the current study was designed to evaluate whether lidocaine and mexiletine may produce changes in relaxations to the ATP-sensitive K+ channel openers cromakalim and pinacidil in isolated rat thoracic aortas.


METHODS
Rings of rat thoracic aortas without endothelia were suspended for isometric force recording. Concentration-response curves were obtained in a cumulative fashion. During submaximal contractions to phenylephrine (3 x 10(-7) M), relaxations to cromakalim (10(-7) to 3 x 10(-5) M), pinacidil (10(-7) to 3 x 10(-5) M), or diltiazem (10(-7) to 3 x 10(-4) M) were obtained. Lidocaine (10(-5) to 3 x 10(-4) M), mexiletine (10(-5) to 10(-4) M) or glibenclamide (5 x 10(-6) M) was applied 15 min before addition of phenylephrine.


RESULTS
During contractions to phenylephrine, cromakalim and pinacidil induced concentration-dependent relaxations. A selective ATP-sensitive K+ channel antagonist, glibenclamide (5 x 10(-6) M), abolished these relaxations, whereas it did not alter relaxations to a voltage-dependent Ca2+ channel inhibitor, diltiazem (10(-7) to 3 x 10(-4) M). Lidocaine (more than 10(-5) M) significantly reduced relaxations to cromakalim or pinacidil in a concentration-dependent fashion, whereas lidocaine (3 x 10(-4) M) did not affect relaxations to diltiazem. In contrast, mexiletine (more than 10(-5) M) significantly augmented relaxations to cromakalim or pinacidil. Glibenclamide (5 x 10(-6) M) abolished relaxations to cromakalim or pinacidil in arteries treated with mexiletine (10(-4) M).


CONCLUSIONS
These results suggest that lidocaine impairs but mexiletine augments vasodilation mediated by ATP-sensitive K+ channels in smooth muscle cells.
Kinoshita
H
H
Department of Anesthesia, Japanese Red Cross Society, Wakayama Medical Center, Wakayama.
Ishikawa
T
T
Hatano
Y
Y
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects* / Q000502:physiology; D019806:Cromakalim / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005905:Glyburide / Q000494:pharmacology; D008012:Lidocaine / Q000494:pharmacology*; D008297:Male; D008801:Mexiletine / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects*; D051381:Rats; D011921:Rats, Inbred WKY; D014664:Vasodilation / Q000187:drug effects*
D000889:Anti-Arrhythmia Agents; D015221:Potassium Channels; D019806:Cromakalim; D008801:Mexiletine; D000255:Adenosine Triphosphate; D008012:Lidocaine; D005905:Glyburide