Mexiletine differentially modulates vasorelaxation mediated by adenosine triphosphate-sensitive K+ channels in aortas from normotensive and hypertensive rats.
The modification of vasodilation through adenosine triphosphate (ATP)-sensitive K(+) channels induced by antiarrhythmic drugs has not been studied in chronic hypertension. We designed the present study to examine whether mexiletine modulates vasorelaxation via these channels in hypertensive rat aortas. Normotensive and hypertensive rat aortas without endothelium were suspended for isometric force recording. Mexiletine (3 x 10(-5) M) increased vasorelaxation induced by levcromakalim (10(-8)-10(-5) M) in normotensive, but not hypertensive, rat aortas. Mexiletine (10(-5) to 3 x 10(-5) M) also augmented vasorelaxation to sodium nitroprusside (10(-10)-10(-5) M) only in normotensive rat aortas, whereas mexiletine (3 x 10(-5) M) did not affect this vasodilation in aortas treated with an ATP-sensitive K(+) channel antagonist glibenclamide (10(-5) M). A nitric oxide scavenger (carboxy-2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide; 10(-3) M) abolished augmented vasorelaxation to sodium nitroprusside induced by mexiletine (3 x 10(-5) M) in normotensive rat aortas, whereas a soluble guanylate cyclase inhibitor (1H-[1,2,4]oxadiazolo [4,3,-a]quinoxaline-1-one; 10(-5) M) failed to alter this augmentation of vasorelaxation. These results suggest that mexiletine induces augmentation of vasodilation via ATP-sensitive K(+) channels activated by the opener as well as a nitric oxide donor only in normotensive rat aortas. The vasodilator effects of mexiletine are partly caused by the soluble guanylate cyclase-independent action of nitric oxide on these channels.


CONCLUSIONS
Mexiletine induces augmentation of vasodilation mediated by adenosine triphosphate (ATP)-sensitive K(+) channels activated by the opener as well as a nitric oxide donor in normotensive, but not hypertensive, rat aortas, partly by the soluble guanylate cyclase-independent action of nitric oxide on ATP-sensitive K(+) channels of vascular smooth muscle cells.
Kimoto
Yoshiki
Y
*Department of Anesthesiology, Wakayama Medical College; and †Department of Anesthesia, Japanese Red Cross Society, Wakayama Medical Center, Japan.
Kinoshita
Hiroyuki
H
Nakahata
Katsutoshi
K
Dojo
Mayuko
M
Iranami
Hiroshi
H
Hatano
Yoshio
Y
D018528:ATP-Binding Cassette Transporters; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology; D019806:Cromakalim / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005905:Glyburide / Q000494:pharmacology; D006973:Hypertension / Q000503:physiopathology*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D054086:KATP Channels; D008297:Male; D008801:Mexiletine / Q000494:pharmacology*; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D024661:Potassium Channels, Inwardly Rectifying; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D018528:ATP-Binding Cassette Transporters; D000889:Anti-Arrhythmia Agents; D007004:Hypoglycemic Agents; D054086:KATP Channels; D020030:Nitric Oxide Donors; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C092520:uK-ATP-1 potassium channel; D019806:Cromakalim; D009599:Nitroprusside; D008801:Mexiletine; D010656:Phenylephrine; D005905:Glyburide