Mexiletine protects myocardium during acute ischemia by opening sarcolemmal K-ATP channel: studies in closed-chest acute ischemia model in rabbits.
OBJECTIVE
Although we have previously shown that mexiletine might protect myocardium during acute ischemia, the precise mechanism was unclear. In the present study, the mechanism of this effect was examined by using selective K-ATP channel blockers in closed-chest acute ischemia model in rabbits.


METHODS
In 40 rabbits, the large left ventricular branch (LLVB) of the left coronary artery was occluded for 30 minutes by inserting a catheter bead (varphi0.5-0.7 x 1.5 mm) through the left carotid artery and was then reperfused. The rabbits were divided into the following 5 groups: (1) control group (n = 8); (2) mexiletine (Mex) group (n = 8, continuous infusion of Mex 24 mg/kg/h); (3) Mex + 5-hydroxydecanoate (5HD) group (n = 8, preadministration of 5HD, 5 mg/kg, followed by Mex infusion); (4) Mex + HMR1098 (selective sarcolemmal K-ATP channel blocker) group (n = 8, preadministration of HMR1098, 3 mg/kg, followed by Mex infusion); and (5) pilsicainide (Pil) group (n = 8, continuous infusion of Pil 18 mg/kg/h). The incidence of ventricular arrhythmia, hemodynamics, left ventricular ejection fraction (LVEF), and infarction size were evaluated and compared among the 5 groups.


RESULTS
The incidence of ventricular arrhythmia was lower in groups treated with Mex than the control. The hemodynamics did not show significant differences among the 5 groups. Although the LVEF at 30 minutes after reperfusion was lower in the Mex group (41 +/- 3%, P < 0.001) than the control group (48 +/- 3%), the LVEF at 360 minutes after reperfusion had recovered and became higher in the Mex group (62 +/- 3%, P < 0.001) than the control group (55 +/- 3%). The infarction size was smaller in the Mex group (30 +/- 5%, P = 0.028) than the control group (51 +/- 8%). These effects of Mex were negated by HMR1098 but not by 5HD and were larger than the effects of Pil.


CONCLUSIONS
Mex showed improvement in the LVEF in the later phase after reperfusion as well as a reduction in ventricular arrhythmia. The cardioprotective effect of Mex was considered to appear through its action on the sarcolemmal K-ATP channel.
Niwano
Shinichi
S
Department of Internal Medicine, Kitasato University School of Medicine, Sagamihara, Japan. shniwano@med.kitasato-u.ac.jp
Inuo
Kimiatsu
K
Morohoshi
Yasuo
Y
Nakayama
Shigenobu
S
Yuge
Masaru
M
Imaki
Ryuta
R
Izumi
Tohru
T
D018528:ATP-Binding Cassette Transporters; D000208:Acute Disease; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004562:Electrocardiography / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D054086:KATP Channels; D008012:Lidocaine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008801:Mexiletine / Q000627:therapeutic use*; D009203:Myocardial Infarction / Q000473:pathology; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000473:pathology*; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000473:pathology; D009206:Myocardium / Q000473:pathology*; D015221:Potassium Channels / Q000819:agonists / Q000187:drug effects*; D024661:Potassium Channels, Inwardly Rectifying; D011817:Rabbits; D012508:Sarcolemma / Q000187:drug effects / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013318:Stroke Volume / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects
D018528:ATP-Binding Cassette Transporters; D000889:Anti-Arrhythmia Agents; D054086:KATP Channels; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D026941:Sodium Channel Blockers; C092520:uK-ATP-1 potassium channel; D008801:Mexiletine; D008012:Lidocaine; C042288:pilsicainide