K(ATP) channel opening is an endogenous mechanism of protection against the no-reflow phenomenon but its function is compromised by hypercholesterolemia.
OBJECTIVE
This study aimed to clarify the role of adenosine triphosphate-sensitive K(+) (K(ATP)) channels in the no-reflow phenomenon and in its extension by hypercholesterolemia.


BACKGROUND
The no-reflow phenomenon is an important target of therapy in patients with acute myocardial infarction, but its mechanism remains unclear.


METHODS
The left circumflex coronary artery was occluded for 30 or 60 min and reperfused in rabbit hearts in situ. The no-reflow zone, area at risk, and infarct size were determined by thioflavin-S, Evans blue, and tetrazolium staining, respectively. No-reflow zone size was expressed as a percentage of infarct size (%NR/IS). Hypercholesterolemia was induced by two weeks of cholesterol-enriched diet.


RESULTS
A K(ATP) channel blocker, glibenclamide (0.3 mg/kg), increased %NR/IS after 30-min ischemia/90-min reperfusion from 33.6 +/- 1.9% to 45.9 +/- 1.6% and %NR/IS after 60-min ischemia/90-min reperfusion from 32.8 +/- 3.4% to 46.1 +/- 1.7%. However, N(G)-monomethyl-L-arginine (L-NMMA), a nitric oxide (NO) synthase inhibitor, and nicorandil, a hybrid of K(ATP) channel opener and nitrate, failed to significantly modify %NR/IS. Hypercholesterolemia increased %NR/IS to 61.6 +/- 0.6%, which was not further enlarged by glibenclamide, and delayed infarct healing during the subsequent five days of reperfusion. These effects of hypercholesterolemia were significantly suppressed by nicorandil. Neither glibenclamide, L-NMMA, nicorandil, nor hypercholesterolemia modified infarct size.


CONCLUSIONS
The K(ATP) channel activation, but not NO, is a major mechanism of protection against microvascular injury, causing the no-reflow phenomenon in the heart. Suppression of K(ATP) channel opening may underlie the hypercholesterolemia-induced extension of no-reflow, which delays infarct healing.
Genda
Satoshi
S
Second Department of Internal Medicine, Sapporo Medical University, Sapporo, Japan.
Miura
Tetsuji
T
Miki
Takayuki
T
Ichikawa
Yoshihiko
Y
Shimamoto
Kazuaki
K
D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors / Q000502:physiology*; D000704:Analysis of Variance; D000818:Animals; D002908:Chronic Disease; D003326:Coronary Circulation; D004195:Disease Models, Animal; D005905:Glyburide / Q000494:pharmacology; D006439:Hemodynamics; D006937:Hypercholesterolemia / Q000150:complications*; D008297:Male; D009203:Myocardial Infarction / Q000209:etiology* / Q000401:mortality / Q000503:physiopathology / Q000517:prevention & control*; D020108:Nicorandil / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000502:physiology*; D011817:Rabbits; D014665:Vasodilator Agents / Q000494:pharmacology; D019323:omega-N-Methylarginine / Q000494:pharmacology
D026902:Potassium Channel Blockers; D015221:Potassium Channels; D014665:Vasodilator Agents; D020108:Nicorandil; D019323:omega-N-Methylarginine; D000255:Adenosine Triphosphate; D019001:Nitric Oxide Synthase; D005905:Glyburide