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CLINICAL STUDY

K_ATP channel opening is an endogenous mechanism of protection against the no-reflow phenomenon but its function is compromised by hypercholesterolemia

^* Second Department of Internal Medicine, Sapporo Medical University, Sapporo, Japan

Manuscript received October 4, 2001; revised manuscript received May 7, 2002, accepted June 27, 2002.

^* Reprint requests and correspondence: Dr. Tetsuji Miura, Second Department of Internal Medicine, Sapporo Medical University School of Medicine, South-1 West-16, Chuo-ku, Sapporo 060-8543 Japan.
miura{at}sapmed.ac.jp

OBJECTIVES: 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.

Abbreviations and Acronyms   ANOVA   analysis of variance   GPTX   pertussis toxin-sensitive G protein   %IS/AR   infarct size as a percentage of area at risk   IV   intravenous   KATP channel   adenosine triphosphate-sensitive K+ channel   KCa channel   Ca2+-activated K+ channel   LDL-C   low density lipoprotein-cholesterol   L-NMMA   NG-monomethyl-L-arginine   NO   nitric oxide   NOS   nitric oxide synthase   %NR/IS   no-reflow zone size as a percentage of infarct size   %OZ/IS   volume of organized infarct as a percentage of whole infarct size   TC   total cholesterol   TG   triglycerides

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