Premium
Plasma‐membrane K ATP channel‐mediated cardioprotection involves posthypoxic reductions in calcium overload and contractile dysfunction: mechanistic insights into cardioplegia
Author(s) -
Baczkó István,
Jones Lynn,
McGuigan Claire F.,
Fox Jocelyn E. Manning,
Gandhi Manoj,
Giles Wayne R.,
Clanachan Alexander S.,
Light Peter E.
Publication year - 2005
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.04-3008fje
Subject(s) - contractility , cardioprotection , myocyte , medicine , chemistry , diastole , calcium , depolarization , cardiology , sodium calcium exchanger , pressure overload , heart failure , ischemia , blood pressure , cardiac hypertrophy
Our recent data demonstrate that activation of pm K ATP channels polarizes the membrane of cardiomyocytes and reduces Na + /Ca 2+ exchange‐mediated Ca 2+ overload. However, it is important that these findings be extended into contractile models of hypoxia/reoxygenation injury to further test the notion that pm K ATP channel activation affords protection against contractile dysfunction and calcium overload. Single rat heart right ventricular myocytes were enzymatically isolated, and cell contractility and Ca 2+ transients in field‐stimulated myocytes were measured in a cellular model of metabolic inhibition and reoxygenation. Activation of pm K ATP with P‐1075 (5µM) or inhibition of the Na + /Ca 2+ exchanger with KB‐R7943 (5 µM) reduced reoxygenation‐induced diastolic Ca 2+ overload and improved the rate and magnitude of posthypoxic contractile recovery during the first few minutes of reoxygenation. Moreover, diastolic Ca 2+ overload and posthypoxic contractile dysfunction were aggravated in ventricular myocytes either subjected to specific blockade of pm K ATP with HMR1098 (20 µM) or expressing the dominant‐negative pm K ATP construct Kir6.2(AAA) in the presence of P‐1075. Our results suggest that a common mechanism, involving resting membrane potential‐modulated increases in diastolic [Ca 2+ ] i , is responsible for the development of contractile dysfunction during reoxygenation following metabolic inhibition. This novel and highly plausible cellular mechanism for pm K ATP ‐mediated cardioprotection may have direct clinical relevance as evidenced by the following findings: a hypokalemic polarizing cardioplegia solution supplemented with the pm K ATP opener P‐1075 improved Ca 2+ homeostasis and recovery of function compared with hyperkalemic depolarizing St. Thomas' cardioplegia following contractile arrest in single ventricular myocytes and working rat hearts. We therefore propose that activation of pm K ATP channels improves posthypoxic cardiac function via reductions in abnormal diastolic Ca 2+ homeostasis mediated by reverse‐mode Na + /Ca 2+ exchange.