Grousset C

Preconditioning with potassium channel openers: ☆ ☆☆ ★ ★★ ♢: A new concept for enhancing cardioplegic protection?

Ischemic preconditioning defines an adaptive endogenous mechanism in which a brief episode of reversible ischemia renders the heart more resistant to a subsequent period of sustained ischemia. Because the cardioprotective effects of ischemic preconditioning might be mediated by an activation of adenosine triphosphate-sensitive potassium channels, this study was designed to assess whether these effects could be duplicated by the preischemic administration of a potassium channel opener. Fifty isolated isovolumic buffer-perfused rat hearts underwent 45 minutes of normothermic potassium arrest followed by 1 hour of reperfusion. They were divided into five equal groups that differed with regard to the preconditioning regimen: Group 1 hearts were left untreated and served a controls; in group 2, preconditioning was achieved with 5 minutes of total global ischemia followed by 5 minutes of buffer reperfusion before cardioplegic arrest; in group 3, the preconditioning stimulus consisted of a 5-minute infusion of the potassium channel opener nicorandil (10 mumol/L) followed by 5 minutes of drug-free buffer perfusion before arrest; group 4 hearts underwent a similar protocol except that the infusion of nicorandil was preceded by that of the potassium channel blocker glibenclamide (10 mumol/L); group 5 hearts were ischemically preconditioned like those of group 2 except that the no-flow preconditioning period was also preceded by a 5-minute infusion of glibenclamide (50 mumol/L). The results demonstrate that ischemic preconditioning significantly improved contractility and reduced contracture during reperfusion, as compared with results in control hearts. These protective effects were duplicated by pretreatment with nicorandil but were abolished when the drug was antagonized by a prior infusion of glibenclamide. Likewise, the glibenclamide-induced blockade of potassium channels largely blunted the beneficial effects of ischemic preconditioning. These data suggest that opening of adenosine triphosphate-sensitive potassium channels substantially contributes to preconditioning-induced cardiac protection in a surgically relevant model of global ischemia and, consequently, that the use of potassium channel openers like nicorandil could be an effective means of enhancing cardioplegic protection.

Evaluation of high-energy phosphate metabolism during cardioplegic arrest and reperfusion: a phosphorus-31 nuclear magnetic resonance study.

Hypothermic potassium cardioplegia is now commonly used to protect the myocardium during surgically induced ischemia. Because the potassium-related membrane depolarization has been shown to increase calcium influx, we undertook this study to define the effects of varying the calcium content in hyperkalemic perfusates and the effects of using magnesium instead of or in addition to potassium as the arresting agent on the ability of hearts to recover normal function after ischemic arrest. We subjected isolated perfused working rat hearts to 60 minutes of cardioplegic arrest followed by 30 minutes of reperfusion, and measured high-energy phosphate levels every 2½ minutes by phosphorus-31 nudear magnetic resonance spectroscopy. These data were correlated with postischemic recovery of function. Our results show that potassium cardioplegia may be harmful when the calcium concentration is greater than 1 mM. The kalemic injury is significantly reduced when the calcium content is lowered to 0.25 mM and the greatest extent of preservation is provided by a calcium-poor perfusate (0.25 mM) containing 13 mM magnesium. The beneficial effects of magnesium are not enhanced by subsequent addition of potassium. Close correlations were found between all observed metabolic changes during arrest and the degree of recovery of contractile performance after reperfusion. We conclude that the ability of the myocardium to maintain or resynthesize high-energy phosphate after cardioplegic arrest may be an important determinant of postischemic mechanical performance. These results show that phosphorus-31 nuclear magnetic resonance spectroscopy is a valuable method for evaluating interventions to reduce the severity of ischemic damage.

Limitations of Potassium Cardioplegia during Cardiac Ischemic Arrest: A Phosphorus 31 Nuclear Magnetic Resonance Study

Cold K+ cardioplegia is commonly used to preserve the myocardium during surgical ischemia. Since the K+-induced membrane depolarization could cause a Ca2+-mediated breakdown of adenosine triphosphate, this study compared the influence of different electrolytes on high-energy phosphate metabolism during cardioplegic arrest phosphate metabolism during cardioplegic arrest and subsequent recovery of mechanical function. An isolated working heart was subjected to hypothermic ischemia for one hour. Metabolic studies were assessed on phosphorus 31 nuclear magnetic resonance (NMR). Results show that (1) K+ cardioplegia is harmful when the Ca2+ content is equal to 2 mEq/I; (2) deleterious effects of K+ are markedly reduced by lowering the Ca2+ content; (3) the most adequate preservation is provided by a Mg2+-rich-Ca2+-poor perfusate; (4) this protection is not enhanced by addition of K+. Finally, 31P NMR appears particularly appropriate for evaluating myocardial protection techniques since it allows noninvasive serial monitoring of high-energy phosphate content and subsequent correlation with functional recovery after ischemia.

Pretreatment with captopril improves myocardial recovery after cardioplegic arrest.

Summary: Among the interventions designed to limit postischemic oxidative injury, those that enhance the myocardial content of thiol groups are attractive because thiols are powerful antioxidants. Indeed, part of the protection afforded by the angiotensin-converting enzyme (ACE) inhibitor captopril in regional myocardial ischemia is attributed to its thiol group. This study assesses the effects of captopril in a surgically relevant model of global ischemic arrest. Thirty rats were implanted subcutaneously (s.c.) with osmotic pumps that allowed continuous delivery of captopril (total dose 75 mg), enalapril (a nonthiol-containing ACE inhibitor, total dose 7.5 mg) or saline in 48 h. Drug concentrations were equipotent in their effect on angiotensin I (ANGI) pressor response. Hearts were then excised, perfused under isovolumic conditions, and subjected to 90-min cardioplegic arrest at 30°C followed by 1-h reperfusion. Pre- and postischemic coronary flows were significantly higher to a similar extent in the two drug-pretreated groups than in controls. However, captopril-pretreated hearts had the best recovery of contractility (dP/dtmax: 3,590 ± 74 versus 2915 ± 64 mm Hg s−1 in the enalapril group, p < 0.001), and diastolic pressures (13.7 ± 0.9 mm Hg vs. 20.0 ± 1.6 mm Hg in the enalapril group, p < 0.05). We conclude that pretreatment with ACE inhibitors improves myocardial recovery after cardioplegic arrest and that captopril is more effective than enalapril. The additional protection afforded by captopril was not flow mediated, suggesting that the cardioprotective effects of this drug not only involve an ACE inhibition-dependent coronary vasodilation but could be related to a thiol-dependent limitation of oxidative injury.