Cardioprotection with cariporide, a sodium-proton exchanger inhibitor, after prolonged ischemia and reperfusion in senescent rats
Introduction
The Na+–H+exchanger (NHE) restores intracellular pH during ischemia and reperfusion by elevating the intracellular Na+which, in turn, stimulates the Na+–Ca2+exchanger in reverse mode and leads to intracellular Ca2+overload in different cells, including cardiocyte and endothelial cells (review in Frohlich and Karmazin, 1997, Ladilov et al., 2000). Such a calcium overload has been reported to be an important mechanism in cardiac dysfunction during ischemia as well as reperfusion, especially during aging (review in Avkiran and Marber, 2002).
Cardioprotection with NHE inhibitors has been demonstrated in adult heart by numerous studies in both animals and humans (review in Frohlich and Karmazin, 1997, Avkiran and Marber, 2002). During ischemia-reperfusion, NHE inhibitors improve cardiac function, reduce infarct size (Rohmann et al., 1995, Klein et al., 2000) and limit ventricular arrhythmias (review in Fröhlich and Karmazyn, 1997) but also reduce neutrophil accumulation in risk area (Muraki et al., 2003), high energy phosphate depletion (Portman et al., 2001) and myocyte necrosis and apoptosis (Klein et al., 1997, Chakrabarti et al., 1997). However the exact mechanism(s) of such a protective effect remains unclear. They were originally thought to exert cardioprotection during early reperfusion by slowing normalisation of intracellular pH and subsequent intracellular Ca+overload (Shimada et al., 1996, Park et al., 1999). However, such a protective effect was, in fact, largely dependent on their administration before the onset of ischemia, suggesting that these drugs act mainly during ischemia (Klein et al., 1998, Klein et al., 2000). Finally, recent studies strongly suggest beneficial effect of NHE inhibitors on endothelial coronary dysfunction, contributing to the improvement of post-ischemic recovery of contractility (Symons and Schaefer, 2001, Gumina et al., 2001, Maczewski and Beresewicz, 2003, Muraki et al., 2003). However, the cardioprotective effect of such NHE inhibitors during ischemia and reperfusion remains to be investigated in senescent heart.
The aged heart is characterised by a reduced coronary flow and perfusion reserve, an impairment of coronary vasoreactivity, an ex-vivo contractile dysfunction and a decreased calcium tolerance (review in Swynghedauw, 1999). Different studies have previously reported a particular vulnerability of the senescent heart to ischemia-reperfusion. Indeed, prolonged low-flow ischemia (LFI) induces severe coronary vasoconstriction and contractile dysfunction (Assayag et al., 1998) while myocardial reperfusion is associated with lower postischemic recovery of both coronary flow and contractility (Ataka et al., 1992, Stewart et al., 1995, Tani et al., 1997, Besse et al., 2001). This age-associated decrease in ischemic tolerance has been attributed to an accelerated accumulation of intracellular Na+(Tani et al., 1997), resulting from pH normalisation by NHE (Stewart et al., 1995), and leading to higher Ca2+overload during ischemia (Ataka et al., 1992). Moreover, ischemic preconditionning is unsuccessful during aging partly because it fails to lessen the increase in intracellular Na+during ischemia (review in Pepe, 2001).
Age, by itself, constitutes an independent morbidity and mortality risk factors during myocardial infarction or angina pectoris (White et al., 1996, Jousilahti et al., 1999). Surprisingly, few cardioprotective strategies, focused on the normalisation of such ionic perturbations with pharmacological agents, have been developed in senescent heart (Besse et al., 2001, Garnier-Raveaud et al., 2002), and none is presently available concerning NHE inhibitors. The objective of the present study was to investigate whether, in senescence, cariporide, a specific NHE1 inhibitor, exerts beneficial effects on contractile function and coronary vasomotricity (1) during prolonged LFI and (2) during reperfusion following LFI, using an isolated perfused rat heart model.
Section snippets
Animals and experimental groups
Adult (4 month-old) and senescent (24 month-old) male Wistar rats were obtained from IFFA CREDO (Lyon, France). The spontaneous mortality rate of the 24 month-old population was 50% (Besse et al., 1993).
Four and 24 month-old (mo) rats were, respectively, subdivided into 2 randomised subgroups submitted to prolonged LFI without (4 mo-I-control, n=12 and 24 mo-I-control, n=13, respectively) or with (4 mo-I-cariporide, n=11 and 24 mo-I-cariporide n=11, respectively) cariporide treatment and into 2
Baseline parameters
In isolated hearts, baseline parameters of coronary flow, resting tension and active tension were decreased in all 24 mo groups as compared to those measured in 4 mo groups (Table 1) but were similar among age-matched groups.
Coronary flow and myocardial function during prolonged ischemia: effect of cariporide
Impairment of active tension, coronary resistances and resting tension during LFI was earlier and greater in senescent than in adult hearts In adult hearts, cariporide treatment unmodified contractile function and coronary resistances during LFI (Fig. 1, Fig. 2). In
Discussion
The present study is the first to show that the selective NHE1 inhibitor, cariporide specifically protects the senescent heart against low-flow ischemia and reperfusion injury.
Acknowledgements
The authors thank Dr Claude Sebban and Brigitte Decros for kindly providing senescent rats. This study was supported by grants from Fondation de France and Région Rhône-Alpes.
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