Cardioprotective efficacy of zoniporide, a potent and selective inhibitor of Na+/H+ exchanger isoform 1, in an experimental model of cardiopulmonary bypass

1 We determined (1) the inhibitory potency of zomporide against the native Na+/H+ exchanger isoform 1 (NHE1) that is expressed in adult rat ventricular myocytes and platelets, and (2) the cardioprotective efficacy of zomporide in isolated, blood-perfused adult rat hearts subjected to cardioplegic arrest, hypothermic ischaemia (150 min at 25degreesC) and normothermic reperfusion (60 min at 37degreesC). 2 In isolated myocytes, in which NHE1 activity was determined directly by measurement of H+ efflux rate following intracellular acidification, zoniporide produced a dose-dependent inhibition of such activity (IC50 73 nm at 25degreesC). A comparable NHE1-inhibitory potency was retained at 37degreesC. 3 In platelets, in which the rate of cell swelling was used as a surrogate index of NHE1 activity, this was again inhibited by zoniporide (IC50 67 nm at 25degreesC). 4 In the isolated heart model, administration of zoniporide (loading bolus of 1 mg kg(-1) i.v. plus continuous infusion at 1.98 mg kg(-1) h(-1) i.v.) to the support animal achieved a free plasma drug concentration of greater than or equal to 1 muM. At this dose, zoniporide afforded significant cardioprotective benefit relative to vehicle treatment, with improved preservation of left ventricular end-diastolic and developed pressures and coronary perfusion pressure during reperfusion. Myocardial myeloperoxidase activity was also attenuated by zomporide treatment, indicating reduced neutrophil accumulation. 5 These data show that zomporide (1) is a potent inhibitor of native NHE1 activity in ventricular myocytes and platelets, and (2) affords significant cardioprotective benefit during ischaemia and reperfusion in an experimental model that mimics several distinctive features of human cardioplegic arrest with cardiopulmonary bypass.