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 zoniporide 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 zoniporide in isolated, blood-perfused adult rat hearts subjected to cardioplegic arrest, hypothermic ischaemia (150 min at 25 degrees C) and normothermic reperfusion (60 min at 37 degrees C). 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 (IC(50) 73 nm at 25 degrees C). A comparable NHE1-inhibitory potency was retained at 37 degrees C. 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 (IC(50) 67 nm at 25 degrees C). 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 >/=1 microm. 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 zoniporide treatment, indicating reduced neutrophil accumulation. 5. These data show that zoniporide (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.
Clements-Jewery
Hugh
H
Centre for Cardiovascular Biology and Medicine, King's College London, The Rayne Institute, St Thomas' Hospital, London.
Sutherland
Fiona J
FJ
Allen
Mary C
MC
Tracey
W Ross
WR
Avkiran
Metin
M
D000818:Animals; D002314:Cardioplegic Solutions / Q000008:administration & dosage; D002315:Cardiopulmonary Bypass / Q000379:methods*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006146:Guanidines / Q000494:pharmacology*; D006324:Heart Arrest, Induced / Q000379:methods*; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors* / Q000378:metabolism
D002314:Cardioplegic Solutions; D002316:Cardiotonic Agents; D006146:Guanidines; D020033:Protein Isoforms; D011720:Pyrazoles; C452850:Slc9a1 protein, rat; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; C424422:zoniporide