| Autor: |
Clements-Jewery, Hugh, Sutherland, Fiona J., Allen, Mary C., Tracey, W. Ross, Avkiran, Metin |
| Předmět: |
|
| Zdroj: |
British Journal of Pharmacology; May2004, Vol. 142 Issue 1, p57-66, 10p |
| Abstrakt: |
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°C) and normothermic reperfusion (60?min at 37°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 (IC50 73?nM at 25°C). A comparable NHE1-inhibitory potency was retained at 37°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 (IC50 67?nM at 25°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?µM. 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.British Journal of Pharmacology (2004) 142, 57-66. doi:10.1038/sj.bjp.0705749 [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
|
