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HOE-642 (cariporide) alters pH(i) and diastolic function after ischemia during reperfusion in pig hearts in situ
M A Portman1, A L Panos, Y Xiao
1Division of Cardiology, Department of Pediatrics, University of Washington and Children's Hospital and Regional Medical Center, Seattle, Washington 98105, USA. mportm@chmc.org
Insights
The Na(+)/H(+) exchange inhibitor HOE-642 delays myocardial intracellular alkalinization during reperfusion. This action is associated with improved diastolic function and preservation of high-energy phosphates in situ.
Area of Science:
- Cardiology
- Biochemistry
- Physiology
Background:
- The Na(+)/H(+) exchanger plays a role in myocardial response to ischemia and reperfusion.
- HOE-642 is a specific inhibitor of Na(+)/H(+) exchange.
- Its effects on ion flux in vitro are known, but in vivo confirmation in complex conditions is needed.
Purpose of the Study:
- To investigate the effects of HOE-642 on myocardial intracellular pH (pH(i)) and high-energy phosphates during ischemia and reperfusion in situ.
- To determine if HOE-642 alters diastolic function and preserves myocardial energy status.
Main Methods:
- Utilized (31)P magnetic resonance spectroscopy to monitor pH(i) and high-energy phosphates in open-chest pigs.
- Animals underwent 10 minutes of ischemia and reperfusion with cardiopulmonary bypass.
- HOE-642 was administered intravenously before ischemia; diastolic stiffness and left ventricular function were assessed.
Main Results:
- HOE-642 administration prevented increases in diastolic stiffness observed in control pigs.
- No changes in pH(i) during ischemia were noted, but realkalinization during reperfusion was significantly delayed.
- Phosphocreatine levels were unaffected, but ATP preservation was improved.
- Postischemic peak-elastance and pressure-rate product were not altered.
Conclusions:
- Na(+)/H(+) exchange inhibition by HOE-642 delays myocardial intracellular alkalinization during reperfusion in vivo.
- This delay is linked to improved diastolic function and better preservation of high-energy phosphates.
- HOE-642 demonstrates potential therapeutic benefits in mitigating ischemic and reperfusion injury.
Abstract:
The specific Na(+)/H(+) exchange inhibitor HOE-642 prevents ischemic and reperfusion injury in the myocardium. Although this inhibitor alters H(+) ion flux during reperfusion in vitro, this action has not been confirmed during complex conditions in situ. Myocardial intracellular pH (pH(i)) and high-energy phosphates were monitored using (31)P magnetic resonance spectroscopy in open-chest pigs supported by cardiopulmonary bypass during 10 min of ischemia and reperfusion. Intravenous HOE-642 (2 mg/kg; n = 8) administered before ischemia prevented the increases in diastolic stiffness noted in control pigs (n = 8), although it did not alter the postischemic peak-elastance or pressure-rate product measured using a distensible balloon within the left ventricle. HOE-642 induced no change in pH(i) during ischemia but caused significant delays in intracellular realkalinization during reperfusion. HOE-642 did not alter phosphocreatine depletion and repletion but did improve ATP preservation. Na(+)/H(+) exchange inhibition through HOE-642 delays intracellular alkalinization in the myocardium in situ during reperfusion in association with improved diastolic function and high-energy phosphate preservation.