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Na(+)/H(+) exchange inhibition-induced cardioprotection in dogs: effects on neutrophils versus cardiomyocytes
R J Gumina1, J Auchampach, R Wang
1Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Insights
Sodium-hydrogen exchanger 1 (NHE-1) inhibition protects the heart by reducing infarct size and mitigating neutrophil activity. This targeted approach offers a novel strategy for treating myocardial ischemia-reperfusion injury.
Area of Science:
- Cardiology
- Cellular Biology
- Pharmacology
Background:
- Numerous studies have investigated Na(+)/H(+) exchanger (NHE) inhibition's effects on the myocardium.
- The specific impact of NHE-1 inhibition on neutrophil function remains underexplored.
Purpose of the Study:
- To investigate the effects of NHE-1 inhibition on infarct size and neutrophil function in a canine model of myocardial ischemia-reperfusion injury.
- To evaluate the protective mechanisms of NHE-1 inhibition on cardiomyocytes.
Main Methods:
- An in vivo canine model of myocardial ischemia-reperfusion injury was employed.
- Selective NHE-1 inhibitor BIIB-513 was administered prior to ischemia.
- Infarct size (IS) as a percentage of area at risk (IS/AAR), neutrophil accumulation, and neutrophil respiratory burst were assessed.
Main Results:
- NHE-1 inhibition significantly reduced IS/AAR and neutrophil accumulation in the ischemic myocardium.
- NHE-1 inhibition attenuated neutrophil respiratory burst induced by phorbol 12-myristate 13-acetate and platelet-activating factor.
- Direct protection of cardiomyocytes against metabolic inhibition-induced damage was observed.
Conclusions:
- Cardioprotection afforded by NHE-1 inhibition is likely attributed to direct cardiomyocyte protection.
- Attenuation of neutrophil activity contributes to the observed cardioprotective effects of NHE-1 inhibition.
Abstract:
Numerous studies have examined the effect of Na(+)/H(+) exchanger (NHE) inhibition on the myocardium; however, the effect of NHE-1 inhibition on neutrophil function has not been adequately examined. An in vivo canine model of myocardial ischemia-reperfusion injury in which 60 min of left anterior descending coronary artery occlusion followed by 3 h of reperfusion was used to examine the effect of NHE-1 inhibition on infarct size (IS) and neutrophil function. BIIB-513, a selective inhibitor of NHE-1, was infused before ischemia. IS was expressed as a percentage of area at risk (IS/AAR). NHE-1 inhibition significantly reduced IS/AAR and reduced neutrophil accumulation in the ischemic myocardium. NHE-1 inhibition attenuated both phorbol 12-myristate 13-acetate- and platelet-activating factor-induced neutrophil respiratory burst but not CD18 upregulation. Furthermore, NHE-1 inhibition directly protected cardiomyocytes against metabolic inhibition-induced lactate dehydrogenase release and hypercontracture. This study provides evidence that the cardioprotection induced by NHE-1 inhibition is likely due to specific protection of cardiomyocytes and attenuation of neutrophil activity.
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