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Na(+)/H(+) exchange subtype 1 inhibition reduces endothelial dysfunction in vessels from stunned myocardium
1Division of Cardiovascular Medicine, Department of Internal Medicine, University of California, Davis 95616, USA. jdsymons@ucdavis.edu
Insights
Inhibiting the Na(+)/H(+) exchanger subtype 1 (NHE(1)) with cariporide lessened ischemia-induced microvascular dysfunction in rats. However, NHE(1) inhibition did not improve myocardial contractile function after reperfusion injury.
Area of Science:
- Cardiovascular Physiology
- Cellular Signaling
- Pharmacology
Background:
- Myocardial ischemia and reperfusion induce cellular dysfunction, known as stunning.
- The Na(+)/H(+) exchanger subtype 1 (NHE(1)) plays a role in cellular response to ischemia.
- Understanding NHE(1) inhibition's effect on myocardial and microvascular stunning is crucial for therapeutic development.
Purpose of the Study:
- To investigate the hypothesis that inhibiting NHE(1) during ischemia and reperfusion limits myocardial and coronary microvascular stunning.
- To assess the impact of cariporide, an NHE(1) inhibitor, on cardiac function and resistance artery reactivity post-ischemia.
Main Methods:
- Anesthetized rats underwent 2 x 10-min coronary artery occlusions with 5-min reperfusion, followed by 15 or 60 min of reperfusion.
- Vehicle or cariporide was administered 15 minutes before ischemia and throughout the protocol.
- Cardiac function (LV pressure, wall thickening) and resistance artery responses to acetylcholine and endothelin-1 were evaluated.
Main Results:
- Myocardial contractile function (LV pressure, wall thickening) was similarly depressed in vehicle- and cariporide-treated rats compared to controls.
- Acetylcholine-induced relaxation was blunted in both vehicle and cariporide groups but was significantly greater in the cariporide group after 15 min of reperfusion.
- Endothelin-1 contractile responses were similarly increased, while sodium nitroprusside relaxation was unchanged among groups.
Conclusions:
- NHE(1) inhibition with cariporide attenuates ischemia-induced microvascular dysfunction in coronary resistance arteries.
- NHE(1) inhibition does not improve myocardial contractile function in the area at risk following ischemia-reperfusion.
- These findings suggest a specific role for NHE(1) in microvascular stunning, distinct from myocardial stunning.
Abstract:
Myocardial ischemia and reperfusion cause myocyte and vascular dysfunction, frequently termed "stunning." We hypothesized that inhibiting the Na(+)/H(+) exchanger subtype 1 isoform (NHE(1)) during ischemia and reperfusion limits myocardial and coronary microvascular stunning. Anesthetized rats completed 2 x 10-min coronary artery occlusions separated by 5-min of reperfusion, followed by 15 or 60 min of reperfusion. Vehicle (saline) or the NHE(1) inhibitor cariporide (HOE-642) was administered 15 min before ischemia and was continued throughout each protocol. After reperfusion, hearts were excised, and the reactivity of resistance arteries (internal diameter, approximately 120 microm) was assessed. The first derivative of left ventricular (LV) pressure, LV developed pressure, and LV systolic wall thickening were depressed (P < 0.05) similarly in vehicle- and cariporide-treated rats during ischemia and after 15 or 60 min of reperfusion compared with sham-operated animals that were not exposed to ischemia (i.e., controls). In vessels obtained after 15 min of reperfusion, the maximal response to acetylcholine-induced relaxation (10(-8)-10(-4) M) was blunted (P < 0.05) in vessels from vehicle- (approximately 35%) and cariporide-treated rats (approximately 55%) compared with controls (approximately 85%). However, the percent relaxation to acetylcholine was greater (P < 0.05) in cariporide-treated rats compared with vehicle-treated rats. Maximal contractile responses to endothelin-1 (10(-11)-10(-7) M) were increased (P < 0.05) similarly in vehicle- and cariporide-treated rats compared with controls. Relaxation to sodium nitroprusside (10(-4) M) was not different among groups. Results were similar in vessels obtained from animals after 60 min of reperfusion. These findings suggest that NHE(1) inhibition before coronary occlusion lessens ischemia-induced microvascular dysfunction for 15-60 min after reperfusion but does not alter myocardial contractile function in the area at risk.