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Published on: August 6, 2015
Blocking Na(+)/H(+) exchange reduces [Na(+)](i) and [Ca(2+)](i) load after ischemia and improves function in intact
J An1, S G Varadarajan, A Camara
1Anesthesiology Research Laboratory, Department of Anesthesiology, The Medical College of Wisconsin, Milwaukee, 53226, USA.
Insights
Inhibiting sodium-hydrogen exchange (NHE) with benzamide (BIIB-513) in guinea pig hearts reduced intracellular sodium and calcium overload during ischemia and reperfusion. This intervention improved cardiac function and significantly reduced infarct size, highlighting NHE
Area of Science:
- Cardiovascular Physiology
- Cellular Electrophysiology
- Pharmacology
Background:
- Ischemia-reperfusion injury significantly impacts cardiac function and viability.
- Intracellular ion overload, particularly sodium (Na+) and calcium (Ca2+), is implicated in reperfusion injury.
- Sodium-hydrogen exchange (NHE) plays a critical role in regulating intracellular pH and Na+ balance.
Purpose of the Study:
- To investigate the effect of NHE inhibition on intracellular Na+ and Ca2+ levels during ischemia and reperfusion in intact hearts.
- To determine if NHE inhibition improves cardiac function and reduces infarct size following ischemia-reperfusion.
- To assess the therapeutic potential of selective NHE-1 inhibitors like benzamide (BIIB-513).
Main Methods:
- Isolated guinea pig hearts were subjected to 30 minutes of ischemia followed by reperfusion.
- Selective NHE-1 inhibitor benzamide (BIIB-513) was administered either before ischemia or upon reperfusion.
- Intracellular Na+ ([Na+]i) and Ca2+ ([Ca2+]i) concentrations were measured using fluorescence dyes.
- Left ventricular pressure (LVP), ventricular fibrillation, and infarct size were assessed.
Main Results:
- Benzamide (BIIB-513) significantly decreased peak increases in [Na+]i and [Ca2+]i during reperfusion.
- Treatment with BIIB-513 improved systolic-diastolic LV pressure, cardiac efficiency, and oxygen consumption.
- BIIB-513 reduced the incidence of ventricular fibrillation by 54% and decreased infarct size from 64% to 20%.
Conclusions:
- Sodium loading is a key marker of reperfusion injury in intact hearts.
- Inhibition of NHE effectively reduces Na+ and Ca2+ loading during reperfusion, thereby improving cardiac function.
- Selective NHE inhibition offers a promising therapeutic strategy for mitigating ischemia-reperfusion injury in the heart.
Abstract:
We determined in intact hearts whether inhibition of Na(+)/H(+) exchange (NHE) decreases intracellular Na(+) and Ca(2+) during ischemia and reperfusion, improves function during reperfusion, and reduces infarct size. Guinea pig isolated hearts were perfused with Krebs-Ringer solution at 37 degrees C. Left ventricular (LV) free wall intracellular Na(+) concentration ([Na(+)](i)) and intracellular Ca(2+) concentration ([Ca(2+)](i)) were measured using fluorescence dyes. Hearts were exposed to 30 min of ischemia with or without 10 microM of benzamide (BIIB-513), a selective NHE-1 inhibitor, infused for 10 min just before ischemia or for 10 min immediately on reperfusion. At 2 min of reperfusion, BIIB-513 given before ischemia decreased peak increases in [Na(+)](i) and [Ca(2+)](i), respectively, from 2.5 and 2.3 times (controls) to 1.6 and 1.3 times pre-ischemia values. At 30 min of reperfusion, BIIB-513 increased systolic-diastolic LV pressure (LVP) from 49 +/- 2% (controls) to 80 +/- 2% of pre-ischemia values. BIIB-513 reduced ventricular fibrillation by 54% and reduced infarct size from 64 +/- 1% to 20 +/- 3%. First derivative of the LVP, O(2) consumption, and cardiac efficiency were also improved by BIIB-513. Similar results were obtained with BIIB-513 given on reperfusion. These data show that Na(+) loading is a marker of reperfusion injury in intact hearts in that inhibiting NHE reduces Na(+) and Ca(2+) loading during reperfusion while improving function. These results clearly implicate the ionic basis by which inhibiting NHE protects the guinea pig intact heart from ischemia-reperfusion injury.
