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Comparison of the protective effects of ischemic preconditioning and the Na+/H+ exchanger blockade
1Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Centro de Investigaciones Cardiovasculares, Universidad Nacional de La Plata, Argentina. smosca@atlas.med.unlp.edu.ar
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Ischemic preconditioning (IP) and Na+/H+ exchanger blockade (NHEb) both protect heart function post-ischemia. However, NHEb prevents ischemic contracture, while IP does not, and IP
Area of Science:
- Cardiology
- Physiology
- Biochemistry
Background:
- Ischemic heart disease remains a leading cause of mortality.
- Understanding protective mechanisms against ischemia-reperfusion injury is crucial for developing effective therapies.
- Ischemic preconditioning (IP) and Na+/H+ exchanger blockade (NHEb) are known cardioprotective strategies.
Purpose of the Study:
- To compare the protective effects of IP and NHEb using specific blockers (EIPA, HOE 642) on cardiac function and energy metabolism in an isolated perfused rat heart model.
- To elucidate the distinct mechanisms underlying the cardioprotection offered by IP and NHEb, particularly concerning ischemic contracture and protein kinase C (PKC) involvement.
Main Methods:
- Utilized an isovolumic perfused rat heart model subjected to 20 minutes of ischemia and 30 minutes of reperfusion.
- Administered IP and NHEb with ethylisopropylamiloride (EIPA) and HOE 642.
- Assessed systolic and diastolic function (e.g., +dP/dtmax), ATP levels, and ischemic contracture (LVEDP).
- Investigated the role of PKC by using chelerythrine, a PKC inhibitor.
Main Results:
- Both IP and NHEb significantly improved post-ischemic systolic function (+dP/dtmax) compared to controls.
- NHEb, but not IP, effectively prevented ischemic contracture (LVEDP).
- ATP levels were partially preserved by IP and EIPA-mediated NHEb post-reperfusion.
- PKC inhibition abolished IP-induced protection but not NHEb-induced protection.
Conclusions:
- IP and NHEb offer comparable protection to post-ischemic cardiac function but differ mechanistically.
- NHEb is superior in preventing ischemic contracture, a key determinant of cardiac damage.
- The protective pathways of IP and NHEb are distinct, with IP involving PKC and NHEb acting independently of PKC in this model.
Abstract:
The protective effects of ischemic preconditioning (IP) and Na+/H+ exchanger blockade (NHEb) by two blockers [ethylisopropylamiloride (EIPA) and HOE 642] were compared in the isovolumic perfused rat heart. The impairment in systolic and diastolic function detected in control ischemic hearts (C) exposed to 20 min of ischemia and 30 min of reperfusion was diminished in similar extent by IP and by NHEb with EIPA and HOE 642. At the end of the reperfusion period +dP/dtmax values were 57+/-9% in C hearts and 94+/-6%, 82+/-6% and 104+/-6% after IP and NHEb with EIPA and HOE 642, respectively. A depletion of ATP levels detected in C hearts after reperfusion (from 20.2+/-0.8 micromol/g dry weight before ischemia to 6.9+/-0.7 micromol/g dry weight) was partially prevented by both IP and NHEb with EIPA (9.2+/-0.7 micromol/g dry weight and 11.1+/-0.5 micromol/g dry weight, respectively). The ischemic contracture (IC), assessed by the left ventricular end diastolic pressure (LVEDP), observed in C hearts (35+/-4 mmHg) was not decreased by IP (40+/-4 mmHg) but it was prevented by NHEb (18+/-4 mmHg and 10+/-3 mmHg with EIPA and HOE 642, respectively). The ATP levels at the end of the ischemic period were similar in C and IP hearts (4.1+/-0.2 micromol/g dry wt vs. 3.3+/-0.4 micromol/g dry wt) but they were significantly higher after NHEb with HOE 642 (7.0+/-1.0 micromol/g dry wt). PKC inhibition by chelerythrine abolished the protection induced by IP after reperfusion although not the improvement induced by NHEb with EIPA. According to the present results, we can conclude that despite the fact that IP and NHEb are protecting the postischemic function in a similar magnitude, both interventions are different in terms of modifying IC that develops during the ischemic period. IC was prevented by NHEb whereas it was not by IP. Furthermore, IP protection and not that obtained by NHEb is abolished by PKC.