Cardioprotective effects of the P2X receptor agonist MRS2339 in dog and mouse models of heart failure

Abstract

Cardiac-specific overexpression of purinergic P2X4 receptors confers protection in murine post-infarct model of heart failure (HF). The goal of the present study was to determine whether chronic subcutaneous infusion of the hydrolysis-resistant P2X receptor agonist MRS2339 can delay the progression of HF in dog and a mouse models. Congestive HF was induced by 4-week left ventricular tachypacing in 5 dogs. Thirty μg/hr of MRS2339 were infused during the last two weeks of pacing. Compared to vehicle-infused dogs, after 1 week of MRS2339 infusion we observed a more preserved dP/dtmax (1827±40.9 vs 1508±88.8 mmHg/sec P=0.034) and stroke volume (39.3±5.4 vs. 27.1±2.1 ml, P=0.045). There were no significant differences in mean arterial pressure or heart rate. HF was also induced in 11 mice by permanent left coronary ligation and 0, 3.3, 10, 100 and 300 μM of MRS2339 was infused over 28 days. Using isolated working heart preparation, MRS2339 preserved dP/dtmax compared to vehicle (6983±499 vs 6250±452, P<0.0001) and stroke volume (6.9±1.2 vs. 5.1 ±1.4, P<0.0001) in a dose-dependent manner in both genders. The improvement in cardiac performance was not due to significant differences in infarct size among groups. In conclusion, P2X receptor stimulation by the agonist MRS2339 activates protective mechanisms that partially oppose the progression towards decompensation in dog and mouse models of HF for either gender.