Cardiac‐specific overexpression of P2X4 receptors enhanced myocyte contractility in the calsequestrin (CSQ) model of cardiomyopathy

Overexpression of the human P2X 4 purinoceptor (P2X 4 R) rescues the heart failure phenotype in the calsequestrin(CSQ)‐overexpressing transgenic (TG) model of cardiomyopathy (Am J Physiol 287:H1096, 2004). The objective is to study the contractility of binary P2X 4 R/CSQ (Binary) TG myocyte by comparing contraction shortening (CS) in ventricular myocytes. Cell length (102±1.8 μm vs. 108±2.3 μm, SE) and basal CS (5.3%±0.45% vs. 5.4%±0.38% of cell length, SE) at 0.2Hz pacing (22ºC) were similar in WT (N=41) vs. P2X 4 R myocytes (N=59). Cell length in Binary (151±1.6μm, N=54) was shorter than that in CSQ (158±2.1μm, N=60, p<0.05), indicating less hypertrophy. Basal CS in Binary (4.1±0.23 %) was greater than that in CSQ (2.6±0.20 %, p<0.02). At 2.0 Hz, basal CS was also greater in Binary (2.0±0.14%, N=30) than in CSQ (0.9±0.11 %, N=23, P<0.05) cells. With 3μM 2me‐SATP, CS increased significantly in myocytes from all four genotypes but the CS increases in P2X 4 R and Binary TG cells were greater than those in WT and CSQ cells respectively (P<0.05). Conclusion: Overexpression of the P2X 4 R in the CSQ model of cardiomyopathy caused enhanced myocyte contractility to agonist as well as increased basal myocyte contractility; the latter may be due to activation of the overexpressed P2X 4 R by endogenous extracellular ATP in vivo. Enhanced contractility may mediate the heart failure rescuing effect of P2X 4 R overexpression.