Inositol-1,4,5-trisphosphate increase by diadenosine tetraphosphate in preparations from failing human myocardium.

In human ventricular trabeculae carneae 100 microM AP4A (diadenosine tetraphosphate) increased force of contraction to 162.8+/-15.7% of predrug value (n=9). This positive inotropic effect was accompanied by a prolongation of time parameters: time to peak tension and time of relaxation were prolonged by 7.8+/-1.3% and 14.9+/-3.8%, respectively (P<0.05). In the same trabeculae, AP4A increased IP3 (inositol-1,4,5-trisphosphate) content from 9.0+/-1.3 pmol/mg to 22.9+/-5.4 pmol/mg protein (n=5-9). In conclusion, the positive inotropic effect of AP4A in the human myocardium is likely due to an increase of IP3 mediated probably via Gq-coupled P2Y-purinoceptors. Because of the prominent role of Gq in the development of cardiac disease, these findings may lay the ground to further investigate the possible role of AP4A and/or related ligands (e.g. AP2A and AP3A) in heart failure.