The therapeutic effect of 2-cyclohexylthio-AMP in heart failure.

Aim: The aim of this study was to investigate the therapeutic effect of 2-cyclohexylthio-adenosine 5 '-monophosphate (AMP) in mice with heart failure (HF). Methods: 2-Cyclohexylthio-AMP was dissolved in phosphate-buffered saline and infused in mice with ischemic HF after permanent left coronary [left anterior descending (LAD)] ligation and in calsequestrin (CSQ) mice with HF. Myocardial function ex vivo was determined in the working heart model. Cardiac function in vivo was assessed by echocardiography. Results: Injection of 2-cyclohexylthio-AMP induced a dose-dependent increase in +dP/dt, -dP/dt, and left ventricular developed pressure in normal wild-type mice and in CSQ mice with HF using the ex vivo working heart model. Spontaneous heart rate did not change after the injection of 2-cyclohexylthio-AMP. Compared with normal saline-treaded mice, chronic infusion of 2-cyclohexylthio-AMP in mice with ischemic HF after left coronary artery (LAD) ligation and in CSQ mice resulted in improved +dP/dt, -dP/dt, left ventricular developed pressure, and fractional shortening, restored the beta-adrenergic response and decreased heart weight/body weight ratios. Conclusions: 2-Cyclohexylthio-AMP improved the cardiac contractile performance and rescued mice from HF. This salutary action may result from the reduction of myocardial hypertrophy and the restoration of the beta-adrenergic response in both LAD ligation and CSQ mouse models of HF. The fact that this agent can increase contractile performance without heart rate increase should be desirable in HF therapy.