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

Abstract

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 β-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 β-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.

Figure 1. The chemical structures of 2-cyclohexylthio-AMP (A) and 2-mes-ATP (B)

Figure 2. An agonist-like effect of 2-cyclohexylthio-AMP

The effects of 2-cyclohexylthio-AMP on various working heart function parameters were determined in WT (A) and CSQ (B) mice. The agent caused an increase in +dP/dt and LVDevP without any change in heart rate in either WT (n=8) or CSQ (n=8) mice. In both WT and CSQ hearts, the increase in +dP/dt caused by 10 nM of the drug was less than that induced by 100 nM; the increase by 100 nM was in turn less than that caused by 1000 nM (Repeated Measures ANOVA and post-test comparison, P<0.05). Similarly, the increase in LVDevP was sequentially greater as the drug concentrations increased from 10 to 1000 nM except that in the WT hearts, the LVDevP was not statistically different between 10 and 100 nM of the drug (Repeated Measures ANOVA and post-test comparison, P<0.05).

Figure 3. Chronic infusion of 2-cyclohexylthio-AMP improved contractile performance in WT mice with LAD ligation

Myocardial function ex vivo was determined in the working heart preparation. Cardiac function in vivo was assessed by echocardiography. Separate series of mice with ischemic heart failure were infused with either drug or vehicle for 7 days, 1 month or 2 months after LAD ligation. The sample size and P values were indicated.

Figure 4. Chronic infusion of 2-cyclohexylthio-AMP restored β-adrenergic responsiveness in mice with ischemic HF using the working heart preparation

Isoproterenol was injected in the KHS buffer at the concentration 20 nmol/L to perfuse the heart via the coronary artery circulation. The effect of isoproterenol was expressed as the percentage of increase in +dP/dt. The sample size and P values were indicated.

Figure 5. Chronic infusion of 2-cyclohexylthio-AMP improved contractile performance in CSQ mice with HF

Cardiac function was determined by the ex vivo working heart preparation and by in vivo echocardiography. The sample size and P values were indicated.