Positive inotropic effect in the heart produced by acetylcholine

The effect of acetylcholine on cardiac muscle contractility and hemodynamics was investigated in human atrial strips and in isolated working rat heart. Activation of the muscarinic receptor in the heart muscle is generally known to result in negative chronotropic and inotropic effects. In our study, positive inotropic effects of acetylcholine (ACh) were observed in both human right atrial strips and in the working rat heart. Exposure of the human right atrial strips to ACh (IO-7 - KM M) produced a dose dependent tri-phasic (positivenegative-positive) inotropic effect in approximately 40% of the strips. In muscle strips that exhibited only a negative inotropic effect, a positive response was observed following washout of ACh. Both positive and negative effects were antagonized by atropine. Exposure of the paced working rat heart to ACh (IO-7 - 10 5 M) resulted in a dose dependent decrease in mean coronary flow followed by depression in cardiac function. When the heart was initially treated with the vasodilator adenosine (2 x 10 6 M), exposure to ACh (lO-7 -105 M) had no effect on coronary flow and produced a dose dependent augmentation of all cardiodynamic indices: left ventricular pressure, isovolumic pressure, cardiac output, maximal aortic flow and stroke work. This positive response was antagonized by atropine. Exposure of the rat ventricular strips increased the formation of [3H]phosphoinositide breakdown products (e.g. inositol phosphates IP, IP2, IP3). These observations demonstrate that cholinergic muscarinic stimulation may produce positive inotropic effects in both human and rat cardiac muscle. Furthermore, our results suggest that IP3 may be a mediator in this process.