The positive inotropic effect of an alpha 1-adrenoceptor agonist, such as phenylephrine, is accompanied by an increase in the presumed second messenger, inositol 1,4,5-trisphosphate (1,4,5-IP3) and inositol 1,3,4,5-tetrakisphosphate (1,3,4,5-IP4), which may release calcium from the sarcoplasmic reticulum (SR) and/or facilitate calcium entry from the extracellular space. In addition, phenylephrine sensitizes the contractile proteins for calcium. Alpha 1-adrenergic positive inotropic effects are enhanced in heart muscle preparations from cardiomyopathic hamsters and are reduced in heart muscle preparations from human failing myocardium. How the negative inotropic effects of M-cholinoceptor agonists work in the presence of cAMP-increasing agents in ventricular heart muscle preparations is discussed. It involves cAMP-reduction, an increase in cGMP and activation of phosphatase activity. In a rat model, chronic beta-adrenergic stimulation leads to increased sensitivity of rat ventricular tissue for the negative inotropic effect of the M-cholinoceptor agonist, carbachol. This might be due to facilitated signal transduction via increased Gi proteins. In human ventricular tissue from hearts with end-stage heart failure, due to idiopathic dilated cardiomyopathy (IDC), an increased Gi protein has also been found. However, the negative inotropic effects of carbachol were unchanged. The data indicate that changes in alpha-adrenergic and M-cholinergic responses in the heart may depend on underlying causes that induce changes.