On the mechanism of positive inotropic effects of alpha-adrenoceptor agonists.

The positive inotropic effect of the alpha 1-adrenoceptor agonist phenylephrine is accompanied by an increase in the presumed second messengers inositol 1,4,5-trisphosphate (1,4,5-IP3) and inositol 1,3,4,5-tetrakisphosphate (1,3,4,5-IP4). Both 1,4,5-IP3 and 1,3,4,5-IP4 sensitize myocardial contractile proteins in chemically skinned fibers. In addition to the Ca++ releasing effect of 1,4,5-IP3 from the sarcoplasmic reticulum the Ca++-sensitizing effect of the inositol phosphates may play a role in alpha 1-adrenergic positive inotropism. In isolated heart muscle preparations from patients with endstage heart failure (due to dilated cardiomyopathy) beta-adrenergic as well as alpha 1-adrenergic effects are reduced compared to preparations from healthy hearts. The reduced beta-adrenergic effects can in part be explained by an increased content of signal transducing G1-proteins. It is tempting to investigate whether other G proteins are also altered in severe congestive heart failure.