Positive inotropic stimulation in the normal and insufficient human myocardium

Cardiac alpha- and beta-adrenoceptors and the positive inotropic effects of several adenylate cyclase dependent and independent agents have been measured in papillary muscle strips from patients without, as well as with moderate and severe heart failure. The number of beta-adrenoceptors was found to be decreased depending on the degree of heart failure. This does not apply to alpha-adrenoceptors, which remain unchanged. The antagonist affinity of adrenoceptors for the different ligands did not change in heart failure. Maximal increases in force of contraction were measured after raising Ca++ up to 15 mM in the muscle strips. In healthy human myocardium, isoprenaline, dobutamine, IBMX or cardiac glycosides increase force of contraction to the same maximal values as Ca++ does. However, in cardiac tissue from heart failure patients, positive inotropic agents which increase intracellular cAMP or are cAMP-dependent are less effective than Ca++. Furthermore, the results seem to indicate a homologous (agonist specific) downregulation of receptors in moderate heart failure and a heterologous downregulation in severe heart failure. Thus, many well known positive inotropic drugs lose their effectiveness just when they are needed most: in severe heart failure.