CYCLIC NUCLEOTIDES AND CARDIAC-FUNCTION

Seventeen years ago Murad et al. (1962) provided the first suggestion that cyclic adenosine 3',5'-monophosphate (cAMP) might be involved in cardiac function. Specifically, they found that the potency of several catecholamines (CA) to stimulate adenylate cyclase in membrane preparations of dog heart was similar to their in vivo potency as inotropic agents. Interest in this possibility heightened in 1965 when Robison et al. (1965) reported that epinephrine (EPI) injected into perfused rat hearts caused a rapid rise in cAMP, which was followed by enhanced contractile force and conversion of glycogen phosphorylase to the activated a form. Since that time much effort has been expended to define the role of cAMP and also of cyclic guanosine 3':5'-monophosphate (cGMP) in the actions of CA and other hormonal and neurohormonal agents on the heart; the subject has been reviewed periodically (Mayer, 1970 and 1974; Sobel and Mayer, 1973; Wollenberger, 1975). CA have multiple actions on the heart. They produce an increase in developed tension (positive inotropism), an increased rate of tension development, a reduction in time to peak tension, and a decrease in relaxation time so that the total time of systole is shortened. They alter ion movements, particularly of Ca2+ and K+. Increased inward current of Ca2+ results in elevation of the plateau phase of the action potential; the repolarization phase of the action potential is accelerated. CA also stimulate metabolic events, particularly glycogenolysis and lipolysis. Except for increase in tension, these effects are produced exclusively by activation of β-receptors. cAMP has been implicated with varying degrees of certainty in all of these actions.