New cardiotonic agents

Abstract

D RUGS THAT INCREASE the positive inotropic (ie, cardiotonic) potential of the myocardium are used in a variety of clinical settings. All catecholamines exert their inotropic effects by stimulating adrenergic mediated receptors in the sympathetic nervous system. 1,2 Stimulation of these adrenergic receptors within the cardiovascular system generates predictable organ specific responses (Table 1). Catecholamines can act either directly or indirectly on these adrenergic receptors. Indirect acting catecholamines stimulate the release of stored neurotransmitters from sympathetic nerve terminals, whereas direct acting agents stimulate the adrenergic receptors directly. Director indirect-acting catecholamines exert their positive inotropic action by stimulation of the ill-receptor. This stimulation activates the second messenger pathway, facilitating the release of cyclic adenosine monophosphate (cAMP). 3 The efficacy of any adrenergic agent is influenced by the availability (ie, density) and responsiveness (ie, affinity) of these beta receptors. A reduction in both the number and sensitivity of B-receptors has been noted with chronically elevated levels of plasma catecholamines (such as that occurring in congestive heart failure [CHF] or hypertension). This was described by Bristow et al4 as B-receptor down regulation. Conversely, B-receptor up regulation has been described in patients undergoing long-term fl-adrenergic antagonist therapy, thus resulting in a significant increase in the numbers of B-receptors. Down regulation, initially thought to develop only when plasma catecholamine levels were chronically elevated, has now been observed with short-term exposure. Marty et al5 recently reported a significant increase in B-receptor density