Catecholamine Refractoriness and their Mechanisms in Cardiocirculatory Shock and Chronic Heart Failure

Abstract

In heart failure, a strong sympathetic activation has been observed and is regarded as the cause of ß-adrenergic desensitization in this condition. On the receptor level, there is a down regulation of ß1-adrenergic receptors. In myocardium of patients on catecholaminetreatment, the number of ß-adrenergic receptors can be further reduced. An uncoupling of ß2-adrenoceptors has been related to an increased activity and gene expression of ß-ARK in failing myocardium leading to phosphorylation and uncoupling of receptors. ß3-adrenoceptors mediate negative inotropic effects, but alterations of these receptors are not known. In addition, an increase of inhibitory G-protein a-subunits (Gia) has been suggested to be causally linked to adenylyl cyclase desensitization in heart failure. In contrast, the catalytic subunit of adenylyl cyclase, stimulatory C-protein a-subunits and ß?-subunits have been observed to be unchanged. In patients with catecholamine-refractory septic or cardiogenic shock, an increase of Gia has been observed and related to the reduced effects of catecholamines in these conditions. The discovered mechanisms set thestage for the development of alternative strategies to increase force of contraction like the combination of PDE-inhibitors and catecholamines or Ca2+ sensitizing agents.

Key words

ß-Adrenoceptors - Adenylyl cyclase - Heart failure - G-proteins - Cardiogenic shock - Septic shock