Catecholamine refractoriness and their mechanisms in cardiocirculatory shock and chronic heart failure.
In heart failure, a strong sympathetic activation has been observed and is regarded as the cause of beta-adrenergic desensitization in this condition. On the receptor level, there is a down-regulation of beta1-adrenergic receptors. In myocardium of patients on catecholamine treatment, the number of beta-adrenergic receptors can be further reduced. An uncoupling of beta2-adrenoceptors has been related to an increased activity and gene expression of beta-ARK in failing myocardium leading to phosphorylation and uncoupling of receptors. Beta3-adrenoceptors mediate negative inotropic effects, but alterations of these receptors are not known. In addition, an increase of inhibitory G-protein alpha-subunits (Gialpha) has been suggested to be causally linked to adenylyl cyclase desensitization in heart failure. In contrast, the catalytic subunit of adenylyl cyclase, stimulatory G-protein alpha-subunits and betagamma-subunits have been observed to be unchanged. In patients with catecholamine-refractory septic or cardiogenic shock, an increase of Gialpha has been observed and related to the reduced effects of catecholamines in these conditions. The discovered mechanisms set the stage for the development of alternative strategies to increase force of contraction like the combination of PDE-inhibitors and catecholamines or Ca2+ sensitizing agents.
Böhm
M
M
Department III of Internal Medicine, University of Cologne, Germany.
D000262:Adenylyl Cyclases / Q000378:metabolism; D002395:Catecholamines / Q000502:physiology*; D019204:GTP-Binding Proteins / Q000502:physiology; D006333:Heart Failure / Q000503:physiopathology*; D006801:Humans; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D012032:Refractory Period, Electrophysiological; D012770:Shock, Cardiogenic / Q000503:physiopathology*; D013564:Sympathetic Nervous System / Q000502:physiology
D002395:Catecholamines; D011943:Receptors, Adrenergic, beta; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases