The cardiac beta-adrenoceptor-mediated signaling pathway and its alterations in hypertensive heart disease.
Hypertension-induced cardiac hypertrophy is a predictor of the development of cardiac failure. It is unknown which cellular markers contribute to the progression from compensated hypertrophy to failure. In heart failure, several signal transduction defects leading to adenylate cyclase desensitization have been demonstrated, such as beta-adrenoceptor downregulation, increase of inhibitory G protein expression, and uncoupling of beta-adrenergic receptors, presumably by an increase of receptor kinase activity. In hypertensive heart disease, most studies have been performed in rat models of hypertension. As in heart failure, heterologous adenylyl cyclase desensitization occurs. The mechanisms are often different between the heterogeneous models for acquired and genetic hypertension, but Gi protein alterations and beta-adrenoceptor downregulation have been observed frequently. The underlying mechanism for desensitization is most likely a sympathetic activation in established hypertension rather than genetic alterations of signal transduction proteins. The data available suggest that beta-adrenergic desensitization could represent a mechanism that contributes to the progression from hypertrophy to failure. The key question remains whether those hypertensive patients who develop heart failure are more prone to beta-adrenergic desensitization or whether early intervention to reduce sympathetic activity is more effective in preventing or delaying the transition from compensated hypertrophy to overt failure.
Castellano
M
M
Scienze Mediche, Universita degli Studi di Brescia, Italy.
Böhm
M
M
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D015536:Down-Regulation; D019204:GTP-Binding Proteins / Q000502:physiology*; D006333:Heart Failure / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D006973:Hypertension / Q000201:enzymology* / Q000503:physiopathology; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D013564:Sympathetic Nervous System / Q000502:physiology*
D011943:Receptors, Adrenergic, beta; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases