Fundamental considerations of beta-adrenoceptor subtypes in human heart failure.

beta-Adrenoceptor antagonists have revolutionized the management of heart failure in humans. However, fundamental questions remain concerning their use. Currently, there is considerable debate about the role of beta2-adrenoceptors in heart failure and whether incremental clinical benefit can be obtained by blockade of beta2-adrenoceptors in addition to beta1-adrenoceptors. Polymorphic forms of beta1- and beta2-adrenoceptors exist, which might contribute to the variable clinical outcomes that are observed with beta-adrenoceptor antagonists. There is evidence for a low-affinity state of beta1-adrenoceptors and ventricular beta3-adrenoceptors, and these are discussed in the context of heart failure. Finally, there is seemingly paradoxical evidence that restoration and normalization of the beta-adrenoceptor system is beneficial in animal models of heart failure. We reconcile this view with the current clinical use and proven benefit of beta-adrenoceptor antagonists.