The role of endogenous noradrenaline in the beta-blocker withdrawal phenomenon--studies with cultured heart cells.

An in vitro model to evaluate the role of endogenous noradrenaline in the beta-blocker withdrawal phenomenon is described: Beating chicken heart muscle cells (5000 beta 1-adrenoceptors/cell) and heart nonmuscle cells (3000 beta 2-adrenoceptors/cell) were cultured in serum-free, hormone-supplemented medium. Basal state, subtype selective down-regulation of beta-adrenoceptors by endogenous noradrenaline (decrease in receptor number, beta 1 more than beta 2) was simulated by addition of noradrenaline to the culture medium; chronic beta-blockade was simulated by exposure of the cells for 3 days to various beta-blockers (propranolol, no ISA; timolol, slight ISA; pindolol, strong ISA). Beta-blocker withdrawal phenomenon--increased response in isoproterenol-induced cAMP production and positive inotropy--is correlated with the increase in the number of beta-adrenoceptors after withdrawal of the drugs. Propranolol induces a withdrawal phenomenon at every degree of noradrenaline-induced basal state down-regulation of beta-adrenoceptors; in contrast, a withdrawal phenomenon by pindolol is only seen at a higher degree of beta-adrenoceptor down-regulation. In the presence of physiological noradrenaline concentrations pindolol affects beta-adrenoceptor subtypes in a qualitatively different manner: the number of beta 1-adrenoceptors is increased, the number of beta 2-adrenoceptors is decreased. This finding demonstrates that the intrinsic sympathomimetic activity of nonselective beta-blockers can manifest itself only if the receptors are not strongly down-regulated. As beta 2-adrenoceptors are present in a much less down-regulated state than beta 1, ISA mainly acts on beta 2-adrenoceptor subtype, thus, presenting a beta 2-"pseudo-selectivity" of ISA.