(−)-CGP 12177 Causes Cardiostimulation and Binds to Cardiac Putative β4-Adrenoceptors in Both Wild-Type and β3-Adrenoceptor Knockout Mice

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Abstract
Some blockers of β1- and β2-adrenoceptors cause cardiostimulant effects through an atypical β-adrenoceptor (putative β4-adrenoceptor) that resembles the β3-adrenoceptor. It is likely but not proven that the putative β4-adrenoceptor is genetically distinct from the β3-adrenoceptor. We therefore investigated whether or not the cardiac atypical β-adrenoceptor could mediate agonist effects in mice lacking a functional β3-adrenoceptor gene (β3KO). (−)-CGP 12177, a β1- and β2-adrenoceptor blocker that causes agonist effects through both β3-adrenoceptors and cardiac putative β4-adrenoceptors, caused cardiostimulant effects that were not different in atria from wild-type (WT) mice and β3KO mice. The effects of (−)-CGP 12177 were resistant to blockade by (−)-propranolol (200 nm) but were blocked by (−)-bupranolol (1 μm) with an equilibrium dissociation constant of 15 nm in WT and 17 nmin β3KO. (−)-[3H]CGP 12177 labeled a similar density of the putative β4-adrenoceptor in ventricular membranes from the hearts of both WT (Bmax = 52 fmol/mg protein) and β3KO (Bmax = 53 fmol/mg protein) mice. The affinity of (−)-[3H]CGP 12177 for the cardiac putative β4-adrenoceptor was not different between WT (Kd = 46 nm) and β3KO (Kd= 40 nm). These results provide definitive evidence that the cardiac putative β4-adrenoceptor is distinct from the β3-adrenoceptor.