(-)-CGP 12177 causes cardiostimulation and binds to cardiac putative beta 4-adrenoceptors in both wild-type and beta 3-adrenoceptor knockout mice.
Some blockers of beta1- and beta2-adrenoceptors cause cardiostimulant effects through an atypical beta-adrenoceptor (putative beta4-adrenoceptor) that resembles the beta3-adrenoceptor. It is likely but not proven that the putative beta4-adrenoceptor is genetically distinct from the beta3-adrenoceptor. We therefore investigated whether or not the cardiac atypical beta-adrenoceptor could mediate agonist effects in mice lacking a functional beta3-adrenoceptor gene (beta3 KO). (-)-CGP 12177, a beta1- and beta2-adrenoceptor blocker that causes agonist effects through both beta3-adrenoceptors and cardiac putative beta4-adrenoceptors, caused cardiostimulant effects that were not different in atria from wild-type (WT) mice and beta3 KO mice. The effects of (-)-CGP 12177 were resistant to blockade by (-)-propranolol (200 nM) but were blocked by (-)-bupranolol (1 microM) with an equilibrium dissociation constant of 15 nM in WT and 17 nM in beta3 KO. (-)-[3H]CGP 12177 labeled a similar density of the putative beta4-adrenoceptor in ventricular membranes from the hearts of both WT (Bmax = 52 fmol/mg protein) and beta3 KO (Bmax = 53 fmol/mg protein) mice. The affinity of (-)-[3H]CGP 12177 for the cardiac putative beta4-adrenoceptor was not different between WT (Kd = 46 nM) and beta3 KO (Kd= 40 nM). These results provide definitive evidence that the cardiac putative beta4-adrenoceptor is distinct from the beta3-adrenoceptor.
Kaumann
A J
AJ
The Babraham Institute, Cambridge, UK. alberto.kaumann@bbsrc.ac.uk
Preitner
F
F
Sarsero
D
D
Molenaar
P
P
Revelli
J P
JP
Giacobino
J P
JP
D000318:Adrenergic beta-Agonists / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D015139:Blotting, Southern; D002316:Cardiotonic Agents / Q000494:pharmacology*; D005260:Female; D005838:Genotype; D006325:Heart Atria / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016254:Mutagenesis, Insertional; D009206:Myocardium / Q000378:metabolism*; D011412:Propanolamines / Q000378:metabolism / Q000494:pharmacology*; D011943:Receptors, Adrenergic, beta / Q000172:deficiency* / Q000235:genetics*; D022702:Receptors, Adrenergic, beta-3
D000318:Adrenergic beta-Agonists; D002316:Cardiotonic Agents; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; D022702:Receptors, Adrenergic, beta-3; C033394:CGP 12177