THE CONTRIBUTION OF CLASSICAL (BETA(1 2)-) AND ATYPICAL BETA-ADRENOCEPTORS TO THE STIMULATION OF HUMAN WHITE ADIPOCYTE LIPOLYSIS AND RIGHT ATRIAL APPENDAGE CONTRACTION BY NOVEL BETA(3)-ADRENOCEPTOR AGONISTS OFDIFFERING SELECTIVITIES/

The role of beta(3)- and other putative atypical beta-adrenaceptors in human white adipocytes and right atrial appendage has been investigat ed using CGP 12177 and novel phenylethanolamine and aryloxypropanolami ne beta(3)-adrenoceptor (beta(3)AR) agonists with varying intrinsic ac tivities and selectivities for human cloned PAR subtypes. The ability to demonstrate beta(1/2)AR antagonist-insensitive (beta(3) or other at ypical beta AR-mediated) responses to CGP 12177 was critically depende nt on the albumin batch used to prepare and incubate the adipocytes. F our aryloxypropanolamine selective beta(3)AR agonists (SB-226552, SB-2 29432, SB-236923, SB-246982) consistently elicited beta(1/2)AR antagon ist-insensitive lipolysis. However, a phenylethanolamine (SB-220646) t hat was a selective full beta(3)AR agonist elicited full lipolytic and inotropic responses that were sensitive to beta(1/2)AR antagonism, de spite it having very low efficacies at cloned beta(1)- and beta(2)ARs. A component of the response to another phenylethanolamine selective b eta(3)AR agonist (SB-215691) was insensitive to beta(1/2)AR antagonism in some experiments. Because novel aryloxypropanolamine had a beta(1/ 2)AR antagonist-insensitive inotropic effect, these results establish more firmly that beta(3)ARs mediate lipolysis in human white adipocyte s, and suggest that putative 'beta(4)ARs' mediate inotropic responses to CGP 12177. The results also illustrate the difficulty of predicting from studies on cloned beta ARs which beta ARs will mediate responses to agonists in tissues that have a high number of beta(1)- and beta(2 )ARs or a low number of beta(3)ARs.