The Contribution of Classical (β1/2-) and Atypical β-Adrenoceptors to the Stimulation of Human White Adipocyte Lipolysis and Right Atrial Appendage Contraction by Novel β3-Adrenoceptor Agonists of Differing Selectivities

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 285; no. 3; p. 1084
• Main Authors: Matthew V. Sennitt, Alberto J. Kaumann, Peter Molenaar, Lee J. Beeley, Paul W. Young, John Kelly, Helen Chapman, Sian M. Henson, John M. Berge, David K. Dean, Nikesh R. Kotecha, Helen K. A. Morgan, Harshad K. Rami, Robert W. Ward, Mervyn Thompson, Shelagh Wilson, Stephen A. Smith, Michael A. Cawthorne, Michael J. Stock, Jonathan R. S. Arch
• Format: Journal Article
• Language: English
• Published: American Society for Pharmacology and Experimental Therapeutics 01.06.1998
• ISSN: 0022-3565; 1521-0103

The role of β 3 - and other putative atypical β-adrenoceptors in human white adipocytes and right atrial appendage has been investigated using CGP 12177 and novel phenylethanolamine and aryloxypropanolamine β 3 -adrenoceptor (β 3 AR) agonists with varying intrinsic activities and selectivities for human cloned βAR subtypes. The ability to demonstrate β 1/2 AR antagonist-insensitive (β 3 or other atypical βAR-mediated) responses to CGP 12177 was critically dependent on the albumin batch used to prepare and incubate the adipocytes. Four aryloxypropanolamine selective β 3 AR agonists (SB-226552, SB-229432, SB-236923, SB-246982) consistently elicited β 1/2 AR antagonist-insensitive lipolysis. However, a phenylethanolamine (SB-220646) that was a selective full β 3 AR agonist elicited full lipolytic and inotropic responses that were sensitive to β 1/2 AR antagonism, despite it having very low efficacies at cloned β 1 - and β 2 ARs. A component of the response to another phenylethanolamine selective β 3 AR agonist (SB-215691) was insensitive to β 1/2 AR antagonism in some experiments. Because novel aryloxypropanolamine had a β 1/2 AR antagonist-insensitive inotropic effect, these results establish more firmly that β 3 ARs mediate lipolysis in human white adipocytes, and suggest that putative ‘β 4 ARs‘ mediate inotropic responses to CGP 12177. The results also illustrate the difficulty of predicting from studies on cloned βARs which βARs will mediate responses to agonists in tissues that have a high number of β 1 - and β 2 ARs or a low number of β 3 ARs.