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Vol. 285, Issue 3, 1084-1095, June 1998
1/2-) and Atypical
-Adrenoceptors to the Stimulation of Human White Adipocyte Lipolysis
and Right Atrial Appendage Contraction by Novel
3-Adrenoceptor Agonists of Differing Selectivities
SmithKline Beecham Pharmaceuticals, Great Burgh, Epsom, Surrey, The
Frythe, Welwyn, Herts and New Frontiers Science Park, Harlow, Essex,
CM19 5AW, UK (L.J.B., P.W.Y., J.K., H.C., S.M.H., J.M.B., D.K.D.,
N.R.K., H.K.A.M., H.K.R., R.W.R., M.T., S.W., S.A.S., J.R.S.A.);
St Georges Hospital Medical School, Tooting, London, SW17 0RE, UK
(M.V.S., M.J.S.);
The Babraham Institute, Babraham, Cambridge, CB2
4AT, UK (A.J.K.) and
Department of Pharmacology, University of
Melbourne, Victoria 3052, Australia (P.M., A.J.K.)
The role of 
3- and other putative atypical
-adrenoceptors in human white adipocytes and right atrial appendage
has been investigated using CGP 12177 and novel phenylethanolamine and aryloxypropanolamine 3-adrenoceptor (3AR)
agonists with varying intrinsic activities and selectivities for human
cloned AR subtypes. The ability to demonstrate 1/2AR
antagonist-insensitive (3 or other atypical
AR-mediated) responses to CGP 12177 was critically dependent on the
albumin batch used to prepare and incubate the adipocytes. Four
aryloxypropanolamine selective 3AR agonists (SB-226552,
SB-229432, SB-236923, SB-246982) consistently elicited 1/2AR antagonist-insensitive lipolysis. However, a
phenylethanolamine (SB-220646) that was a selective full
3AR agonist elicited full lipolytic and inotropic
responses that were sensitive to 1/2AR antagonism,
despite it having very low efficacies at cloned 1- and
2ARs. A component of the response to another
phenylethanolamine selective 3AR agonist (SB-215691) was
insensitive to 1/2AR antagonism in some experiments.
Because novel aryloxypropanolamine had a 1/2AR
antagonist-insensitive inotropic effect, these results establish more
firmly that 3ARs mediate lipolysis in human white adipocytes, and suggest that putative `4ARs` mediate
inotropic responses to CGP 12177. The results also illustrate the
difficulty of predicting from studies on cloned ARs which ARs
will mediate responses to agonists in tissues that have a high number
of 1- and 2ARs or a low number of
3ARs.
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