Is the "atypical" beta-receptor in the rat stomach fundus the rat beta 3 receptor?
The rat gastric fundus is known to possess an "atypical" beta-adrenergic receptor that mediates relaxation to isoproterenol. The purpose of this study was to characterize the relationship between this "atypical" beta receptor in the rat stomach and the cloned rat beta 3 receptor by taking advantage of highly selective pharmacological and molecular biological probes of the beta 3 receptor. Nuclease protection analysis of RNA from the rat gastric fundus identified beta 3 receptor mRNA whose levels in the stomach were exceeded only by those in adipose tissue. Pharmacological analysis of the recombinant rat beta 3 receptor expressed in Chinese hamster ovary cells indicated low affinity of propranolol with a Ki value of 2.3 microM. Therefore, 0.3 microM propranolol was chosen as a concentration that would completely block beta 1 and beta 2 receptors (Ki = 1-5 nM) but would leave beta 3 receptors largely intact in the rat stomach fundus. In the presence of propranolol, several beta-adrenergic receptor agonists relaxed the rat stomach fundus with a rank potency order of (R,R)-5-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]-amino]-propyl]1,3- benzodioxole-2,2-dicarboxylate (CL316,243) > isoproterenol > norepinephrine = epinephrine = dl-4-3[(1,1-dimethylethyl)amino]-2- hydroxylproproy]1,3 dihydro-2H-benzimidazol-2-one hydrochloride (CGP12177) > clenbuterol > terbutaline > pindolol. Isoproterenol, norepinephrine and epinephrine were full agonists, whereas (R,R)-5-[2-[[2-(3-chlorophenyl)-2- hydroxyethyl]-amino]-propyl]1,3-benzodioxole-2,2-dicarboxylate was only a partial agonist with 66% intrinsic activity relative to isoproterenol.(ABSTRACT TRUNCATED AT 250 WORDS)
Cohen
M L
ML
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
Granneman
J G
JG
Chaudhry
A
A
Schenck
K W
KW
Cushing
D J
DJ
Palkowitz
A D
AD
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D004149:Dioxoles / Q000494:pharmacology*; D004789:Enzyme Activation; D015870:Gene Expression / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D010869:Pindolol / Q000031:analogs & derivatives / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000145:classification* / Q000502:physiology; D013270:Stomach / Q000502:physiology*
D004149:Dioxoles; D012333:RNA, Messenger; D011943:Receptors, Adrenergic, beta; C076126:disodium (R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)-amino)propyl)-1,3-benzodioxole-2,3-dicarboxylate; C047975:cyanopindolol; D011433:Propranolol; D010869:Pindolol; D000262:Adenylyl Cyclases