Sulfoconjugated catecholamines: lack of beta-adrenoceptor binding and adenylate cyclase stimulation in human mononuclear leukocytes.
The racemic 3-O-sulfates of epinephrine and norepinephrine as well as 4-O-sulfoconjugated dopamine were synthesized, highly purified and investigated with respect to their beta-adrenoceptor affinities and relative potencies in the receptor-coupled adenylate cyclase system in isolated human mononuclear leukocytes. The receptor affinities of all catecholamine sulfates were reduced at least 1,000-fold when compared to those of the free catecholamines. Furthermore, catecholamine sulfoconjugates did not produce intracellular cAMP signals. In contrast to the sulfated catecholamine metabolites, the 3-O-methylated catecholamines metanephrine and normetanephrine were found to behave as endogenous beta-adrenoceptor-competing agents with lower beta-receptor affinities than the corresponding free catecholamines. No beta-receptor agonist activity in the adenylate cyclase system was found with metanephrine and normetanephrine. Our data provide direct evidence that sulfoconjugation renders catecholamines inactive as beta-receptor ligands and must thus be regarded as a mechanism to control adrenergic action at the prereceptor level by a buffering of the concentration of free catecholamines. The physiological significance of a potential role of 3-O-methylated catecholamines as endogenous beta-receptor antagonists has to be further clarified.
Michel
G L
GL
Department of Pathophysiology and Sport Medicine, University of Heidelberg, F.R.G.
Lenz
T
T
Lernhardt
U
U
Weicker
H
H
Bieger
W P
WP
Werle
E
E
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000328:Adult; D002395:Catecholamines / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D006719:Homovanillic Acid / Q000378:metabolism; D006801:Humans; D020120:Iodocyanopindolol; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology*; D010869:Pindolol / Q000031:analogs & derivatives; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism*
D002395:Catecholamines; D011943:Receptors, Adrenergic, beta; D020120:Iodocyanopindolol; D010869:Pindolol; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D006719:Homovanillic Acid