O-Methylated and sulfoconjugated catecholamines: differential activities at human platelet alpha 2-adrenoceptors.
The physiological effects of the sulfoconjugates of epinephrine, norepinephrine, and the 3-O-methylated catecholamines, metanephrine, normetanephrine, and methoxytyramine were examined with regard to their alpha 2-adrenoceptor binding properties and aggregation activity in human platelets. Sulfoconjugation of catecholamines resulted in the loss of both their competitive potency for [3H]yohimbine binding and their influence on platelet aggregation. O-Methyl substituted catecholamines showed attenuation of their alpha 2-adrenoceptor binding affinities when compared with those of the corresponding non-esterified amines. Unlike the free amine epinephrine, which stimulated platelet aggregation, the O-methylated catecholamine derivatives inhibited aggregation. Inhibition was dose-dependent and restricted to the alpha 2-adrenoceptor mediated aggregation response stimulated by epinephrine (1 microM) or potentiated by subthreshold concentrations of epinephrine (30-300 nM) in the presence of subaggregatory doses of vasopressin (10-30 nM). Collagen- and ADP-induced platelet aggregation was not affected. The hydrophilic beta-antagonist CGP 12177 displayed no effects. However, high concentrations (0.1 mM) of both isomers of the strongly lipophilic beta-adrenoceptor antagonist propranolol inhibited the actions of all aggregators by stabilizing the membrane. Such a nonspecific membrane interaction of the methylated catecholamines could be excluded because of their low lipid solubility calculated in a n-octanol-phosphate buffer system at pH 7.4. We suggest therefore that methylated catecholamines are biological alpha 2-adrenoceptor antagonists acting on alpha 2-adrenoceptor stimulated reactions of human platelets. Whether this receptor antagonism is relevant to other human tissues needs clarification. Sulfated catecholamines, however, are wholly ineffective at this receptor site and may constitute a pathway to control the concentration of the active free catecholamines.
2nd Department of Physiology, University of Heidelberg, F.R.G.
T
T
Lenz
E
E
Werle
G
G
Strobel
H
H
Weicker
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000328:Adult; D001667:Binding, Competitive / Q000187:drug effects; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D002395:Catecholamines / Q000737:chemistry / Q000494:pharmacology*; D004298:Dopamine / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008055:Lipids / Q000737:chemistry; D008333:Mandelic Acids / Q000494:pharmacology; D008745:Methylation; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D011869:Radioligand Assay; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects*; D013455:Sulfur / Q000737:chemistry; D015016:Yohimbine / Q000378:metabolism
D000319:Adrenergic beta-Antagonists; D002395:Catecholamines; D008055:Lipids; D008333:Mandelic Acids; D010975:Platelet Aggregation Inhibitors; D011412:Propanolamines; D011942:Receptors, Adrenergic, alpha; D015016:Yohimbine; D013455:Sulfur; C000989:3,4-dihydroxymandelic acid; D011433:Propranolol; C033394:CGP 12177; D004298:Dopamine