Covalent binding of a selective agonist irreversibly activates guinea pig coronary artery A2 adenosine receptors.
Experiments employing guinea pig heart Langendorff preparations compared the coronary vasoactivity of a functionalized congener of adenosine, 2-[(2-aminoethyl-aminocarbonylethyl)phenylethylamino]-5'-N-e thyl- carboxamidoadenosine, APEC, with the vasoactivity of the product of the reaction of APEC with 1,4-phenylene-diisothiocyanate, 4-isothiocyanatophenylaminothiocarbonyl-APEC (DITC-APEC). Previous experiments showed that whereas APEC binds reversibly to the A2A adenosine receptor of brain striatum, DITC-APEC binds irreversibly. APEC caused concentration-dependent coronary vasodilation that persisted unchanged when agonist administration continued for up to 165 min, but promptly faded when the agent was withdrawn. The unselective adenosine receptor antagonist 8-(4-sulfophenyl)theophyline (8-SPT) antagonized the vasoactivity of APEC. By contrast, DITC-APEC (0.125-1.0 nM) caused progressive, concentration-independent vasodilation that persisted unchanged for as long as 120 min after the agent was stopped and that was insensitive to antagonism by subsequently applied 8-SPT. However, perfusion of the heart with buffer containing 0.1 mM 8-SPT strongly antagonized the coronary vasodilatory action of DITC-APEC given subsequently. Such observations indicate that the covalent binding of DITC-APEC causes irreversible activation of the guinea pig coronary artery A2A adenosine receptor. Neither APEC nor DITC-APEC appeared to desensitize the coronary adenosine receptor during two or more hours of exposure to either agonist.
Niiya
K
K
Department of Internal Medicine, University of South Florida, Tampa 33612.
Jacobson
K A
KA
Silvia
S K
SK
Olsson
R A
RA
D000241:Adenosine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D006168:Guinea Pigs; D017879:Isothiocyanates; D010627:Phenethylamines / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D011983:Receptors, Purinergic / Q000378:metabolism*; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology; D013861:Thiocyanates / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects
D017879:Isothiocyanates; D010627:Phenethylamines; D011983:Receptors, Purinergic; D013861:Thiocyanates; C063208:2-((2-aminoethylamino)carbonylethylphenylethylamino)-5'-N-ethylcarboxamidoadenosine; C082039:4-isothiocyanatophenylaminothiocarbonyl-2-((2-aminoethylaminocarbonylethyl)phenylethylamino)-5'-N-ethylcarboxamidoadenosine; C031433:8-(4-sulfophenyl)theophylline; D013806:Theophylline; D000241:Adenosine