A2A-adenosine receptor reserve for coronary vasodilation.
BACKGROUND
Adenosine is a potent coronary vasodilator and causes an increase of coronary blood flow by activation of A2A-adenosine receptors (A2A-AdoRs). The purpose of this study was to test the hypothesis that the high potency of adenosine and adenosine analogues to cause coronary vasodilation is explained by the presence of a large A2A-AdoR reserve ("spare receptors").


RESULTS
A novel, irreversible antagonist of A2A-AdoRs was used to inactivate receptors and reduce the response to agonist. Agonist-induced increases of coronary conductance before and after exposure of hearts to the irreversible antagonist were compared. Three agonists were studied: 2-p-(2-carboxyethyl)-phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS21680), adenosine, and 2-chloro-N6-cyclopentyladenosine (CCPA). Data were analyzed to determine agonist KA (equilibrium dissociation constant) and EC50 values. Values of KA for activation of A2A-AdoRs by CGS21680, adenosine, and CCPA were 105, 1800, and 2630 nmol/L, respectively. In contrast, values of EC50 for CGS21680, adenosine, and CCPA to increase coronary conductance were 1.5, 85, and 243 nmol/L, respectively. By use of the law of mass action, it was calculated that half-maximal responses to CGS21680, adenosine, and CCPA occurred when only 1.3%, 5%, and 9%, respectively, of A2A-AdoRs were occupied by agonist.


CONCLUSIONS
Receptor reserves for 3 A2A-AdoR agonists were large. The receptor reserve for A2A-AdoRs to cause an increase of coronary conductance can explain both the high potency of adenosine to cause coronary vasodilation and the observation that an A2A-AdoR agonist can cause coronary vasodilation without systemic effects.
Shryock
J C
JC
Department of Medicine, University of Florida, Gainesville 32610, USA.
Snowdy
S
S
Baraldi
P G
PG
Cacciari
B
B
Spalluto
G
G
Monopoli
A
A
Ongini
E
E
Baker
S P
SP
Belardinelli
L
L
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology*; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D010627:Phenethylamines / Q000494:pharmacology; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D011743:Pyrimidines / Q000138:chemical synthesis / Q000494:pharmacology; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1 / Q000502:physiology*; D014227:Triazines / Q000494:pharmacology; D014230:Triazoles / Q000138:chemical synthesis / Q000494:pharmacology; D014664:Vasodilation / Q000502:physiology*
C098657:5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine; C114055:FSPTP pyrimidine; D010627:Phenethylamines; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1; D014227:Triazines; D014230:Triazoles; C097270:ZM 241385; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; C058394:2-chloro-N(6)cyclopentyladenosine; D000241:Adenosine