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Vol. 284, Issue 3, 1066-1073, March 1998
Departments of
Medicine (L.B., J.C.S., S.S., Y.Z.),
Pharmacology
(L.B., D.M.D.) and
Anesthesiology (D.M.D.), College of Medicine,
University of Florida, Gainesville, Florida;
Schering-Plough Research
Institute (A.M., G.L., E.O.), San Raffaele Science Park, Milan, Italy;
and
Department of Internal Medicine, University of South Florida,
Tampa, Florida (R.A.O.)
The coronary vasodilation caused by adenosine is due to activation of
A2 adenosine receptors (A2AdoRs), but the
subtype or subtypes of A2AdoR (A2A and/or
A2B) that mediate this action are uncertain. The purpose of
this study was to test the hypothesis that A2AAdoRs mediate
coronary vasodilation caused by exogenous or endogenous adenosine in
the guinea pig isolated perfused heart. The newly described
A2AAdoR antagonist SCH58261 was used to selectively block
A2AAdoRs. Attenuations by SCH58261 of increases in coronary conductance (A2 response) and of atrioventricular nodal
conduction time (A1 response) caused by exogenous and
endogenous adenosine and by agonists with relative selectivity for
A2A and A1AdoRs were measured. The
CGS21680-induced increase of coronary conductance was antagonized by
SCH58261 in a concentration-dependent and competitive manner with a
KB value of 5.01 nm. Also reversed by SCH58261 (60 nmol/L) were the increases in coronary conductance caused by the
relatively selective A1AdoR agonists CCPA (70 nM), and (R)-(
)Nb-(2-phenyl-isopropyl)adenosine (60 nM)
but not those caused by sodium nitroprusside (1.2 µM) and diltiazem
(0.4 µM). SCH58261 (
100 nM) did not attenuate the
A1AdoR-mediated prolongations of S-H interval caused by
either adenosine or CCPA. SCH58261 attenuated the coronary vasodilation
caused by 50 nM adenosine with an IC50 value of 6.8 ± 0.6 nM. The coronary vasodilations caused by the nucleoside uptake
inhibitor draflazine and the adenosine kinase inhibitor iodotubercidin
were completely reversed by 60 nM SCH58261 or adenosine deaminase (7 U/ml). Thus, the A2AAdoR plays a major role as mediator of
coronary vasodilation caused by exogenous and endogenous adenosine and
by AdoR agonists.
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