Activation of cardiac A1
adenosine receptors slows atrioventricular conduction and attenuates the effects of
catecholamines, whereas activation of A2
adenosine receptors causes coronary dilation. This study investigates the antagonism of the action of
adenosine on A1 and A2
adenosine receptor subtypes by (+-)-N6-endonorbornan-2-yl-9-methyladenine (N-0861) in guinea pig isolated perfused hearts. Stimulus to His bundle interval, coronary perfusion pressure and left ventricular pressure were measured. In normoxic hearts,
N-0861 competitively and reversibly antagonized stimulus to His bundle interval prolongation induced by
adenosine (1-30 microM) but not that caused by
carbachol (0.09 microM),
verapamil (1 microM),
MgCl2 (6.5 mM) or
hypothermia.
N-0861 (up to 100 microM) did not attenuate the decrease in coronary perfusion pressure caused by
adenosine.
N-0861 significantly attenuated the antagonism by
adenosine of an
isoproterenol-mediated elevation of left ventricular pressure.
N-0861 significantly reduced stimulus to His bundle prolongation induced by either
hypoxia or reduced perfusion ("
ischemia") but did not attenuate the
hypoxia-induced decrease in coronary perfusion pressure. Receptor binding studies indicated that
N-0861 competitively displaced the binding of 8-cyclopentyl-1,3-[3H]dipropylxanthine to crude guinea pig and human atrial membranes (Ki values of 0.62 and 0.7 microM, respectively) but did not displace the binding of S-(p-nitro[3H]benzyl)-6-
thioinosine. The results indicate that in the heart
N-0861 is a reversible, specific and selective antagonist of
adenosine at the A1 receptor subtype.