Cardiovascular effects of a non-xanthine-selective antagonist of the A1 adenosine receptor in the anaesthetised pig: pharmacological and therapeutic implications.
OBJECTIVE
To study antagonism of A1 adenosine receptors in an anaesthetised open chest swine model, the selective A1 receptor antagonist, N6-endonorbornan-2-yl-9-methyladenine (N-0861), was examined to see if it attenuates bradycardia, augments reflex tachycardia associated with adenosine infusion, or both. Its effects were compared with those of the non-selective antagonist of adenosine A1 and A2 receptors, 8-(p-sulphophenyl)-theophylline (8-pST).


METHODS
Twenty nine pigs were studied. The prolongation of P-R interval mediated by A1 receptors, the increase in left anterior descending coronary artery blood flow mediated by A2 receptors, and decreases in systemic and left ventricular pressures and first derivative of left ventricular pressure (dP/dt) were monitored in each animal assigned to one of three protocols. (1) Adenosine, 40 to 180 micrograms.kg-1.min-1, was infused for more than 6 min before and immediately after rapid infusion of 8-pST, 5 mg.kg-1 intravenously, or a solvent that did or did not contain N-0861, 0.2 mg.kg-1 intravenously (n = 14). (2) In the same animal, we compared N-0861 and 8-pST in reversing responses mediated by A1 and A2 receptors during two 10 min infusions of adenosine separated by a 1 h washout period (n = 7). (3) N-0861 with adenosine (mean dose, 0.4 mg.kg-1) was infused with or without complete autonomic blockade with atropine (2.5 mg.kg-1) and propranolol (2 mg.kg-1) (n = 8).


RESULTS
Adenosine prolonged P-R interval (and cycle length in non-paced hearts), increased coronary flow, and decreased calculated coronary resistance. N-0861 alone did not affect any variable, but N-0861 with adenosine prevented or reversed A1 receptor mediated prolongation of P-R interval in paced hearts and cycle length in non-paced hearts and enhanced A2 receptor mediated coronary vasodilatation. Left ventricular dP/dt and rate-pressure product were maintained with N-0861 and adenosine, and N-0861 unmasked a postadenosine reflex tachycardia. Prolonged PR interval, decreased heart rate, and increased coronary flow were prevented or reversed by the non-selective antagonist 8-pST.


CONCLUSIONS
Selectivity of N-0861 for the adenosine A1 receptor may, without reducing coronary blood flow, ameliorate bradyarrhythmia and maintain the positive inotropic response when exogenous adenosine is given or when interstitial myocardial adenosine is increased.
Sidi
A
A
Department of Anesthesiology, University of Florida College of Medicine, Gainesville 32610-0254.
Wesley
R
R
Barrett
R
R
Rush
W
W
Belardinelli
L
L
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000241:Adenosine / Q000494:pharmacology; D000758:Anesthesia; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002319:Cardiovascular System / Q000187:drug effects*; D003331:Coronary Vessels / Q000187:drug effects; D005260:Female; D006321:Heart / Q000187:drug effects; D008297:Male; D009636:Norbornanes / Q000494:pharmacology*; D011433:Propranolol / Q000494:pharmacology; D058915:Purinergic P1 Receptor Antagonists; D012039:Regional Blood Flow / Q000187:drug effects; D013552:Swine; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology
D009636:Norbornanes; D058915:Purinergic P1 Receptor Antagonists; C073387:N 0861; D001285:Atropine; C031433:8-(4-sulfophenyl)theophylline; D011433:Propranolol; D013806:Theophylline; D000225:Adenine; D000241:Adenosine