title: The cardiac effects of a novel A1-adenosine receptor agonist in guinea pig isolated heart.
abstract: Adenosine increases atrioventricular (AV) nodal conduction time and is used for termination of AV nodal re-entrant tachycardias, but it is rapidly metabolized. The purposes of the present study were to characterize the cardiac actions and effects of an orally active and stable adenosine analog, N6-cyclohexyl-2-O-methyladenosine (SDZ WAG-994) and to evaluate its potential as an antiarrhythmic agent. Guinea pig hearts were isolated and perfused with oxygenated Krebs-Henseleit solution. SDZ WAG-994 slowed the atrial rate and prolonged the AV nodal conduction time of spontaneously beating hearts in a concentration-dependent manner. The EC50 values for the negative chronotropic and dromotropic effects of SDZ WAG-994 were 0.69 +/- 0.04 and 1.49 +/- 0.54 microM, respectively. The A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (0.2 microM) significantly antagonized SDZ WAG-994-induced stimulus-to-His bundle (S-H) interval prolongation. The negative dromotropic effect of SDZ WAG-994 showed very strong frequency dependence. In hearts paced at an atrial cycle length of 300 msec (200 beats/min), the EC50 value of SDZ WAG-994 to prolong the S-H interval was 3.7-fold lower (0.40 +/- 0.02 microM) than in unpaced hearts, and at atrial pacing cycle lengths of 500 and 250 msec, 0.3 microM SDZ WAG-994 prolonged the S-H interval by 8 and 26 msec, respectively. SDZ WAG-994 also decreased coronary perfusion pressure (EC50 = 1.50 +/- 0.80 microM); this effect of SDZ WAG-994 was attenuated by adenosine deaminase and by 8-cyclopentyltheophylline (2 microM). Radioligand binding assays revealed that SDZ WAG-994 had a 280-fold greater affinity for A1- than for A2a receptors of the guinea pig brain. The marked frequency dependence of the negative dromotropic effect of SDZ WAG-994 suggests that this A1 agonist may be highly effective in the termination of AV nodal re-entrant tachycardias.
authors.affiliation: Department of Medicine and Pharmacology, University of Florida, Gainesville.
authors.forename: L
authors.initials: L
authors.lastname: Belardinelli
authors.forename: J
authors.initials: J
authors.lastname: Lu
authors.forename: D
authors.initials: D
authors.lastname: Dennis
authors.forename: J
authors.initials: J
authors.lastname: Martens
authors.forename: J C
authors.initials: JC
authors.lastname: Shryock
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002352:Carrier Proteins / Q000378:metabolism; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006329:Heart Conduction System / Q000187:drug effects / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D033703:Nucleoside Transport Proteins; D010477:Perfusion; D058906:Purinergic P1 Receptor Agonists; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects
chemical_list: D000889:Anti-Arrhythmia Agents; D002352:Carrier Proteins; D008565:Membrane Proteins; D033703:Nucleoside Transport Proteins; D058906:Purinergic P1 Receptor Agonists; D018047:Receptors, Purinergic P1; C090949:N(6)-cyclohexyl-2-O-methyladenosine; D000241:Adenosine