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: L Belardinelli, J Lu, D Dennis, J Martens, J C Shryock
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 271 Issue 3 Pg. 1371-82 (Dec 1994) ISSN: 0022-3565 [Print] United States
• PMID: 7996449 (Publication Type: Journal Article)

Chemical References

• Anti-Arrhythmia Agents
• Carrier Proteins
• Membrane Proteins
• Nucleoside Transport Proteins
• Purinergic P1 Receptor Agonists
• Receptors, Purinergic P1
• N(6)-cyclohexyl-2-O-methyladenosine
• Adenosine

Topics

• Adenosine (analogs & derivatives, metabolism, pharmacology)
• Animals
• Anti-Arrhythmia Agents (pharmacology)
• Carrier Proteins (metabolism)
• Coronary Vessels (drug effects, physiology)
• Dose-Response Relationship, Drug
• Female
• Guinea Pigs
• Heart (drug effects)
• Heart Conduction System (drug effects, physiology)
• Heart Rate (drug effects)
• Male
• Membrane Proteins (metabolism)
• Nucleoside Transport Proteins
• Perfusion
• Purinergic P1 Receptor Agonists
• Receptors, Purinergic P1 (metabolism)
• Vasodilation (drug effects)