Negative chronotropic effect of CVT-510 in anesthetized and awake rats

CVT-510 (N-(3(R)-tetrahydrofuranyl)-6-aminopurine riboside), a selective A(1) adenosine recaptor (AdoR) agonist, is being developed as an "AV nodal blocking" agent for acute control of ventricular rate during atrial fibrillation and flutter and management of AV nodal reentrant tachycardias. A(1) AdoR agonists are also known to cause sinus bradycardia. In the present study, we characterized the bradycardic effect of CVT-510 in anesthetized and awake rats. In anesthetized rats, intravenous infusions of CVT-510 slowed heart rare in a dose-dependent manner. At doses of 0.5-1.0 mug/kg (1.5-3.0 nmol/kg) and >1.5 mug/ kg (4.5 nmol/kg), CVT-510 slowed heart rate by 30-40% and >50% of baseline, respectively. The sinus bradycardia caused by CVT-510 was reversible upon termination of infusion. The decreases in heart rate caused by CVT-510 were accompanied by stepwise increases in plasma levels of CVT-510. The relationship between plasma levels of CVT-510 and slowing of heart rate yielded a correlation coefficient (R value) of 0.9. In awake rats CVT-510 given by repeated (n = 7) intraperitoneal lip) injections or by chronic (4 days) subcutaneous isc) administration caused reproducible, dose-dependent, and persistent bradycardia. Injections ip of 50 mug/kg (148 nmol/kg) CVT-510 caused sinus bradycardias of >100 bpm. Continuous sc administration of CVT-510 (e.g., 100 nmol/kg/h) slowed heart rate by 80-60 bpm throughout the duration of infusion, i.e., 4 days. Thus, in rats the sinus bradycardia caused by CVT-510 does not undergo desensitization due to repeated injections and is persistent, with minimal attenuation during chronic administration. Drug Dev. Res. 52:424-430, 2001. (C) 2001 Wiley-Liss, Inc.