Electrophysiologic Effects of a Novel Selective Adenosine A1 Agonist (CVT-510) on Atrioventricular Nodal Conduction in Humans

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Abstract
Background: CVT-510, N-(3(R)-tetrahydrofuranyl)-6-aminopurine riboside, is a selective A,-adenosine receptor agonist with potential potent antiarrhythmic effects in tachycardias involving the atrioventricular (AV) node. This study, the first in humans, was designed to determine the effects of CVT-5 10 on AV nodal conduction and hemodynamics. Methods and Results: Patients in sinus rhythm with normal AV nodal function at electrophysiologic study (n = 32) received a single intravenous bolus of CVT-5 10. AH and HV intervals were measured during sinus rhythm and during atrial pacing at 1, 5, 10, 15, 20, 30, 45, and 60 minutes after the bolus. Increasing doses of CVT-510 (0.3 to 10 pg/kg) caused a dosedependent increase in the AH interval. At 1 minute, a dose of 10,ug/kg increased the AH interval during sinus rhythm from 93 ± 23 msec to 114 ± 37 msec, p = 0.01 and from 114 ± 31 msec to 146 ± 44 msec during atrial pacing at 600 msec, p = 0.003). The AH interval returned to baseline by 20 minutes. CVT-510 at doses of 0.3 to 10,ug/kg had no effect on sinus rate, HV interval, or systemic blood pressure, and was not associated with serious adverse effects. At doses of 15 and 30 pg/kg, CVT-510 produced transient second/third degree AV heart block in all four patients treated. One of these patients also had a prolonged sedative effect that was reversed with aminophylline. Conclusions: CVT-510 promptly prolongs AV nodal conduction and does not affect sinus rate or blood pressure. Selective stimulation of the A,-adenosine receptor by CVT-510 may be useful for immediate control of heart rate in atrial fibrillation/flutter and to convert paroxysmal supraventricular tachycardia to sinus rhythm, while avoiding vasodilatation mediated by the A2-adenosine receptor, as well as the vasodepressor and negative inotropic effects associated with 3-adrenergic receptor blockade and/or calcium channel blockers.