A comparison of an A(1) adenosine receptor agonist (CVT-510) with diltiazem for slowing of AV nodal conduction in guinea-pig

1 The purpose of this study was to compare the pharmacological properties ( i.e. the AV nodal depressant, vasodilator, and inotropic effects) of two AV nodal blocking agents belonging to different drug classes; a novel A(1) ad enosine receptor (A(1) receptor) agonist, N-(3(R)-tetrahydrofuranyl)-6-amin opurine riboside (CVT-510), and the prototypical calcium channel blocker di ltiazem. 2 In the atrial-paced isolated heart, CVT-510 was approximately 5 fold more potent to prolong the stimulus-to-His bundle (S-H interval), a measure of slowing AV nodal conduction (EC50 = 41 nM) than to increase coronary conduc tance (EC50 = 200 nM). At concentrations of CVT-510 (40 nM) and diltiazem ( 1 mu M) that caused equal prolongation of S-H interval (similar to 10 ms), diltiazem, but not CVT-510, significantly reduced left ventricular develope d pressure (LVP) and markedly increased coronary conductance. CVT-510 short ened atrial (EC50 = 73 nM) but not the ventricular monophasic action potent ials (MAP). 3 In atrial-paced anaesthetized guinea-pigs, intravenous infusions of CVT-5 10 and diltiazem caused nearly equal prolongations of P-R interval. However , diltiazem, but not CVT-510, significantly reduced mean arterial blood pre ssure. 4 Both CVT-510 and diltiazem prolonged S-H interval, i..e., slowed AV nodal conduction. However, the Al receptor-selective agonist CVT-510 did so with out causing the negative inotropic, vasodilator, and hypotensive effects as sociated with diltiazem. Because CVT-510 did not affect the ventricular act ion potential, it is unlikely that this agonist will have a proarrythmic ac tion in ventricular myocardium.