January 1999, Volume 126, Issue 1, Pages 137 - 146

Original Article

A comparison of an A1 adenosine receptor agonist (CVT-510) with diltiazem for slowing of AV nodal conduction in guinea-pig Stephen Snowdy1, Hui Xiu Liang1, Brent Blackburn3, Robert Lum5, Marek Nelson3, Lisa Wang3, Jürg Pfister4, Bhavender P. Sharma3, Andrew Wolff3 & Luiz Belardinelli1,2,6 1Department of Medicine, University of Florida College of Medicine, Gainsville, Florida, U.S.A.     2Department of Pharmacology, University of Florida College of Medicine, Gainsville, Florida, U.S.A.     3CV Therapeutics, Palo Alto, California, U.S.A.     4Roche Bioscience, Palo Alto, California, U.S.A.     5Telik, Inc., San Francisco, California, U.S.A.     6Author for correspondence at: University of Florida College of Medicine, 1600 SW Archer Road, Box 100277, Gainesville, FL 32610, U.S.A.

Keywords

Adenosine;   adenosine agonist;   diltiazem;   supraventricular tachycardia;   re-entry;   AV node;   ventricular contractility;   coronary vasodilation;   action potential

Abstract

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 A1 adenosine receptor (A1 receptor) agonist, N-(3(R)-tetrahydrofuranyl)-6-aminopurine riboside (CVT-510), and the prototypical calcium channel blocker diltiazem. 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 conductance (EC50=200 nM). At concentrations of CVT-510 (40 nM) and diltiazem (1 µM) that caused equal prolongation of S - H interval (~10 ms), diltiazem, but not CVT-510, significantly reduced left ventricular developed pressure (LVP) and markedly increased coronary conductance. CVT-510 shortened atrial (EC50=73 nM) but not the ventricular monophasic action potentials (MAP). 3   In atrial-paced anaesthetized guinea-pigs, intravenous infusions of CVT-510 and diltiazem caused nearly equal prolongations of P - R interval. However, diltiazem, but not CVT-510, significantly reduced mean arterial blood pressure. 4   Both CVT-510 and diltiazem prolonged S - H interval, i.e., slowed AV nodal conduction. However, the A1 receptor-selective agonist CVT-510 did so without causing the negative inotropic, vasodilator, and hypotensive effects associated with diltiazem. Because CVT-510 did not affect the ventricular action potential, it is unlikely that this agonist will have a proarrythmic action in ventricular myocardium.

Received 7 August 1998; Revised 8 October 1998; Accepted 9 October 1998

^© Macmillan Publishers Ltd 1999