A comparison of an A1 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 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 microM) that caused equal prolongation of S-H interval (approximately 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.
Department of Medicine, University of Florida College of Medicine, Gainesville 32610, USA.
S
S
Snowdy
H X
HX
Liang
B
B
Blackburn
R
R
Lum
M
M
Nelson
L
L
Wang
J
J
Pfister
B P
BP
Sharma
A
A
Wolff
L
L
Belardinelli
D000200:Action Potentials / Q000187:drug effects; D000241:Adenosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000494:pharmacology; D000758:Anesthesia; D000818:Animals; D016275:Atrial Function; D001283:Atrioventricular Node / Q000187:drug effects* / Q000502:physiology; D001667:Binding, Competitive; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology; D004110:Diltiazem / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005663:Furans / Q000494:pharmacology*; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D006329:Heart Conduction System / Q000187:drug effects / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008297:Male; D058906:Purinergic P1 Receptor Agonists; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D013552:Swine; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D016276:Ventricular Function; D016277:Ventricular Function, Left / Q000187:drug effects
D002121:Calcium Channel Blockers; D005663:Furans; D058906:Purinergic P1 Receptor Agonists; D018047:Receptors, Purinergic P1; D014665:Vasodilator Agents; D019830:Adenosine-5'-(N-ethylcarboxamide); D004110:Diltiazem; C118601:tecadenoson; D000241:Adenosine