title: A partial agonist of the A(1)-adenosine receptor selectively slows AV conduction in guinea pig hearts.
abstract: The use of full agonists of the A(1)-adenosine receptor (A(1)-ADOR) as antiarrhythmic agents is limited by their actions to cause high-grade atrioventricular (AV) block, profound bradycardia, atrial fibrillation, and vasodilation. It may be possible to avoid these undesired actions by use of partial agonists. We determined the effects of CVT-2759, a potential partial agonist of A(1)-ADORs, on guinea pig hearts. CVT-2759 (0.1-100 microM) increased the S-H interval of the isolated heart from 45 +/- 1 to 60 +/- 3 ms (P < 0. 01) with a half-maximal effect at 3.1 microM. CVT-2759 did not cause second-degree AV block. CVT-2759 significantly attenuated the actions of the full agonists N(6)-cyclopentyladenosine and adenosine. CVT-2759 caused a moderate slowing of atrial rate by </=13% and did not shorten the durations of either the atrial or the ventricular monophasic action potential. Coronary conductance was increased by CVT-2759 only at concentrations >10 microM. In contrast, CVT-2759 was a full agonist to decrease cAMP content of rat adipocytes and Fischer rat thyroid line 5 cells. Results of radioligand binding assays indicated that CVT-2759 stabilized a high-affinity, G protein-coupled state of the A(1)-ADOR in membranes prepared from rat adipocytes but not in membranes prepared from the guinea pig brain. The results suggest that a weak A(1)-ADOR agonist, such as CVT-2759, may be useful to slow AV nodal conduction and thereby ventricular rate without causing AV block, bradycardia, atrial arrhythmias, or vasodilation.
authors: Department of Medicine, University of Florida, Gainesville, Florida 32610, USA.
authors: L
authors: L
authors: Wu
authors: L
authors: L
authors: Belardinelli
authors: J A
authors: JA
authors: Zablocki
authors: V
authors: V
authors: Palle
authors: J C
authors: JC
authors: Shryock
mesh_terms: D000200:Action Potentials; D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001283:Atrioventricular Node / Q000187:drug effects* / Q000502:physiology; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D011687:Purines / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D011916:Rats, Inbred F344; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D013961:Thyroid Gland / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
chemical_list: D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D011687:Purines; D018047:Receptors, Purinergic P1; C048599:N(6)-cyclopentyladenosine; C419102:CVT 2759; D000241:Adenosine