Selective potentiation by an A1 adenosine receptor enhancer of the negative dromotropic action of adenosine in the guinea pig heart.
The drug (2-amino-4,5-dimethyl-3-thienyl)-[3(trifluoromethyl)-phenyl]methanone (PD 81,723) has been shown to enhance allosterically A1 adenosine receptor binding in brain membranes. The objective of this study was to determine the specificity and selectivity (A1 versus A2) of PD 81,723 as an enhancer of the negative dromotropic effect of exogenous adenosine in guinea pig isolated and in situ hearts. In isolated hearts, PD 81,723 alone produced only a small stimulus to His bundle (S-H) interval prolongation of 1.5 to 4 msec, which was completely reversed by the A1 adenosine receptor antagonist 8-cyclopentyltheophylline and adenosine deaminase. PD 81,723 (5 microM) significantly decreased the EC50 value of adenosine for prolongation of the S-H interval from 6.7 +/- 0.6 to 4.4 +/- 0.5 microM. The potentiation of the negative dromotropic effect of adenosine by PD 81,723 was dose dependent, i.e., 5 and 10 microM PD 81,723 enhanced the maximal S-H interval prolongation caused by 3 microM adenosine by 207% and 609%, respectively. In contrast, the same concentration of PD 81,723 had no effect on either the S-H interval prolongation caused by carbachol or MgCl2 or the coronary vasodilatory effect of adenosine. In in situ hearts, PD (2 mumol/kg i.v.) alone caused only a small but not significant negative dromotropic effect, increasing the atrium to His interval from 58 +/- 2 to 61 +/- 1 msec. However, the same dose of PD 81,723 caused a significant leftward and upward shift of the adenosine dose-response curve for inducing atrium to His bundle interval prolongation and increased the degree of atrioventricular block caused by adenosine.(ABSTRACT TRUNCATED AT 250 WORDS)
Amoah-Apraku
B
B
University of Florida, Department of Medicine, Gainesville.
Xu
J
J
Lu
J Y
JY
Pelleg
A
A
Bruns
R F
RF
Belardinelli
L
L
D000241:Adenosine / Q000494:pharmacology*; D000818:Animals; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D006168:Guinea Pigs; D006329:Heart Conduction System / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D011983:Receptors, Purinergic / Q000187:drug effects*; D013876:Thiophenes / Q000494:pharmacology*
D011983:Receptors, Purinergic; D013876:Thiophenes; C075004:PD 81723; D000241:Adenosine