Xanthine derivatives that selectively inhibit cyclic GMP hydrolysis potentiate cardiac contractile effects of isoproterenol but not those of bethanecol
Mushlin, P.; Boerth, R.C.; Wells, J.N.
Molecular Pharmacology 20(1): 190-194
1981
ISSN/ISBN: 0026-895X PMID: 6270532 Document Number: 176373
This study examines the abilities of xanthines to alter contractile and cyclic nucleotide responses to isoproterenol or bethanechol in left atria isolated from rabbits. Two of the xanthines studied (1-methyl-3-isobutyl-8-methoxymethylxanthine and 1-methyl-3-isobutyl-8-tert-butylxanthine) inhibited cGMP hydrolysis more potently than cAMP hydrolysis; another xanthine, theophylline, was equipotent at inhibiting the hydrolysis of the 2 cyclic nucleotides. All of the xanthines studied comparably potentiated contractile and cAMP responses to isoproterenol (10-8 M), regardless of their potencies to inhibit cGMP hydrolysis. cGMP is not antiadrenergic. The selective inhibitor, 1-methyl-3-isobutyl-8-methoxymethylxanthine, at a concentration that elevated cGMP content to a level that was 3-fold above that observed with bethanechol alone, failed to depress contractile force, alter cardio-depressant effects of bethanechol or alter atrial cGMP content in the presence of this choline ester. The inhibition of cGMP phosphodiesterase does not produce negative inotropic effects and enhance the cardio-depressant effects of cholinergic agents.