PT - JOURNAL ARTICLE AU - G. L. KRAMER AU - J. N. WELLS TI - Effects of Phosphodiesterase Inhibitors on Cyclic Nucleotide Levels and Relaxation of Pig Coronary Arteries DP - 1979 Nov 01 TA - Molecular Pharmacology PG - 813--822 VI - 16 IP - 3 4099 - http://molpharm.aspetjournals.org/content/16/3/813.short 4100 - http://molpharm.aspetjournals.org/content/16/3/813.full SO - Mol Pharmacol1979 Nov 01; 16 AB - A series of xanthine derivatives and papaverine have been studied to determine their abilities to alter tissue levels of cyclic AMP and cyclic GMP, inhibit phosphodiesterase activities, and cause relaxation of pig coronary arteries. The agents selected for this study exhibited a wide range of potencies to inhibit phosphodiesterase activities in the coronary artery supernatant fraction. In addition, some of these agents were up to 10 times more potent as inhibitors of cyclic GMP hydrolysis than of cyclic AMP hydrolysis, while others were 2-4 times more potent as inhibitors of cyclic AMP than of cyclic GMP hydrolysis. The rank order of potencies of these agents to cause relaxation of coronary artery strips was similar to the rank order of potencies to inhibit cyclic nucleotide phosphodiesterase activities. There were, however, some notable exceptions to the correlation between inhibition of cyclic nucleotide phosphodiesterase activities and relaxation. 1-Isoamyl-3-isobutylxanthine was a more potent relaxing agent than might be expected from its relatively low potency to inhibit cyclic nucleotide hydrolysis in tissue extracts. On the other hand, 1-methyl-3-isobutyl-7-(3-chlorobenzyl)-xanthine was one of the more potent inhibitors of cyclic nucleotide hydrolysis but was not as potent in causing relaxation as might have been expected. Exposure of the coronary artery strips to inhibitors caused increases in tissue levels of cyclic AMP and cyclic GMP and there was a statistically significant multiple linear regression of cyclic AMP and cyclic GMP levels on percent relaxation after 5 min of exposure to the agents. Cyclic AMP and cyclic GMP levels made approximately equal contributions to the regression of changes in percent relaxation, as determined by analysis of variance methods. While 1-isoamyl-3-isobutylxanthine did not fit the correlation between phosphodiesterase inhibition and potency to relax the arterial strips as well as the other agents, this agent also was found to cause unexpectedly large increases in cyclic AMP levels. Some agents caused relaxation accompanied by significant elevation of cyclic GMP levels and no significant change in cyclic AMP levels while other agents caused relaxation accompanied by significant increases in cyclic AMP but not cyclic GMP. These data offer some support for a hypothesis that both cyclic AMP and cyclic GMP are involved in the relaxation processes of pig coronary arteries. ACKNOWLEDGMENTS The authors wish to thank Rae Ann Bellet and Susan S. Mitchel for their expert technical help and Drs. Joel G. Hardman and Günter Schultz for valuable discussion and constructive criticism.