Effects of phosphodiesterase inhibitors on cyclic nucleotide levels and relaxation of pig coronary arteries
Kramer, G.L.; Wells, J.N.
Molecular Pharmacology 16(3): 813-822
1979
ISSN/ISBN: 0026-895X PMID: 231194 Document Number: 154207
A series of xanthine derivatives and papaverine have been studied to determine their abilities to alter tissue levels of cyclic activities, and cause relaxation of pig coronary arteries. The agents selected for this study exhibited a wide range of potencies to inhibit PD activities in the coronary artery supernatant fraction. Some agents were up to 10 .times. more potent as inhibitors of cGMP hydrolysis than of cAMP hydrolysis, while others were 2-4 .times. more potent as inhibitors of cAMP than of cGMP 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 PD activities. There were some notable exceptions to the correlation between inhibition of cyclic nucleotide PD 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. 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 cAMP and cGMP and there was a statistically significant multiple linear regression of cAMP and cGMP levels on percent relaxation after 5 min of exposure to the agents. cAMP and cGMP 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 PD inhibition and potency to relax the arterial strips as well as the other agents, this agent also caused unexpectedly large increases in cAMP levels. Some agents caused relaxation accompanied by significant elevation of cGMP levels and no significant change in cAMP levels, while other agents caused relaxation accompanied by significant increases in cAMP but not cGMP. Both cAMP and cGMP are apparently involved in the relaxation processes of pig coronary arteries.