In vitro vascular relaxation by new inotropic agents: relationship to phosphodiesterase inhibition and cyclic nucleotides.
Several novel cardiotonic vasodilators including bipyridines (amrinone and milrinone), imidazolones (enoximone and piroximone), dihydropyridazinones (Cl-914, Cl-930 and LY195115) and an imidazopyridine (isomazole) relaxed rat aortic strips contracted previously with 30 microM serotonin. LY195115 and Cl-930 were the most potent vasorelaxant agonists (ED50 approximately 10(-7) M), whereas piroximone and amrinone were the least potent (ED50 approximately 10(-5) M). In addition to these positive inotropic agents, vascular relaxation was examined further for a series of novel dihydropyridazinones, and relaxant potencies correlated directly with the ability of these agents to inhibit an isozyme of cyclic nucleotide phosphodiesterase (PDE) located in the sarcoplasmic reticulum of cardiac muscle (SR-PDE) (r = 0.87, P less than .01). This excellent correlation suggests that vascular relaxation produced by these agents is related to their ability to inhibit a vascular enzyme similar or identical to SR-PDE. Furthermore, LY195115, milrinone and isomazole (10(-4) M) produced significant increases in both aortic cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Time courses for these changes were consistent with a role for cyclic nucleotides in relaxation; however, differences between the relative increases in cAMP or cGMP produced by these drugs were evident. Removal of the aortic endothelium had no effect upon relaxation produced by milrione and only a modest (approximately 2-fold decrease in potency) effect on relaxation produced by LY195115 and isomazole, indicating that the relaxant effect of these cardiotonics is primarily an endothelium-independent event.(ABSTRACT TRUNCATED AT 250 WORDS)
Kauffman
R F
RF
Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana.
Schenck
K W
KW
Utterback
B G
BG
Crowe
V G
VG
Cohen
M L
ML
D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D001011:Aorta / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D000242:Cyclic AMP / Q000032:analysis*; D006152:Cyclic GMP / Q000032:analysis*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D008751:Methylene Blue / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D014664:Vasodilation / Q000187:drug effects*
D002316:Cardiotonic Agents; D000242:Cyclic AMP; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases; D006152:Cyclic GMP; D008751:Methylene Blue