CHARACTERIZATION OF THE PHOSPHODIESTERASE INHIBITION BY HYLSULFINYL-2-THIENYL)-1H-IMIDAZO-(4,5-C)-PYRIDINE HCL AND ITS SULFIDE AND SULFONE DERIVATIVES IN MYOCARDIAL PREPARATIONS FROM FAILING HUMAN HEARTS

The effects of HN-10200 -(3-methoxy-5-methylsulfinyl-2-thienyl)-1H-imi dazo (4,5-c)-pyridine HCl) and its derivatives HN-10201-sulfide and HN -10202-sulfone on the activities of the phosphodiesterase (PDE) isoenz yme activities isolated from ventricular myocardium of failing human h earts (end-stage myocardial failure, NYHA IV) were investigated. Four PDE isoenzymes (PDE I-IV) were separated by DEAE-sepharose chromatogra phy. Milrinone, 3-isobutyl-1-methylxanthine (IBMX), and a derivative o f pimobendan (2-(4-hydroxyphenyl)-5-(5-methyl-3-oxo-4, 5-dihydro-2H-6- pyridazinyl)-benzimidazole HCl, PiD) were studied for comparison. Furt hermore, the influence of HN-10200 on force of contraction and cAMP co ntent of ventricular trabeculae of these hearts were determined HN-102 00 inhibited the activities of PDE I-IV concentration-dependently. The IC50 values were (mu mol/l). 218.7, 283.1, 119.6, and 85.8 for PDE I- IV, respectively. The IC50 values of its derivatives were in the same range, i.e. the parent compound ol its derivatives inhibited the PDE i soenzymes nonselectively. IBMX also inhibited PDE I-IV nonselectively, but was about ten times mole potent based on IC50 values. In contrast , PiD was the most selective and potent PDE III inhibitor tested. Milr inone inhibited both, PDE III and IV, up to two orders of magnitude mo re potently than PDE I and II. HN-10200 (30 mu mol/l) only marginally and insignificantly increased force of contraction and cAMP content of the ventricular trabeculae. Thus, HN-10200 and it's derivatives HN-10 201-sulfide and HN-10202-sulfone are nonselective inhibitors of myocar dial PDE I-IV. HN-10200 revealed only neglectable positive inotropic e ffects in preparations from failing human heart.