Characterization of the phosphodiesterase inhibition by 2-(3-methoxy-5-methylsulfinyl-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 (2-(3-methoxy-5-methylsulfinyl-2-thienyl)-1H-imidazo(4,5-c)-pyridine HCl) and its derivatives HN-10201-sulfide and HN-10202-sulfone on the activities of the phosphodiesterase (PDE) isoenzyme activities isolated from ventricular myocardium of failing human hearts (end-stage myocardial failure, NYHA IV) were investigated. Four PDE isoenzymes (PDE I-IV) were separated by DEAE-sepharose chromatography. Milrinone, 3-isobutyl-1-methylxanthine (IBMX), and a derivative of pimobendan (2-(4-hydroxyphenyl)-5-(5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl)- benzimidazole HCl, PiD) were studied for comparison. Furthermore, the influence of HN-10200 on force of contraction and cAMP content of ventricular trabeculae of these hearts were determined. HN-10200 inhibited the activities of PDE I-IV concentration-dependently. The IC50 values were (mumol/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 or its derivatives inhibited the PDE isoenzymes nonselectively. IBMX also inhibited PDE I-IV nonselectively, but was about ten times more potent based on IC50 values. In contrast, PiD was the most selective and potent PDE III inhibitor tested. Milrinone inhibited both, PDE III and IV, up to two orders of magnitude more potently than PDE I and II, HN-10200 (30 mumol/l) only marginally and insignificantly increased force of contraction and cAMP content of the ventricular trabeculae. Thus, HN-10200 and it's derivatives HN-10201-sulfide and HN-10202-sulfone are nonselective inhibitors of myocardial PDE I-IV. HN-10200 revealed only neglectable positive inotropic effects in preparations from failing human heart.