Effect of the Phosphodiesterase Inhibitor UK 61260 on Human Myocardial Inotropy and Diastolic Relaxation

SummaryThe phosphodiesterase inhibitor UK 61260 exhibits positive inotropic activity in animal studies and is under clinical investigation for treatment of congestive heart failure (CHF). We examined the lusitropic and inotropic responses to UK 61260 in electrically driven (1 Hz, 37C) human auricular trabeculae (AUT, aortocoronary bypass operation, nonfailing hearts, n = 13) and in papillary muscle strips (PAP) from moderately (New York Heart Association, NYHA II–III, mitral valve replacement, n = 6) and terminally (NYHA IV, heart transplantation, n = 7) failing human hearts. For comparison, we studied the effects of UK 61260 after prestimulation with forskolin (FOR 0.03 μ.M) and isoprenaline (ISO 0.03 μ.M), as well as the effects of milrinone (MIL 1–1,000 μ.M), ISO (0.01–10 μ. M), ouabain (OUA, 0.1 μ. M) and Ca (1.8–15 m M) in failing human myocardium alone. UK 61260 increased force of contraction (FOC), peak rate of tension increase ( + T) and decay (-T) significantly (p < 0.01) in AUT but not in PAP of NYHA II-III and NYHA IV.Only after prestimulation (FOR and ISO), was UK 61260 effective in stimulating FOC in NYHA II-III and NYHA IV. UK 61260 increased (p < 0.01) +T and -T, resulting in a shortening of twitch time. As judged from the EC50 values, UK 61260 increased FOC more potently than MIL. The effectiveness of OUA and Ca in increasing developed tension in human failing myocardium was significantly higher as compared with UK 61260. We conclude that during stimulation of the cardiac β-adrenoceptor-adenylate-cyclase system, UK 61260 increases myocardial systolic and diastolic function in failing human myocardium. Therefore, UK 61260 might be able to exert inotropic and lusitropic actions in patients with enhanced sympathoadrenergic stimulation. The functional data are compatible with cyclic AMP-phosphodiesterase inhibition as the mechanism of action.