The
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, 37 degrees C) 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 microM) and
isoprenaline (ISO 0.03 microM), as well as the effects of
milrinone (
MIL 1-1,000 microM), ISO (0.01-10 microM),
ouabain (OUA, 0.1 microM), and Ca2+ (1.8-15 mM) in failing human myocardium alone.
UK 61260 increased force of contraction (FOC), peak rate of tension increase (+T) and decay (-T) significantly (p less than 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 less than 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 Ca2+ in increasing developed tension in human failing myocardium was significantly higher as compared with
UK 61260. We conclude that during stimulation of the cardiac beta-
adrenoceptor-
adenylate-cyclase system,
UK 61260 increases myocardial systolic and diastolic function in failing human myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)