SPECIES-DEPENDENT PHARMACODYNAMIC EFFECTS OF THE SELECTIVE LOW K-M CYCLIC-AMP PHOSPHODIESTERASE-III INHIBITORS WIN-58993 AND WIN-62005

We describe the biochemical and pharmacologic effects of two novel fus ed pyridinones derived from milrinone: WIN 58993 and WIN 62005. Both W IN 58993 and WIN 62005 competitively inhibit cyclic GMP-inhibitable lo w K-m cyclic AMP phosphodiesterase (PDE III) from rat heart and canine aorta with K-i values of 25 +/- 3 and 26 +/- 5 nM, respectively, and are selective (at least 160-fold) for PDE III inhibition relative to o ther PDE isozymes. WIN 58993 and WIN 62005 were given to conscious, ch ronically instrumented rats and dogs intravenously (i.v.) or perorally (p.o.). Because the doses of WIN 58993 and WIN 62005 required to decr ease mean arterial blood pressure (MAP) by 20% were estimated to be 0. 9 and 0.7 mg/kg, respectively, the compounds appear to be equipotent a fter acute i.v. administration in rats. However, the duration of the d epressor responses in rats apparently differs since MAP remained signi ficantly decreased 6 h after i.v. or p.o. administration of WIN 58993, but returned to control levels less than or equal to 4 h after admini stration of WIN 62005, WIN 58993 may be slightly less potent than WIN 62005 after acute i.v. administration to dogs since significant increa ses in left ventricular (LV)dP/dt(max) first occurred at doses of 0.1 and 0.03 mg/kg, respectively. LVdP/dt(max) significantly increased in 30 min and returned to baseline 3 h after p.o. administration of 1 mg/ kg WIN 58993. After p.o. administration of 1 mg/kg WIN 62005, LVdP/dt( max) was significantly increased in 30 min and remained increased for at least 6 h. These data suggest that WIN 58993 and WIN 62005 are pote nt, selective, p.o.-active inhibitors of PDE III. However, the pharmac odynamic effects of WIN 58993 and WIN 62005 appear to be species-depen dent.