PHARMACOLOGICAL AND PHARMACODYNAMIC EFFECTS OF THE SELECTIVE LOW K-M CYCLIC-AMP PHOSPHODIESTERASE-III INHIBITORS WIN-63291 AND WIN-62582

We describe the biochemical, pharmacologic, and in vivo pharmacodynami c profiles of two novel inhibitors of the cyclic GMP-inhibitable, low K-m cyclic AMP phosphodiesterase (PDE) III; WIN 63291, a 6-quinolinyl analogue of the prototypic PDE III inhibitor milrinone and WIN 62582, an imidazopyridinone. Both WIN 62582 and WIN 63291 competitively inhib it PDE III from rat, dog, and human heart and from rat and canine aort a with IC50 values of 5-37 and 55-80 nM, respectively; the IC50 values for milrinone ranged from 300 to 520 nM. WIN 62582 and WIN 63291 are at least 1,000-fold selective for PDE III relative to inhibition of PD E isozymes I, II, IV, and V. We evaluated WIN 62582 and WIN 63291 in c onscious rats and dogs after intravenous (i.v.) and oral (p.o.) admini stration. The dose of WIN 62582 required to reduce mean arterial blood pressure (MAP) by 20% (ED(20)) in rats was 1.8 mg/kg, with a pharmaco dynamic duration of action of similar to 2 h. In comparison, the estim ated i.v. ED(20) for WIN 63291 in rats was 0.4 mg/kg, with a pharmacod ynamic duration of action >6 h. In conscious dogs, the i.v. doses of W IN 62582 and 63291 required to increase left ventricular (LV)dP/dt(max ) significantly were 0.1 and 0.01 mg/kg, respectively. In dogs, WIN 63 291 0.1 mg/kg p.o. increased LV dP/dt(max) by 86% in 30 min; LV dP/dt( max) remained increased by 60% for at least 6 h. In comparison, WIN 62 582, 0.3 mg/kg p.o., increased LV dP/dt by 56% in 30 min and remained increased by 40% at 6 h. These data suggest that WIN 62582 and WIN 632 91 are potent, selective, orally active inhibitors of PDE III and have a relatively long duration of action in vivo. Although WIN 62582 is s imilar to 10-fold more potent than WIN 63291 as an inhibitor of PDE II I in vitro, WIN 63291 is a slightly more potent cardiovascular agent i n vivo after i.v. and p.o. administration to conscious rats and dogs.