MC2, a new phosphodiesterase-3 inhibitor with antilipolytic and hypolipidemic effects in normal and diabetic rats

Selective PDE3 inhibitors are considered as useful pharmacological agents with variety of inotropic, vasodilatory, anti-thrombotic, anti-inflammatory, and insulin secretory effects. Yet, metabolic effects of these agents have not been completely elucidated. In this work, the effects of seven new derivatives of cilostamide (a selective PDE3 inhibitor), MC1, MC2, MC3, MC4, MC5, MC6, and MC7, were studied on lipolysis in vitro and serum lipids levels in vivo. Retroperitoneal adipose tissue was excised from normal rat and incubated with cilostamide derivatives in the absence or presence of isoproterenol, a non-selective β-adrenergic agonist. MC5, MC6, and MC7, like cilostamide, could increase (p < 0.05–p < 0.01) isoproterenol-induced lipolysis. However, MC2 significantly decreased both basal and isoproterenol- or forskolin-induced lipolysis (p < 0.05). MC1, MC3, and MC4 failed to show any significant effect on basal or stimulated lipolysis. MC2 was also able to decrease serum triglyceride and increase high-density lipoproteins levels in diabetic rats. The effects of MC2 were associated with increase in triglyceride clearance from blood stream. In conclusion, unlike cilostamide, MC2 has antilipolytic property, and this effect is most probably mediated by a mechanism independent of the PDE3 inhibition. Therefore, it has the potential to be considered as a new cilostamide derivative with beneficial effects on diabetic, obese, or hyperlipidemic patients, since it seems to promote better lipid profile compare to other cardiotonic PDE inhibitors.