Cardiovascular pharmacology of FK664, a novel venodilator with cardiotonic properties

The cardiovascular effects of FK664, [6‐(3, 4‐dimethoxyphenyl)‐1‐ethyl‐4‐mesitylimino‐3‐methyl‐3, 4‐dihydro‐2 (1H)‐pyrimidinone], were examined in both in vitro and in vivo preparations. FK664 is an orally effective noncatechol and nonglycoside cardiotonic agent. FK664 has vasodilating activity not only in resistance vessels but also in capacitance vessels in both in vitro and in vivo studies (venodilation). This venodilating effect of FK664 has been observed at much lower concentrations than those required to produce an inotropic response. FK664 is effective in the conscious dog at 1 mg/kg (2.5 μmol/kg) orally and in a dog model of congestive heart failure at 3.2 μg/kg/min (7.8 nmol/kg/min), intravenously. The vasodilating and positive‐inotropic activities of FK664 are mainly due to an increase in cyclic adenosine 3′,5′‐monophosphate (cyclic AMP) levels due to inhibition of cyclic AMP phosphodiesterase. Moreover, FK664 does not affect the balance between myocardial oxygen supply and demand due to a significant increase in coronary blood flow, though the agent does increase myocardial oxygen consumption. In conclusion, the agent produces potent preload reduction and mild cardiac stimulation. This unique pharmacological profile may be beneficial in the management of congestive heart failure. © 1993 Wiley‐Liss, Inc.