Takashi Imaizumi

Cardiovascular actions of OPC-18790: A novel positive inotropic agent with little chronotropic action

SummaryOPC-18790 [(±)-6-[3-(3,4-dimethoxy-benzylamino)- 2 - hydroxypropoxy] - 2(1H) - quinolinone], a novel positive inotropic agent, was investigated in several in vitro and in vivo experiments to elucidate its cardiovascular effects and its mechanism of action. In isolated blood-perfused dog heart preparations, OPC-18790 increased contractile force at 10 to 1,000 nmol i.a.; increased coronary arterial blood flow at 30 to 1,000 nmol; and deceased sinus rate slightly at 1,000 nmol. Atrio-ventricular nodal conduction was slightly facilitated with OPC-18790 (10 to 1,000 nmol), whereas ventricular automaticity tended to decrease. OPC-18790 (10−6 to 10−4 M) increased contractile force in isolated ventricular muscles of dogs, cats, rabbits and guinea pigs but not rats. OPC-18790 increased left ventricular contractile force dosedependently in anesthetized open-chest dogs and in conscious dogs with slight or no changes in heart rate and blood pressure. The positive inotropic effect of OPC-18790 was not affected by β-blockade. OPC-18790 (10−5 to 10−4 M) prolonged the duration of action potential in guinea pig papillary muscles. Na+, K+-ATPase was not inhibited, but peak-III phosphodiesterase (low Km cyclic AMP specific fraction, inhibited by cyclic GMP) was inhibited by OPC-18790 (IC50 = 0.41 × 10−6 M) in dog myocardium. However, such an inhibitory action of phosphodiesterase can hardly be reconciled with the lack of a positive chronotropic effect shown by OPC-18790. Thus, these results suggest that OPC-18790 may have an additional mechanism. The cardiovascular effects revealed by this study suggest that OPC-18790 may exert a beneficial effect in the treatment of congestive heart failure.

Role of active oxygen species in diethyldithiocarbamate-induced gastric ulcer in the rat.

Diethyldithiocarbamate, an inhibitor of Cu,Zn-superoxide dismutase, was recently found to be ulcerogenic in the rat stomach, and active oxygen species were found to be responsible for its ulcerogenicity. To clarify which active oxygen species play a role in ulcerogenesis, the effects of various scavengers and iron-chelators were studied. As superoxide dismutase and catalase reduced the ulcerogenesis induced by diethyldithiocarbamate, the superoxide radical and hydrogen peroxide were considered to play a pathogenic role in this ulcer model.

α2-adrenoceptor antagonist properties of OPC-28326, a novel selective peripheral vasodilator

Antagonistic properties of OPC‐28326 ([4‐(N‐methyl‐2‐phenylethylamino)‐1‐(3,5‐dimethyl‐4‐propionyl‐aminobenzoyl)] piperidine hydrochloride monohydrate), a selective peripheral vasodilator, were investigated by analysing the data from functional studies in various tissues from the rat and binding studies of the drug to α2‐adrenoceptor subtypes. Using a human recombinant receptor and rat kidney cortex, we found that OPC‐28326 displays affinities to α2A‐, α2B‐ and α2C‐adrenoceptors with Ki values of 2040, 285, and 55 nM, respectively. The Ki values of yohimbine for α2A‐, α2B‐, and α2C‐adrenoceptors were 3.0, 2.0 and 11.0 nM, respectively. B‐HT 920, an α2‐adrenoceptor agonist, produced a pressor response via peripheral postsynaptic α2‐adrenoceptor stimulation (thought to be an α2B‐subtype) in a reserpine‐pretreated pithed rat preparation. OPC‐28326 (3 – 30 mg kg−1, i.v.) and yohimbine (0.3 – 3 mg kg−1, i.v.) caused dose‐dependent rightward shift in the pressor dose‐response curve induced by B‐HT 920. The apparent pA2 values were 1.55 (0.87 – 2.75, 95% confidence interval) and 0.11 (0.06 – 0.21) mg kg−1, respectively. The potency of OPC‐28326 was about 14 times less than that of yohimbine. Clonidine inhibited the tension developed by electrical stimulation, of the rat vas deferens, by its peripheral presynaptic α2A/D‐adrenoceptor action. OPC‐28326 (1 – 100 μM) and yohimbine (10 – 1000 nM) caused a rightward shift in the concentration‐response curve of clonidine. The pA2 values were 5.73 (5.54 – 5.91) and 7.92 (7.84 – 8.01), respectively, providing evidence for a potency of OPC‐28326 of about 155 times less than that of yohimbine. Mydriasis was induced by brimonidine via stimulation of central α2A/D‐adrenoceptors in anaesthetized rats. Intravenous OPC‐28326 had no effect on this action, even at a very high dose of 10 mg kg−1 i.v., while yohimbine (0.1 – 0.3 mg kg−1 i.v.) inhibited mydriasis in a dose‐dependent manner, indicating that OPC‐28326 was at least 100 times less potent than yohimbine in regard to the anti‐mydriatic effect. These data suggest that OPC‐28326 preferentially exerts peripheral and postsynaptic antagonistic actions on the α2B‐ and α2C‐adrenoceptor subtypes.

EFFECTS OF VASODILATORS ON THE SIGNAL INTENSITY OF PERFLUOROCARBON MONITORED BY IN VIVO 19F-NMR SPECTROSCOPY

The effects of vasodilators on peripheral vessels were examined by monitoring the 19F-NMR signal of perfluorocarbon in vivo. Nitroglycerin, a venodilator that acts mainly on venous smooth muscle, increased the signal intensity of FC-43, whereas hydralazine, a typical arteriolar dilator that acts on arteriolar smooth muscle, decreased the signal intensity. These results indicate that the in vivo effects of vasodilators on smooth muscles of the venous and arterial systems are reflected by their effects on the signal intensity of FC-43.

OPC-18790, a novel positive inotropic agent, has both arterial and venous vascular dilating actions in the dog

OPC-18790, (+/-)6-[3-(3,4-dimethoxybenzylamino)-2- hydroxypropoxy]-2(1H)-quinolinone, is a novel positive inotropic agent with a moderate vasodilating action. We examined the vasodilating action of OPC-18790 in detail in the pentobarbital-anesthetized dogs using a colored microsphere technique for resistance vessels and a mean circulatory filling pressure method for capacitance vessels. Intravenously (i.v.) infused OPC-18790 increased the first derivative of left ventricular pressure (LVdP/dt max), cardiac output, heart rate and decreased total peripheral resistance but did not affect mean blood pressure. OPC-18790 significantly increased arterial blood flow distribution to heart and decreased vascular resistance in heart. OPC-18790 at 300 micrograms/kg i.v. and nitroglycerin at 50 micrograms/kg i.v. did not affect mean circulatory filling pressure in intact anesthetized dogs, but both compounds decreased mean circulatory filling pressure in spinally anesthetized dogs. OPC-18790 also decreased resistance to venous return but nitroglycerin did not. These results suggest that OPC-18790 has both arterial and venous vasodilating actions in addition to its positive inotropic action. These actions may produce an improvement of cardiohemodynamics in heart failure.