Quinolinone Derivative Research Articles

Effects of a Cardiotonic Quinolinone Derivative Y-20487 on the Isoproterenol-Induced Positive Inotropic Action and Cyclic AMP Accumulation in Rat Ventricular Myocardium

The effect of a new cardiotonic agent Y-20487 [6-(3,6-dihydro-2-oxo-2H-1,3,4-thiadiazin-5-yl)-3,4-dihydro-2(1H)- quinolinone] on cyclic AMP levels of rat ventricular cardiomyocytes and the contractile force of papillary muscles was investigated in comparison with selective cyclic AMP phosphodiesterase (PDE) inhibitors, milrinone (PDE-III selective), rolipram and Ro 20-1724 (PDE-IV selective), and a nonselective inhibitor 3-isobutyl-1-methylxanthine (IBMX). Rolipram and Ro 20-1724 did not elicit cyclic AMP accumulation and positive inotropy, but they potentiated the isoproterenol (ISO)-induced cyclic AMP accumulation more effectively than IBMX. Rolipram was more effective than Ro 20-1724 in enhancing ISO-induced cyclic AMP accumulation but was less effective in enhancing the ISO-induced positive inotropic effect, indicating that these agents produce a differential action on cyclic AMP metabolism and inotropy. Milrinone and Y-20487 elicited cyclic AMP accumulation and positive inotropy by themselves. Whereas milrinone scarcely affected the ISO-induced effects, Y-20487 shifted the concentration-response curve for the positive inotropic effect of ISO to the left to the same extent that IBMX did. Y-20487, however, was much less effective than IBMX in enhancing the ISO-induced cyclic AMP accumulation. The present results indicate that in rat ventricular myocardium, PDE-IV may play a crucial role in breakdown of cyclic AMP generated by beta-adrenoceptor stimulation, whereas other types of PDE isoenzymes, including PDE-III, may be responsible for the cyclic AMP accumulation and direct positive inotropic effect induced by PDE inhibitors.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of a Cardiotonic Quinolinone Derivative Y-20487 on the Isoproterenol-Induced Positive Inotropic Action and Cyclic AMP Accumulation in Rat Ventricular Myocardium

Effects of a Cardiotonic Quinolinone Derivative Y-20487 on the Isoproterenol-Induced Positive Inotropic Action and Cyclic AMP Accumulation in Rat Ventricular Myocardium

What do the newer inotropic drugs have to offer?

Intensive interest and passion have been generated in the search for orally effective inotropes over the past few decades. Several extensive clinical evaluations of these agents have now been completed. Both beta-adrenergic agonists and phosphodiesterase inhibitors that exert cardiotonic action by increasing intracellular cyclic adenosine monophosphate produced dramatic short-term hemodynamic benefits in patients with advanced heart failure. However, patients who received long-term treatment with these agents had unfavorable outcomes, including a higher mortality and morbidity rate, and deleterious side effects. The principal mechanisms responsible for the limitations in its usefulness in long-term therapy may be related to increased energy expenditure and potential arrhythmogenic effects. In contrast to these pessimistic views, one quinolinone derivative has been shown to exert a positive inotropic action without a chronotropic effect. Patients with mild heart failure responded favorably to this agent in long-term therapy. The lack of an increase in heart rate might be the cause of this salutary effect. Concerns regarding the possible improvement in the prognosis of patients with heart failure due to the use of positive inotropic therapy still continue.

Usefulness of OPC-8212, a quinolinone derivative, for chronic congestive heart failure in patients with ischemic heart disease or idiopathic dilated cardiomyopathy

To evaluate the safety and efficacy of the inotropic agent OPC-8212 in patients with chronic congestive heart failure, 76 patients with impaired cardiac function and diminished exercise tolerance were studied. They were randomized to 12 weeks of double-blind therapy with either 60 mg/day of OPC-8212 or placebo. The study drug was added to their baseline medical regimen. The primary study outcome was the combined outcome of the time to either mortality (of all cause) or substantial worsening of heart failure (major morbidity), whichever occurred first. Treatment with OPC-8212 significantly (p < 0.01) decreased the combination of major morbidity/mortality over 12 weeks of therapy. Quality of life, assessed by the Sickness Impact Profile questionnaire, was significantly improved in patients receiving OPC-8212 (p < 0.01). Furthermore, ventricular premature contractions as assessed by 24-hour Holter monitoring were not increased with OPC-8212 treatment. Although patients treated with OPC-8212 were able to reach a significantly higher peak oxygen uptake and exercise longer during symptom-limited exercise, when data were analyzed as percent change from baseline, the absolute increases were small. These results suggest that OPC-8212 is beneficial in treating patients with congestive heart failure and that further evaluation of this new inotropic agent is warranted.

D-2 receptor-mediated inhibition by a substituted quinolinone derivateive, 7-{3-(4-(2,3-dimethylphenyl)piperazinyl)propoxy}-2(1h)-quinolinone (OPC-4392), of dopaminergic neurons in the ventral tegmental area

A microiontophoretic study was performed to investigate the effects of a newly synthesized quinolinone derivative, 7-{3-(4-(2,3-dimethylphenyl) p piperazinyl) propoxy} 2-(1H)-quinolinone (OPC-4392), on neuronal activities of the ventral tegmental area (VTA) of rats anesthetized with chloral hydrate. The VTA neurons, which were identified by antidromic stimulation of the nucleus accumbens (Acc), were classified into type I and type II neurons according to the responses to Acc stimulation: type I neurons had a long spike latency of over 7 msec (9.63 ± 0.25 msec), upon Acc stimulation. This inhibition was 7 msec (2.98 ± 0.27 msec) upon Acc stimulation. In all of 11 type I neurons, iontophoretically applied OPC-4392 and dopamine inhibited the antidromic spikes elicited by Acc stimulation. This inhibition was antagonized by simultaneous application of domperidone (dopamine D-2 antagonist). However, in 16 out of 19 type II neurons the antidromic spikes were not affected by either OPC-4392 or dopamine. When the effects of iontophoretically applied OPC-4392 and dopamine on spontaneous firings were tested in 32 VTA neurons identified by Acc stimulation (including type I and type II neurons), there was a relationship between the effects of these two drugs. These results suggest that OPC-4392 acts on dopamine D-2 receptors of the dopaminergic neurons in the VTA, thereby inhibiting neuronal activity.

New Positive Inotropic Agent OPC-8212 Modulates Single Ca2+ Channels in Ventricular Myocytes of Guinea Pig

The effects of a new positive inotropic drug, OPC-8212 (a quinolinone derivative, 3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1 -piperazinyl]-2(1H)-quinolinone), on whole-cell and single-channel calcium currents of guinea pig ventricular myocytes were studied by the patch-clamp method. OPC-8212 increased whole-cell calcium currents in a concentration-dependent manner. The concentration-response curve was fitted by a single binding site model that has an ED50 of 2.7 microM. At the single-channel level, OPC-8212 increased calcium currents mainly by increasing the probability of channel opening on depolarization; the open times were slightly increased, but single-channel conductance did not change. The actions of OPC-8212 on single calcium channel currents were compared with those of forskolin, isoproterenol, and caffeine, agents that cause positive inotropic effects associated with an increase in cytoplasmic cyclic AMP level, and with those of the dihydropyridine calcium channel agonist (-)Bay K 8644, an agent that has a positive inotropic effect but does not act through cyclic AMP. OPC-8212 increased calcium currents in a manner that resembled the actions of forskolin, isoproterenol, and caffeine rather than the actions of (-)Bay K 8644. We suggest that activation of calcium currents by OPC-8212 is mediated by an elevation of intracellular cyclic AMP. Since OPC-8212 produces bradycardia and antitachycardiac effects in animals and humans, unlike agents that increase cyclic AMP, additional effects on other currents are likely.

Presynaptic inhibition of excitatory input from the substantia nigra to caudate nucleus neurons by a substituted quinolinone derivative, 7-{3-(4-(2,3-dimethylphenyl)piperazinyl)propoxy}-2(1H)-quinolinone (OPC-4392)

The effects of a newly synthesized quinolinone derivative, 7-{3-(4-(2,3-dimethylphenyl)piperazinyl)propoxy} -2(1H)-quinolinone (OPC-4392) on neuronal activities of the caudate nucleus (CN) were investigated in cats anesthetized with α-chloralose using a microiontophoretic method. In the CN neurons of which spikes elicited by stimulation of the pars compacta of substantia nigra (SN) were suppressed by iontophoretically applied domperidone, D-2 receptor antagonist, application of OPC-4392 (100–200 nA) inhibited the spike generation induced by SN stimulation. Conversely, the CN neurons insensitive to domperidone were unaffected by OPC-4392. Iontophoretic application of OPC-4392 up to 200 nA did not affect glutamate-induced firing of the CN neurons, of which the firing was blocked by dopamine less than 100 nA. In addition, OPC-4392 did not inhibit firing induced by bromocriptine, a dopamine D-2 agonist; while domperidone suppressed the bromocriptine-induced firing without affecting the glutamate-induced firing. These results suggest that OPC-4392 acts on the dopaminergic nerve terminals and inhibits excitatory transmission from the SN to the CN.

Cardiotonic activity of a new inotropic agent, 3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)- quinolinone (OPC-8212), in the dog with and without beta-blocker and Ca++-antagonist pretreatment.

Hemodynamic effects of a new inotropic agent, OPC-8212 (2(1H)-quinolinone derivative) were studied in anesthetized open chest dogs pretreated with propranolol and diltiazem. Three doses (1, 3 and 10 mg/kg) of OPC-8212 were administered intravenously and the net hemodynamic effect (% change) was obtained by subtraction of the effect of the solvent from the gross effect, since the vehicle has a transient, but significant hemodynamic effect. The maximal inotropic effect occurred 3 minutes after administration: LV dP/dt max and cardiac output (CO) increased by 19 +/- 2.5% and 28 +/- 8.5%, respectively, at 3 mg/kg. These cardiotonic effects were dose-dependent, whereas heart rate, peak LV pressure (PLVP) and mean aortic pressure were minimally changed at any dose. Accordingly, systemic vascular resistance (SVR) decreased in a dose-dependent manner although the decrease was much less than that in administration of isoproterenol. The inotropic effect was not blocked by beta-adrenoceptor blockade (propranolol 1 mg/kg), indicating that the cardiotonic action of this agent is not due to beta-adrenergic stimulation. Thus, this agent could reverse beta-blocker-induced heart failure. During infusion of diltiazem (0.1 mg/kg/min following bolus intravenous administration of 0.5 mg/kg), the increases in LV dP/dt max and CO due to OPC-8212 were similar to those in the control study. In contrast to the effects under beta-adrenoceptor blockade, however, decreased PLVP was restored by OPC-8212. Neither chronotropic nor rrhythmogenic effects were observed in the control or with either pharmacological intervention. These results indicate that OPC-8212 has a potent inotropic action with modest vasodilatory effect even with propranolol or diltiazem pretreatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Beneficial effect of OPC-8212 (3,4-dihydro-6-(4-(3,4-dimethoxy benzoyl)-1-piperazinyl)-2(1H)-quinolinone on myocardial oxygen consumption in dogs with ischemic heart failure.

The effect of a new inotropic agent, OPC-8212 (2(1H)-quinolinone derivative), on myocardial oxygen consumption (MVO2) following intravenous administration (1 and 3 mg/kg/min) was studied in normal and ischemic failing hearts in open chest dogs. Ischemic failing heart was obtained by intracoronary injection of 15-micron microspheres and volume loading. OPC-8212 significantly increased LV max dP/dt and decreased mean aortic pressure, whereas heart rate was not altered in both normal and failing hearts. Despite the remarkable positive inotropic effect, this agent did not increase MVO2 in the normal hearts and even decreased MCO2 in the ischemic failing hearts associated with a decrease in LV end-diastolic pressure and hence, LV chamber size. These results indicate that OPC-8212 does not increase myocardial oxygen demand, probably because the increase in MVO2 by positive inotropic effect is offset by a decrease in MVO2 due to a decrease in chamber size. Thus, OPC-8212 may be promising for the treatment of congestive heart failure with reduced coronary flow reserve.