Quinolinone Derivative Research Articles

Effects of quinolinone derivative, vesnarinone, in combination with irradiation on human lung cancer cell lines.

The quinolinone derivative, vesnarinone, is a novel inotropic agent used in the treatment of heart failure. It has also been found that vesnarinone has a potential anti-cancer activity. To evaluate the anti-cancer activity of vesnarinone in combination with irradiation, we investigated the cytostatic and cytotoxic effects on human lung cancer cell lines (PC-9 and Lu 134A) using MTT assay and isobologram analysis. We also analyzed the nuclear fragmentation of tumor cells by flow cytometric analysis. Our study demonstrated that combination of vesnarinone with irradiation had an additive inhibitory effect on both PC-9 and Lu 134A tumor cell growth. Vesnarinone could improve the sensitivity of tumor cells to irradiation and thus the dose of irradiation could be reduced to half without decreased inhibitory effect. Significant increase of the tumor cell nuclear fragmentation was observed with combination of vesnarinone and irradiation. These results indicate that vesnarinone not only directly inhibited tumor cell growth, but also improved the sensitivity to irradiation. Combination of vesnarinone with irradiation may be an efficacious protocol for lung cancer treatment. The inhibitory effect was ascribed to inducing tumor cell apoptosis.

Antitumor effect of vesnarinone on human hepatocellular carcinoma cell lines.

Vesnarinone, a quinolinone derivative, induces apoptosis and differentiation in some tumor cell lines. We examined the antitumor effect of vesnarinone on three human hepatocellular carcinoma (HCC) cell lines. Vesnarinone suppressed the proliferation of all three HCC cell lines, but did not induce apoptosis and differentiation. Vesnarinone has also been reported to inhibit both nucleoside and nucleobase transport. Concomitant administration of vesnarinone and a de novo nucleotide synthesis inhibitor potentiated the growth-inhibitory effect of vesnarinone on HCC cells. Vesnarinone may be useful as a new biochemical modulator of anticancer agents.

Effect of vesnarinone in combination with anti-cancer drugs on lung cancer cell lines.

Vesnarinone, a quinolinone derivative which is used as an oral inotropic agent in the clinic, has recently also been shown to have anti-cancer activity. We have studied the anti-cancer effect of vesnarinone in combination with cisplatin, VP-16 (etoposide) and gemcitabine, against human lung cancer cell lines (PC-9 and Lu 134A) using the MTT assay and isobologram analysis. Simultaneously, by establishing two cisplatin-resistant sublines, i.e. PC-9/CDDP and Lu 134A/CDDP, we analyzed the cross-resistance between vesnarinone and cisplatin and the resistance-reversing effect of vesnarinone. Nuclear fragmentation, as the presumed mechanism of tumor cell growth inhibition, was further studied quantitatively using flow cytometric analysis. Combination of vesnarinone with the studied anti-cancer drugs had a synergic or additive inhibitory effect on both PC-9 and Lu 134A tumor cell growth. Neither decrease of the sensitivity to vesnarinone nor cross-resistance between vesnarinone and anti-cancer drugs was observed. On the contrary, vesnarinone showed a resistance-reversing effect. Both vesnarinone and the studied anti-cancer drugs could induce tumor cell apoptosis, but a definite correlation between nuclear fragmentation and the growth inhibitory effect was not established.

A quinolinone derivative, vesnarinone (OPC-8212), significantly inhibits the in vitro and in vivo growth of human pancreatic cancer cell lines.

A quinolinone derivative, vesnarinone, has been used as a cardiotonic agent. Previous studies have demonstrated that vesnarinone has potent antitumor activity. The present study was designed to assess the antitumor effects of vesnarinone on human pancreatic cancer cell lines in vitro and in vivo. The in vitro effects of vesnarinone on the human pancreatic cancer cell lines (PANC-1, MIA PaCa-2 and BxPC-3) were assessed by the MTT assay, the Trypan blue dye exclusion test and the Matrigel invasion chamber assay. The inhibition of in vivo tumor growth was evaluated on two human pancreatic cancer xenografts (BxPC-3 and SPa-1) transplanted s.c. into nude mice. The dose of vesnarinone for 50% inhibition of cell growth in a 7 day culture ranged between 10 and 20 micrograms/ml as verified by the Trypan blue dye exclusion test. The dose for 50% cytotoxicity after a 3 day culture in the MTT assay was 32 micrograms/ml for PANC-1 and 30 micrograms/ml for BxPC-3, but 50% cytotoxicity for MIA PaCa-2 was not achieved by the maximal dose of vesnarinone (50 micrograms/ml). Nomalsky optic microscopy and acridine orange staining demonstrated the vacuolization and crater-like changes in the cell nucleus after vesnarinone treatment. Moreover, staining of an apoptosis marker (Le(y) protein) and nick end-labeling increased. Vesnarinone also inhibited cancer invasion in the Matrigel invasion chamber assay. In vivo, BxPC-3 and SPa-1 were s.c. transplanted into the nude mice, and vesnarinone (5 or 50 mg/kg) was daily administered orally for 21 days. In both lines, vesnarinone at 50 mg/kg achieved significant inhibition. The present study suggests that vesnarinone may be a new therapeutic agent for pancreatic cancer.

Unique Pharmacological Profile of a Novel Antipsychotic Drug, Aripiprazole (OPC‐14597)

Aripiprazole (OPC-14597) is a novel antipsychotic agent with an unusual pharmacological profile that is atypical of compounds affecting the dopaminergic system. This agent is a quinolinone derivative related to OPC-4392 (Fig. 1). OPC-4392 acts on dopamine (DA) neurons and their nerve terminals as an autoreceptor agonist, eliciting inhibitory effects on ventral tegmental and nigral DA neurons (14,20). OPC-4392 has no postsynaptic DA receptor blocking activities (20). In clinical trials OPC-4392 improved the negative and the positive symptoms of chronic schizophrenic patients, such as hallucination, delusion, and psychiatric excitement. Similar effects on negative symptoms were observed with other DA autoreceptor agonists, such as EMD 49980, talipexole and terguride (8,20,17). Further attempts to develop a useful antipsychotic drug that displays both presynaptic DA agonistic and postsynaptic DA antagonistic activities and improves negative as well as positive symptoms in schizophrenic patients resulted in the discovery of aripiprazole. An early phase 11 clinical study on aripiprazole was recently performed in 56 schizophrenic patients by M. Toru et al. in Japan (24). According to the assessment by BPRS in this study, significant global improvement of negative symptoms (emotional withdrawal, motor retardation, blunted affect) and positive signs (suspiciousness, unusual thoughts, hallucinatory behaviors) was achieved. Negligible side effects, including mild extrapyramidal symptoms, were encountered. Aripiprazole may be considered a useful antipsychotic agent with a unique pharmacological profile.

Aripiprazole, a novel antipsychotic drug, inhibits quinpriole-evoked GTPase activity but does not up-regulate dopamine D 2 receptor following repeated treatment in the rat striatum

Aripiprazole, a quinolinone derivative, is a new dopaminergic agent which has been recently developed and demonstrated to be clinically useful as an antipsychotic drug with reduced extrapyramidal motor side effects. Here, we found that aripiprazole competed [ 3H]spiperone binding with a 100-fold higher affinity than [ 3H]SCH23390 binding, and inhibited the quinpriole-induced facilitation of high-affinity GTPase activity in rat striatal membranes. The effects of chronic administration of aripiprazole and haloperidol on dopamine D 2 receptor binding and mRNA level in rat striata were examined by a [ 3H]spiperone binding assay and a ribonuclease protection assay. Haloperidol induced a significant rise in B max of [ 3H]spiperone binding at 1 mg/kg and in the level of dopamine D 2L receptor mRNA at 4 mg/kg. A high dose of aripiprazole (100 mg/kg) only tended to increase the B max of [ 3H]spiperone binding non-significantly, and had no effect on the level of dopamine D 2L receptor mRNA. These results indicated that aripiprazole had an antagonistic activity to dopamine D 2 receptors with a high affinity, but that the potency of aripiprazole to up-regulate dopamine D 2 receptors in the striatum was much smaller than that of haloperidol. This small up-regulation may be related to the ability of aripiprazole to act without side effects including tardive dyskinesia.

The quinolinone derivative vesnarinone potentiates the cytotoxicity of doxorubicin in HL-60 leukemia cells

Vesnarinone, (3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1- piperazinyl]-2(1H)-quinolinone), a quinolinone derivative, is a positive inotropic agent. We examined the cytotoxicity either by vesnarinone alone or in combination with doxorubicin (DXR), in vitro. The cytotoxic effect of vesnarinone against HL-60 cells did not increase, even at concentrations as high as (50 mu g/ml). The cytotoxicity of DXR, however, was enhanced after being combined with 30 mu g/ml of vesnarinone. The intracellular level of DXR increased when DXR was administered after incubation with vesnarinone and the efflux of DXR was delayed when the cells were incubated in the presence of vesnarinone after DXR exposure. Flow cytometry showed that the combination of DXR and vesnarinone increased the cell population below the G(0)/G(1) region. Vesnarinone induced DNA ladder formation, but only when these cells were incubated for 72 h, while in addition, when DXR was combined with vesnarinone, the DNA ladder formation was enhanced. Based on the above findings, we thus conclude that the cytotoxicity of DXR was enhanced when combined with vesnarinone.

Inhibition by a putative antipsychotic quinolinone derivative (OPC-14597) of dopaminergic neurons in the ventral tegmental area

The effects of the newly synthesized quinolinone derivative, OPC-14597 (7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butyloxy}-3,4-dihydro-2(1 H)-quinolinone), on dopaminergic neuronal activity in the ventral tegmental area were examined using both in vivo microiontophoretic methods in chloral hydrate-anesthetized rats and the tight-seal whole-cell patch-clamp technique in thin-slice preparations of the rat brain. Neurons in the ventral tegmental area were classified as type I or type II according to their responses to antidromic stimulation of the nucleus accumbens, probably corresponding to dopaminergic and non-dopaminergic neurons, respectively. Antidromic spikes elicited by nucleus accumbens stimulation were inhibited by microiontophoretic application of dopamine and OPC-14597 in type I, but not in type II neurons. Although the OPC-14597-induced inhibition was antagonized by simultaneous application of domperidone (5-chloro-1-[1-[3-(2,3-dihydro-2-oxo-1 H-benzimidazo-1-yl)-propy]-4-piperidinyl]-1,3-dihydro-2 H-benzimidazol-2-one; dopamine D 2 receptor antagonist), SCH 23390 ( R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1 H-3-benzazepine hydrochloride; dopamine D 1 receptor antagonist) had no such effect. Spontaneous firing of type I neurons was also inhibited by iontophoretically applied OPC-14597 and dopamine, whereas that of type II neurons was unaffected. The inhibitory effect of OPC-14597 on the spontaneous firing of type I neurons was antagonized by domperidone, but not by SCH 23390. In a whole-cell patch-clamp study using a thin-slice preparation of the rat brain, bath application of OPC-14597 induced hyperpolarization accompanied by inhibition of spontaneously occurring action potentials in the large neurons (20 μm in diameter) in a concentration-dependent manner. These results suggest that OPC-14597 acts on dopaminergic neurons in the ventral tegmental area as a dopamine D 2 receptor agonist to inhibit neuronal activities, probably by increasing membrane potassium conductance.

Acute Cardiovascular Effects of OPC-18790 in Patients With Congestive Heart Failure

OPC-18790 is a water-soluble quinolinone derivative that shares the pharmacological properties of vesnarinone and that may be useful for treating heart failure. We studied the contribution and relative dose sensitivities of the inotropic, lusitropic, and vascular effects of OPC-18790 in patients with dilated cardiomyopathy. Pressure-volume (PV) analysis was performed in 17 patients who received either 5 micrograms.kg-1.min-1 (low dose, n = 10) or 10 micrograms.kg-1.min-1 (high dose, n = 7) OPC-18790 by 1-hour IV infusion. Right heart pressures and flow and left heart PV relations (conductance catheter) were measured at baseline and every 15 minutes during infusion. Transient inferior vena caval obstruction was used to determine PV relations. Both doses produced venodilation reflected by a 10% decline in left ventricular end-diastolic volume and a 30% fall in atrial and pulmonary artery pressures. Arterial dilation was four times greater at the high dose, with an approximately 40% fall in effective arterial elastance and systemic resistance. Contractility rose by 25% to 100% (depending on PV index) with both doses. Ventricular-arterial coupling (ratio of ventricular end-systolic to arterial elastances) was approximately 0.25 at baseline and doubled (or tripled) at low (or high) dose, correlating with improved efficiency. Isovolumetric relaxation shortened, whereas the diastolic PV relation was generally unchanged. Heart rate was unaltered. OPC-18790 has potent venous and arterial vasodilator effects and moderate inotropic and lusitropic effects without a change in heart rate. These combined actions suggest a unique potential of OPC-18790 for heart failure treatment.

慢性心不全患者における強心薬ＯＰＣ‐１８７９０（Ｔｏｂｏｒｉｎｏｎｅ）の心血行動態および心筋エネルギー効率に及ぼす急性効果

We examined the acute effects and safety of OPC-18790 (toborinone), a novel water-soluble quinolinone derivative, on mechanoenergetics in 12 patients with chronic congestive heart failure. OPC-18790 was intravenously administered at a rate of 5μg/kg/ min or 10 μg/kg/min. Left ventricular (LV) pressure-volume data were obtained by conductance methods and myocardial oxygen consumption (MVO2) was measured using a Webster catheter.Heart rate was slightly increased in all patients after receiving OPC-18790. Ventricular preload as assessed by LV end-diastolic volume index significantly declined, and mean and systolic pulmonary artery pressure also fell after OPC-18790 infusion. In addition to venodilation, systemic vasodilation was observed after OPC-18790 infusion. Systolic and mean arterial pressure, and systemic vascular resistance significantly declined after OPC-18790 infusion. Effective arterial elastance (Ea), which represents both the mean vascular resistance and the pulsatile components, fell significantly.LV contractility as assessed by end-systolic elastance (Ees) significantly rose after OPC-18790 infusion. Cardiac index and ejection fraction improved significantly. External work (EW) was unchanged.The isovolumic relaxation time constant was prolonged before OPC-18790 infusion and OPC-18790 shortened this time constant rate. MVO2 was reduced after OPC-18790 infusion probably due to a reduction of wall tension. Ventricular-arterial coupling (Ea/Ees) was far less than optimal before OPC-18790 infusion and was near optimal after OPC-18790 infusion. Mechanical efficiency (EW/MVO2) was improved along with the Ea/Ees ratio. Systolic arterial pressure fell by 40 or 50 mmHg after OPC-18790 infusion in 2 patients probably due to vasodilation.In conclusion, OPC-18790 had favorable mechanoenergetic effects in patients with congestive heart failure. Despite enhancing contractility, OPC-18790 reduced MVO2 and improved mechanical efficiency probably due to its favorable effects on loading conditions. These findings suggest that OPC-18790 may be useful for short-term treatment of patients with congestive heart failure.

Antagonizing effects of a novel antipsychotic quinolinone derivative (OPC-14597) on dopaminergic inhibition of neuronal activities in the nucleus accumbens

1. 1. The effects of a newly synthesized quinolinone derivative, 7-{4-[4-(2,3-dichlorophenlyl)-1-piperazinyl]butyloxy}-3,4-dihydro-2-(1 H)-quinolinone (OPC-14597), an antipsychotic drug, on neuronal activities of the nucleus accumbens (Acc) were investigated in rats anesthetized with chloral hydrate using a microiontophoretic method. 2. 2. Spikes elicited by stimulation of the parafascicular nucleus (Pf) of the thalamus were extracellularly recorded in the Acc neuron of chloral hydrate-anesthetized adult Wistar rats using a glass microelectrode attached along a seven-barreled micropipette, each of which was filled with dopamine, OPC-14597, SKF 38393 (D1 receptor agonist), quinpirole (D2 receptor agonist) and 2M NaCl. The drugs were microiontophoretically applied to the target neurons recorded. 3. 3. Effects of the drugs on the Acc neurons activated monosynaptically by stimulation of the Pf were examined. Spikes elicited by Pf stimulation were inhibited by iontophoretic application of dopamine, SKF 38393 and quinpirole in a dose-dependent manner. 4. 4. Microiontophoretic application of OPC-14597 alone affected the spikes elicited by the Pf stimulation in none of 26 neurons tested. However, the dopamine-, SKF 38393- and quinpirole-induced inhibition of the spike generation in the Acc neurons was antagonized during simultaneous application of OPC-14597. 5. 5. The firing induced by iontophoretically applied glutamate was inhibited by dopamine, SKF 38393 and quinpirole, but not by OPC-14597. However, the dopamine-, SKF 38393- and quinpirole-induced inhibition of the glutamate-induced firing was also antagonized during simultaneous application of OPC-14597 in a dose-dependent manner in all neurons tested. 6. 6. These findings suggest that OPC-14597 blocks dopaminergic inhibition of the Acc neurons receiving input from the Pf by acting on both D1 and D2 receptors located on the neurons.

Neutropenia occurring during treatment with vesnarinone (OPC-8212)

To date, long-term use of oral inotropic agents other than digoxin in patients with heart failure has been controversial because these agents improve symptoms but are associated with an increased risk of death. 1,2 A new inotropic agent, vesnarinone (OPC-8212), a quinolinone derivative, has recently been shown to improve congestive symptoms and reduce cardiovascular morbidity and mortality. 3–6 Studies in different animal species demonstrate direct positive cardiac inotropic in addition to potassium channel effects. 7,8 In contrast to other agents, vesnarinone produces no increase in heart rate or myocardial oxygen consumption or decrease in afterload, but it does have class III antiarrhythmic properties. Its mechanism of action is direct augmentation of the transmembrane ion channel activity. Vesnarinone increases inward calcium current, increases intracellular sodium, and blunts the inward and outward potassium rectifying current. Its net effect lengthens action potential duration and enhances contraction. Also, a recent study suggests that vesnarinone may inhibit the production of cytokines, such as TNF-α and INF-γ. 9 In healthy volunteers, cumulative doses ranging from 7.5 to 480 mg of vesnarinone result in no significant adverse effects other than headache. Vesnarinone has a plasma half-life of 45 hours, which allows once-a-day dosing. During clinical trials with the drug, however, neutropenia (absolute granulocyte count <1,000/mm 3) with sparing of the other cellular lines was reported. 3–6 From the Japanese experience with vesnarinone, the reported incidence of neutropenia was thought to be <1%. A recent preliminary report describes the incidence of neutropenia from the U.S. experience to be 2.3%. 10 This paper will review the European/U.S. experience with vesnarinone-induced neutropenia through August 28, 1992.

Vesnarinone, a new inotropic agent, inhibits cytokine production by stimulated human blood from patients with heart failure.

Vesnarinone, a quinolinone derivative, is a recently synthesized positive inotropic agent that has been shown to dramatically improve the survival of patients with heart failure. However, the mechanism of action of vesnarinone remains unknown. Reversible neutropenia complicated with vesnarinone therapy suggests that vesnarinone may modulate the production of cytokines. Because tumor necrosis factor (TNF)-alpha and other cytokines have been shown to depress myocardial contractility, we investigated the effects of vesnarinone on the production of various cytokines. We studied the effects of vesnarinone on cytokine production by lipopolysaccharide (LPS)-stimulated whole blood from seven patients with heart failure and from five healthy volunteers. Heparinized blood was diluted in RPMI and stimulated with LPS. Vesnarinone was added in a range of 1 to 30 micrograms/mL, the blood was incubated for 24 hours, and interleukin (IL)-1 alpha, IL-1 beta, IL-6, TNF-alpha, interferon (IFN)-gamma, and granulocyte colony-stimulating factor (G-CSF) were measured by an enzyme-linked immunosorbent assay. LPS stimulation induced a more prominent increase in TNF-alpha in patients with heart failure than in healthy volunteers. Vesnarinone inhibited the production of TNF-alpha and IFN-gamma both in healthy volunteers and in patients with heart failure. IL-1 alpha and IL-1 beta were also suppressed in healthy volunteers, but this response was variable, and a significant reduction was not seen in patients with heart failure. Marked inhibition of G-CSF and other cytokines by vesnarinone was observed in one patient who had developed neutropenia as a result of vesnarinone therapy. Although the number of study patients was small and the results are preliminary, these findings provide evidence that vesnarinone plays an important role in the regulation of cytokines and suggest that the reduction of cytokine release may contribute to the beneficial effects of the drug in the treatment of heart failure. Furthermore, the measurement of cytokines may be useful in predicting the occurrence of neutropenia, which has been occasionally reported in patients treated with vesnarinone.

Vesnarinone prolongs survival and reduces lethality in a murine model of lethal endotoxemia

Vesnarinone (3,4-Dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperanizyl]-2(1H)-quinolinone), a recently synthesized quinolinone derivative with positive inotropic properties, has been reported to improve the survival of patients with chronic congestive heart failure. However, the mechanisms that contribute to this improvement are not yet well understood. There is increasing evidence that vesnarinone has novel immunosuppresive properties related to its inhibition of cytokine production. Cytokines have been shown to play a pivotal role in the pathophysiologic consequences of fatal bacteremic shock. In this study, we investigated the effects of vesnarinone in a murine model of lethal endotoxemia induced by lipopolysaccharide (LPS). Eight-week-old female BALB/c mice were given 300 or 400 μg of LPS, and 50 or 100 mg/kg of vesnarinone was administered by oral gavage and/or 10 or 30 μg of vesnarinone was given intra peritoneally. Vesnarinone prolonged the median survival time and reduced lethality when given at the same time as the LPS injection. However, vesnarinone did not have a beneficial effect when administered 2 hours after LPS treatment. Plasma TNF-α reached a maximum level 1 hour after LPS challenge, and vesnarinone reduced the plasma level of TNF-α, when administered at the same time as LPS injection. Vesnarinone had protective effects against lethal endotoxemia; these effects were considered to be due to the suppression of TNF-α production. These findings suggest that vesnarinone may be a promising agent for the treatment of bacterial sepsis and shock.

Inhibition of cytokine production by a new inotropic agent, vesnarinone, in human lymphocytes, T cell line, and monocytic cell line

Vesnarinone, a recently synthesized quinolinone derivative with positive inotropic properties, has been reported to improve survival of patients with congestive heart failure. However, the mechanisms that contribute to the increased survival are unknown. In this study, we showed vesnarinone had inhibitory effects on the production of tumor necrosis factor-α, interferon-γ, interleukin-1β and interleukin-2 by stimulated human peripheral blood mononuclear cells, human Jurkat T cell line and THP-1 monocytic cell line. Vesnarinone may exert its beneficial effect on patients with congestive heart failure, in part, by its immunomodulating activity.

P-52 - Effects of a novel antipsychotic quinolinone derivative (OPC-14597) on striatal neurons receiving input from the substantia nigra.

P-52 - Effects of a novel antipsychotic quinolinone derivative (OPC-14597) on striatal neurons receiving input from the substantia nigra.

Production of 3- benzoyl-2,1-benzisoxazoles,2-phenyl-4H-3,1-benzoxazin-4-ones, and novel quinolinone derivatives from 2-phenylquinolin-4(1H)-ones and sodium dichloroisocyanurate

A simple synthesis of certain 3-benzoyl-2,1-benzisoxazoles 6 is accomplished via treatment of the corresponding 2-phenylquinolin-4(1H)-one 1 with sodium dichloroisocyanurate 2 in methanolic aq. alkali; the isomeric 2-phenyl-4H-3,1-benzoxazin-4-one 7 is also a product. Under different conditions the same reactants furnish two new types of quinolinone derivative, viz. 3,3-dichloro-2phenylquinolin-4(3H)-one 4 and 2-alkoxy-3,3-dichloro-2,3-dihydro-2-phenylquinolin-4(1H)-one 5, as chief products; the former is an intermediate in the synthesis of products 6 and 7. Some of the chemical properties of the dichloro compounds 4 and 5 are described. Mechanistic pathways and proposals to explain the results and observations are presented.

Effects of a Cardiotonic Quinolinone Derivative Y-20487 on the Isoproterenol-Induced Positive Inotropic Action and Cyclic AMP Accumulation in Rat Ventricular Myocardium: Comparison with Rolipram, Ro 20-1724, Milrinone, and Isobutylmethylxanthine

Summary: 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-I-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 (3-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. Y-20487 may exert a characteristic action different from other agents, probably through inhibition of PDE-III and PDE-IV isoenzymes

Effects of vasopressin on phosphoinositide hydrolysis and myocardial contractility

The effects of vaopressin on phosphoinositide hydrolysis, ventricular contractility and adrenoceptor-mediated inotropy were studied in the rabbit. Vasopressin caused an accumulation of [ 3H]inositol monophosphate in ventricular slices prelabelled with myo-[ 3H]inositol, whereas it elicited a small but definite negative inotropic effect. In addition, vasopressin attenuated the positive inotropic effect elicited via α 1- and endothelin receptors without affecting the β-adrenoceptor-mediated effect. The nonpeptide-selective V 1 receptor antagonist OPC 21268 (a quinolinone derivative) inhibited the vasopressin-induced accumulation of [ 3H]inositol monophosphate. The present results indicate that vasopressin stimulates phosphoinositide hydrolysis via V 1 receptors, but inhibits force and the α 1-mediated positive inotropic effect in the rabbit ventricular myocardium.

The inhibitory effects of a positive inotropic quinolinone derivative, 3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)- quinolinone (OPC-8212), on bone-marrow progenitor cells and peripheral lymphocytes.

3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)-quinolinone (OPC-8212) is a quinolinone derivative with positive inotropic properties. In order to elucidate the effect of OPC-8212 on the haemopoietic system we studied its in vitro effect on bone-marrow progenitor cells (granulocyte/monocyte colony-forming units [CFU-GM] and erythroid burst-forming units [BFU-E]), on the proliferation and secretion of granulocyte/monocyte colony-stimulating factor (GM-CSF) and interferon-gamma (IFN-gamma) by peripheral lymphocytes, and on GM-CSF secretion by fibroblasts from healthy individuals. The dose-effect relations of OPC-8212 on CFU-GM proliferation and on lymphocytic GM-CSF secretion showed no effect at very low drug concentrations, with a threshold at the lower end of the therapeutic range and highly significant dose-dependent inhibition at concentrations above that threshold. BFU-E, peripheral lymphocyte proliferation and lymphocytic IFN-gamma secretion were depressed, although to a lesser extent, in a linear dose-dependent fashion. OPC-8212 did not affect GM-CSF secretion by one strain of fibroblasts but reduced it at higher concentrations in assays with another strain of cells. We conclude that direct toxic effects on bone-marrow progenitor cells, in combination with the inhibition of cytokines involved in the regulation of haemopoiesis in certain susceptible individuals, may be responsible for idiosyncratic reactions to OPC-8212.