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Biomedical subjects

A Nishida

Publications and source records attributed to A Nishida.

At least 109 records · Page 6Linked to original sources
PubMed1994

Serotonin (5-HT)3-receptor antagonism of 4,5,6,7-tetrahydrobenzimidazole derivatives against 5-HT-induced bradycardia in anesthetized rats.

We investigated the mode of the 5-HT3-receptor antagonism of 4,5,6,7-tetrahydrobenzimidazole derivatives, YM060, YM114 (KAE-393), YM-26103-2 and YM-26308-2, against 5-HT-induced transient bradycardia in anesthetized rats. Results were compared with those of ondansetron and granisetron. YM060 (0.03-0.1 microgram/kg, i.v.), YM114 (0.03-0.3 microgram/kg, i.v.), YM-26103-2 (0.01-0.03 microgram/kg, i.v.), YM-26308-2 (0.01-0.03 microgram/kg, i.v.) and granisetron (0.3-3 micrograms/kg, i.v.) displaced the 5-HT dose-response curve to the right, with apparent DR2 values of 0.068, 0.068, 0.019, 0.011 and 0.69 microgram/kg, i.v., respectively. Higher doses of these compounds inhibited 5-HT-induced bradycardia with a reduced maximal response. In contrast, ondansetron displaced the 5-HT dose-response curve to the right without affecting the maximal response. Judged by the apparent DR2 values, YM060, YM114, YM-26103-2 and YM-26308-2 were approximately 13, 13, 50 and 79 times more potent than ondansetron, respectively, whereas granisetron was equipotent to ondansetron. Single i.v. doses of YM060 and granisetron inhibited 5-HT-induced bradycardia significantly longer than ondansetron. Moreover, inhibitory effects of p.o. doses of YM060 (3 micrograms/kg), YM114 (80 micrograms/kg), YM-26103-2 (12 micrograms/kg), YM-26308-2 (5 micrograms/kg) and granisetron (250 micrograms/kg) on the von Bezold-Jarisch reflex lasted for 3-6 hr, whereas ondansetron (700 micrograms/kg, p.o.) antagonized 5-HT3 receptors for only 1 hr. In isolated guinea pig colon, the inhibitory effect of YM-compounds on 5-HT-induced contraction persisted significantly longer than those of ondansetron and granisetron after washout of the bath containing compounds.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

[A case of muscle metastasis of renal cell carcinoma treated by local resection and tensor fascia lata myocutaneous flaps].

A 44-year-old male with a little finger tip-sized tumor palpable on the left epigastric wall and a left renal tumor detected on computerized tomography (CT) was referred to this hospital in June 1991. Nephrectomy was performed in July 1991 under the diagnosis of a left renal tumor. Histologically, the tumor was a renal cell carcinoma, grade 2, clear and granular cell type. The tumor in the left abdominal wall was not extracted. As a tumor also developed in the scapular tunica muscularis, tumors in the left musculus rectus abdominis and the scapular tunica muscularis were extracted to the extent possible in July of 1992. Histologically, these tumors were metastatic clear cell carcinomas. The tumor in the left musculus rectus abdominis recurred and another was palpable in the left lateral femur. In August of 1993, the tumors in the left musculus vastus lateralis and the left musculus abdominis were extracted together with the tunica muscularis, and the defective region on the abdominal wall was closed with a left musculus tensor fascia lata flap. No evidence of recurrence has been observed to date.

Adult↗
PubMed1994

Pharmacological profile of (R)-1-[2,3-dihydro-1-(2'-methylphenacyl)-2-oxo- 5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(3-methylphenyl)urea (YM022), a new potent and selective gastrin/cholecystokinin-B receptor antagonist, in vitro and in vivo.

(R)-1-[2,3-dihydro-1-(2'-methylphenacyl)-2-oxo-5-phenyl-1H-1,4- benzodiazepin-3-yl]-3-(3-methylphenyl)urea (YM022) is an extremely potent and highly selective gastrin/cholecystokinin (CCK)-B receptor antagonist. We compared the gastrin/CCK-B receptor-blocking properties of this compound with those of the racemate (mixture of YM022 and its S-form), its enantiomer (S-form), L-365, 260 and Cl-988 in vitro and in vivo. YM022 replaced specific binding of [125I]CCK-8 to rat brain gastrin/CCK-B receptors in a stereoselective and competitive manner. The Ki value of YM022 for gastrin/CCK-B receptors in brain were estimated to be 0.068 nM. The racemate, the S-form of YM022, L-365,260 and Cl-988 also replaced gastrin/CCK-B receptor binding, with Ki values of 0.11, 140, 19 and 6.3 nM, respectively. The affinity of YM022 for gastrin/CCK-B receptor was more than 2 orders of magnitude higher than that for rat pancreatic CCK-A receptor and various other receptors, such as benzodiazepine. In vivo, intravenous (i.v.) administration of YM022 inhibited pentagastrin-induced gastric acid secretion in anesthetized rats, with an ED50 value of 0.0078 mumol/kg. Inhibition by the S-form of YM022 was only 33.8% even at the relatively high dose of 1 mumol/kg i.v. L-365,260 (1-10 mumol/kg i.v.) and Cl-988 (0.3-3 mumol/kg i.v.) also antagonized acid secretion induced by pentagastrin, with ED50 values of 4.23 and 1.01 mumol/kg, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

YM022 [(R)-1-[2,3-dihydro-1-(2'-methylphenacyl)-2-oxo-5-phenyl- 1H-1,4-benzodiazepin-3-yl]-3-(3-methylphenyl)urea], a potent and selective gastrin/cholecystokinin-B receptor antagonist, prevents gastric and duodenal lesions in rats.

We evaluated the effect of YM022 [(R)-1-[2,3-dihydro-1-(2'- methylphenacyl)-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3- (3-methylphenyl)urea], a potent and selective gastrin/cholecystokinin-B receptor antagonist, on gastric acid secretion and gastric and duodenal lesions in rats. Oral YM022 (0.1-10 mumol/kg), famotidine (0.3-30 mumol/kg) and omeprazole (3-100 mumol/kg) dose-dependently suppressed acid secretion in pylorusligated rats with ED50 values of 0.83, 1.63 and 10.9 mumol/kg, respectively. YM022 (1-10 mumol/kg p.o.), famotidine (1-10 mumol/kg p.o.) and omeprazole (10-100 mumol/kg p.o.) prevented indomethacin-induced gastric lesions in a dose-related manner. The potency of YM022 was comparable to that of famotidine and was 8 times greater than that of omeprazole. YM022 and famotidine partially inhibited gastric damage induced by water-immersion and restraint stress, whereas omeprazole abolished these lesions. In an acidified ethanol-induced gastric injury model, all three drugs inhibited the formation of erosions. The YM022 dosage required in this model was much greater than that required in the inhibition of gastric acid. The inhibitory effect of YM022 was partially reversed by indomethacin, indicating the involvement of a prostaglandin-mediated pathway. YM022 (3-100 mumol/kg p.o.), famotidine (1-30 mumol/kg p.o.) and omeprazole (3-100 mumol/kg p.o.) inhibited mepirizole-induced duodenal ulcers. On the basis of ED50 values, YM022 was 5 times less potent than famotidine and as potent as omeprazole against mepirizole-induced duodenal ulcers. These results suggest that YM022 possesses antisecretory and antiulcer activities that are as potent as those of famotidine in rats and that YM022 represents a useful therapeutic agent in the treatment of peptic ulcer disease.

Animals↗
PubMed1994

[Effects of repeated treatment with electroconvulsive shock or imipramine on [3H]prazosin binding sites in the rat frontal cortex].

Two subtypes (alpha 1A and alpha 1B) of alpha 1-adrenoceptors have been defined on the basis of radioligand binding studies with 2-(2,6-dimethoxyphenoxyethyl)-1,4-benzodioxane (WB4101). In contrast, functional studies with blood vessels have proposed another subclassification, where the alpha 1-adrenoceptors can be classified into putative two (alpha 1H and alpha 1L) or three (alpha 1H, alpha 1L and alpha 1N) subtypes. The present study was performed to elucidate the effects of repeated treatment with electroconvulsive shock (ECS) or imipramine on the subtypes of alpha 1-adrenoceptors. The density of the alpha 1H binding sites (including alpha 1A and alpha 1B binding sites) in the frontal cortex was increased by repeated treatment with ECS but decreased by imipramine. These treatments did not change the density of alpha 1L binding sites. These results indicated that repeated treatment with ECS and imipramine had different effects on the alpha 1H binding sites in the rat frontal cortex. In addition, the effects of antipsychotic drugs, antidepressant drugs and calcium channel antagonists on [3H]prazosin binding were studied. The order of inhibition of [3H]prazosin binding was: antipsychotic drugs (1.4-4.2 nM) > antidepressant drugs (69-116 nM) > calcium channel antagonists. The calcium channel antagonists, verapamil (720 nM), diltiazem (4.3 microM) and nicardipine (75 microM) were weakly bound. These results suggested that the antimanic effects of calcium channel antagonists were not associated with inhibition of alpha 1-adrenoceptors.

Animals↗
PubMed1994

[Survey of activities of daily living in non-institutionalized elderly residents].

To investigate the states of activities of daily living (ADLs) in the elderly, non-institutionalized residents-aged 65 and over living in Azuchi (population of approximately 12,000) were interviewed. Data was collected from 1,287 subjects (509 men and 778 women; 92.1%) for the 3 years, 1990 to 1992. Differences in difficulties with the 6 basic ADLs (BADLs) and the 7 instrumental ADLs (IADLs) were analyzed according to gender and age. For the BADLs (eating, dressing, bathing, using the toilet, mobility, and incontinence), only the percentage of incontinence was significantly higher in women than in men (p < 0.01). The percentage of those fully independent in the 6 BADLs in men was 87%, which was higher than that in women (77%), but except for incontinence there were no significant differences between the sexes. The percentages of disability in the BADLs for women and for both sexes combined were higher according to age (p < 0.01), but for men, only those of dressing (p < 0.05) and of incontinence (p < 0.01) were related with age. The disability percentage for cooking was the only activity among the IADLs (cooking, using the telephone, cleaning house, walking, shopping, going up and down steps, and using transportation) which was significantly higher in men (p < 0.01), but those for walking, going up and down steps, and using transportation were higher in women (p < 0.01). The percentage of those who were fully independent was 74% in both sexes.(ABSTRACT TRUNCATED AT 250 WORDS)

Activities of Daily Living↗
PubMed1994

[Studies on lithium potentiation of antidepressant treatment].

The effects of chronic administration of clomipramine or citalopram (CMI or CIT, 20 mg/kg i.p. daily for 19 days) with/without short-term administration of lithium (Li, 2 mEq/kg i.p. daily for 5 days) on the concentration of monoamines and their metabolites and serotonergic receptors were studied in the rat cerebral cortex. Li or CMI by itself had no effects on the concentration of monoamines and their metabolites, but a combination of CMI and Li increased that of 5-HIAA. CIT alone increased that of 5-HIAA, and a combination of CIT and Li increased that of 5-HIAA more than CIT alone. There were no changes in 5-HT or 5-HIAA after acute administration of CMI or CIT with/without Li. For the serotonergic receptors, [3H] 8-OH-DPAT and [3H] paroxetine binding did not change in any of the treatments. CMI alone or a combination of CMI and Li reduced [3H] ketanserin binding, but Li did not potentiate this effect. It is speculated that the therapeutic action of Li when added to tricyclic antidepressants in the treatment of refractory depression may partly have its basis in potentiation of effects on the activation of presynaptic serotonergic system.

Animals↗
PubMed1993

Comparison of the effects of trimebutine and YM114 (KAE-393), a novel 5-HT3 receptor antagonist, on stress-induced defecation.

YM114 (KAE-393), (R)-5-[(2,3-dihydro-1-indolyl)carbonyl]-4,5,6,7- tetrahydro-1H-benzimidazole hydrochloride, is a derivative of YM060, a potent 5-HT3 receptor antagonist. We investigated the effects of YM114 on 5-HT3 receptors, both in vitro and in vivo, and on bowel dysfunction induced by restraint stress, 5-HT and thyrotropin-releasing hormone (TRH), and compared them with the effect of trimebutine. YM114 dose dependently inhibited the reduction in heart rate induced by 5-HT (30 micrograms/kg i.v.) in rats (ED50 = 0.31 micrograms/kg i.v.), and the potency of YM114 was almost the same as that of the racemate. The S-form of YM114 also inhibited 5-HT-induced bradycardia, but 1350 times less potent than the R-form. YM114 and its S-form inhibited [3H]GR65630 binding to N1E-115 cell membranes in a concentration-dependent manner with Ki values of 0.341 and 616 nM, respectively, showing the isomeric activity ratio (R-/S-form) of YM114 to be much greater (1800). YM114 antagonized 5-HT-induced depolarization of the nodose ganglion (EC50 = 1.39 nM). Trimebutine (1 mg/kg i.v.) failed to inhibit 5-HT-induced bradycardia, implying that it does not possess 5-HT3 receptor antagonistic activity. YM114 significantly and dose dependently prevented restraint stress-, 5-HT- and TRH-induced increases in fecal pellet output, and restraint stress- and 5-HT-induced diarrhea in rats and mice (ED50 = 6.9, 72.5, 154.6, 9.7 and 52.4 micrograms/kg p.o., respectively). Trimebutine significantly prevented stress- and 5-HT-induced diarrhea (ED50 = 29.4 and 87.3 mg/kg p.o., respectively), but only partially affected stress-, 5-HT- and TRH-induced increases in fecal pellet output. Thus, YM114 is a potent and stereoselective 5-HT3 receptor antagonist with much greater protective effects against stress-induced defecation than trimebutine.

Animals↗
PubMed1993

Mechanisms of cisplatin- and m-chlorophenylbiguanide-induced emesis in ferrets.

We investigated the involvement of peripheral and central serotonin (5-HT)3 receptors in cisplatin- and 5-HT3 receptor agonist-induced emesis in ferrets. Cisplatin (10 mg/kg i.v.)-induced emesis was inhibited by intravenous YM060 (0.003-0.1 microgram/kg). A highly selective and potent 5-HT3 receptor agonist, m-chlorophenylbiguanide (1-10 mg/kg i.p.), dose dependently elicited emesis an effect which was inhibited by YM060 (0.003-0.3 microgram/kg i.v.). Vagotomy markedly reduced this emesis, and the combination of abdominal vagotomy and greater splanchnicectomy abolished emesis. Lesion of greater splanchnic nerves alone did not markedly inhibit emesis. Intracerebroventricularly (4th ventricle) administered YM060 inhibited cisplatin- and m-chlorophenylbiguanide-induced emesis only at higher doses (0.01-0.1 and 0.01-0.03 microgram, respectively). Intracerebroventricularly (4th ventricle) administered m-chlorophenylbiguanide (30-100 micrograms) produced only a weak retching response. These results indicate that stimulation of abdominal vagal afferent nerves via peripheral 5-HT3 receptors is important for triggering cisplatin- and m-chlorophenylbiguanide-induced emesis in ferrets.

Animals↗
PubMed1993

Ca2+ release from inositol 1,4,5-trisphosphate-sensitive Ca2+ store by antidepressant drugs in cultured neurons of rat frontal cortex.

The ability of antidepressant drugs (ADs) to increase the concentration of intracellular Ca2+ ([Ca2+]i) was examined in primary cultured neurons from rat frontal cortices using the Ca(2+)-sensitive fluorescent indicator fura-2. Amitriptyline, imipramine, desipramine, and mianserin elicited transient increases in [Ca2+]i in a concentration-dependent manner (100 microM to 1 mM). These four AD-induced [Ca2+]i increases were not altered by the absence of external Ca2+ or by the presence of La3+ (30 microM), suggesting that these ADs provoked intracellular Ca2+ mobilization rather than Ca2+ influx. All four ADs increased inositol 1,4,5-trisphosphate (IP3) contents by 20-60% in the cultured cells. The potency of the IP3 production by these ADs closely correlated with the AD-induced [Ca2+]i responses. Pretreatment with neomycin, an inhibitor of IP3 generation, significantly inhibited amitriptyline- and imipramine-induced [Ca2+]i increases. In addition, by initially perfusing with bradykinin (10 microM) or acetylcholine (10 microM), which can stimulate the IP3 generation and mobilize the intracellular Ca2+, the amitriptyline responses were decreased by 76% and 69%, respectively. The amitriptyline-induced [Ca2+]i increases were unaffected by treatment with pertussis toxin. We conclude that high concentrations of amitriptyline and three other ADs mobilize Ca2+ from IP3-sensitive Ca2+ stores and that the responses are pertussis toxin-insensitive. However, it seems unlikely that the effects requiring high concentrations of ADs are related to the therapeutic action.

Acetylcholine↗
PubMed1993

Forskolin and phorbol myristate acetate inhibit intracellular Ca2+ mobilization induced by amitriptyline and bradykinin in rat frontocortical neurons.

Regulations of the increase in intracellular Ca2+ concentration ([Ca2+]i) and inositol 1,4,5-trisphosphate (IP3) production by increasing intracellular cyclic AMP (cAMP) levels or activating protein kinase C (PKC) were studied in rat frontocortical cultured neurons. Amitriptyline (AMI; 1 mM), a tricyclic antidepressant, and bradykinin (BK; 1 microM) stimulated IP3 production and caused transient [Ca2+]i increases. Pretreatment with forskolin (100 microM, 15 min) decreased the AMI- and BK-induced [Ca2+]i increases by 33 and 48%, respectively. However, this treatment had no effect on the AMI- and BK-induced IP3 productions. Dibutyryl-cAMP (2 mM, 15 min) also decreased the AMI- and BK-induced [Ca2+]i increases by 23 and 47%, respectively. H-8 (30 microM), an inhibitor of protein kinase A (PKA), attenuated the ability of forskolin to inhibit the AMI- and BK-induced [Ca2+]i increases, suggesting that the activation of cAMP/PKA was involved in these inhibitory effects of forskolin. On the other hand, forskolin treatment had no effect on 20 mM caffeine-, 10 microM glutamate-, or 50 mM K(+)-induced [Ca2+]i increases. Pretreatment with phorbol 12-myristate 13-acetate (PMA; 100 nM, 90 min) decreased both the AMI-induced [Ca2+]i increases and the IP3 production by 31 and 25%, respectively. H-7 (200 microM), an inhibitor of PKC, inhibited the ability of PMA to attenuate the [Ca2+]i increases. PMA also inhibited the BK-induced IP3 production and the [Ca2+]i increases.(ABSTRACT TRUNCATED AT 250 WORDS)

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1993

Antisecretory effects of a novel and long-lasting histamine H2-receptor antagonist, YM-14471, in rats and dogs.

We investigated some properties of YM-14471 (2-2(-[2-(diaminomethyleneamino)thiazol-4-yl]methylthio)ethy l-5-[3- (diethylamino)propyl]-6-methyl-pyrimidine-4-one trihydrochloride), a new H2-receptor antagonist, in comparison with those of famotidine, cimetidine and omeprazole. In guinea pig atria, famotidine and cimetidine produced a competitive dose-dependent displacement of histamine-induced tachycardia. In contrast, low concentrations of YM-14471 showed competitive inhibition of tachycardia, whereas high concentrations were irreversible or slowly dissociable. In pylorus-ligated rats, intravenous YM-14471, famotidine and cimetidine dose-dependently inhibited basal gastric secretion with ED50 values of 0.04, 0.43 and 31.2 mg/kg, respectively. ED50 values for oral YM-14471, famotidine, cimetidine and omeprazole were 0.81, 0.42, 28.9 and 7.7 mg/kg when given at 1 hr before ligation, and 5.7, 26.7, 1639.5 and 18.6 mg/kg at 5 hr before ligation. In anesthetized dogs, intravenous YM-14471, famotidine, cimetidine and omeprazole also dose-dependently inhibited histamine (160 micrograms/kg.hr)-induced acid secretion with ED50 values of 13.7, 8.7, 333.3 and 65.3 micrograms/kg, respectively. In Heidenhain pouch dogs, YM-14471 inhibited histamine (40 micrograms/kg.hr)-induced acid secretion by both intravenous (0.02 mg/kg) and oral administration (0.3 mg/kg). Moreover, the inhibitory effect of YM-14471 was more prolonged than those of famotidine and cimetidine by either route, and it was as long as that of omeprazole dosed orally. These results suggest that YM-14471 is an irreversible or slowly dissociable H2-receptor antagonist, and has long antisecretory effect.

Animals↗
PubMed1993

Histamine H2-receptor plays only a minor role in histamine-induced wheal response in the squirrel monkey and guinea pig.

We examined the contribution of the histamine H2-receptor to the histamine-induced wheal response in squirrel monkeys and guinea pigs. Intradermal injection of histamine, 2-pyridylethylamine (a selective H1-agonist), and dimaprit (a selective H2-agonist) dose-dependently induced the wheal response in squirrel monkeys and guinea pigs, although the reaction to dimaprit was much weaker than that to the other agonists. Chlorpheniramine dose-dependently depressed the wheal response in squirrel monkeys and guinea pigs at doses of 0.03-1 mg/kg and 0.03-3 mg/kg, p.o., respectively. However, famotidine, ranitidine and cimetidine had no effect at doses up to 30, 100 and 300 mg/kg, p.o. in guinea pigs and up to 1, 10 and 400 mg/kg, p.o. in squirrel monkeys, respectively. Cimetidine (3-300 mg/kg, p.o.) dose-dependently potentiated the inhibitory effects of chlorpheniramine (0.1 mg/kg, p.o.) in guinea pigs, but had no effects in squirrel monkeys. Famotidine and ranitidine did not alter the response to chlorpheniramine in either animal. These results suggest that the histamine H2-receptor plays only a minor role in the histamine-induced wheal response in squirrel monkeys and guinea pigs.

Animals↗
PubMed1993

Trabeculotomy ab externo: an alternative treatment in adult patients with primary open-angle glaucoma.

Seventy-nine adult patients with primary open-angle glaucoma (POAG) were randomly assigned to treatment by modified trabeculotomy ab externo (TAB) (n = 44) and by trabeculectomy with adjunctive mitomycin C (TMC) (n = 35), and the postoperative outcomes achieved with these two techniques were compared. With TAB, the probability of successful intraocular pressure control 1 year postoperatively was .8644; with TMC, .8432; the difference is not significant (P = .7956). However, postoperative complications such as corneal epithelial damage, bleb leaks, hypotony, flat anterior chamber, and serous choroidal detachment were significantly less frequent in the TAB group. Largely because of this latter consideration, in selected cases, TAB may be a viable alternative to TMC.

Adult↗
PubMed1992

Characterization of phospholipase D in a cell-free system of cultured cells derived from rat frontal cortex.

The existence and regulation of phospholipase D (PLD) activity in cell-free system from primary cultured cells of fetal rat frontal cortex were investigated. PLD activity was detectable only in the presence of Triton X-100. Other detergents examined (deoxycholate, taurocholate, CHAPS, Tween 20, sodium dodecyl sulfate) caused only a small increase in PLD activity. Triton X-100 enhanced PLD activity maximally at 0.1% (w/v) and reduced at higher concentrations. The optimal pH was about 7.2. Both Ca2+ and Mg2+ inhibited PLD activity in a dose-dependent manner. When comparing the primary cultured cells with adult rat frontal cortices, all of the results of the primary cultured cells were in agreement with those of the frontal cortices. Moreover, the apparent Km value of the enzyme in primary cultured cells for phosphatidyl-choline was the same as that in rat frontal cortex. These results suggest that the same kinds of PLD exist in the primary cultured cells and the rat frontal cortex, and that the primary cultured cells are a good experimental model for analyzing the mechanism of PLD in neuronal system.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1992

Antidepressants inhibit spontaneous oscillations of intracellular Ca2+ concentration in rat cortical cultured neurons.

In rat cortical cultured neurons, spontaneous oscillations in the intracellular Ca2+ concentration ([Ca2+]i) were observed by direct [Ca2+]i measurements using the fluorescent indicator fura-2. These [Ca2+]i responses were eliminated by the removal of extracellular Ca2-, L-type Ca2+ channel blockers or a glutamate receptor antagonist. Three antidepressants (amitriptyline, imipramine and mianserin) suppressed the [Ca2+]i oscillations in the range of 1-50 microM. In addition, amitriptyline inhibited high K(+)-and glutamate-induced [Ca2+]i increases with IC50 values of 19 and 27 microM, respectively. Imipramine and mianserin also inhibited the high K(+)-induced [Ca2+]i increases with IC50 values of 45 and 24 microM, respectively. These results suggest that blocking actions by the antidepressants on voltage-dependent Ca2+ influx and glutamate receptor-mediated Ca2+ influx may be involved in the suppression of the [Ca2+]i oscillations.

Amitriptyline↗
PubMed1992

Calcium rather than protein kinase C is the major factor to activate phospholipase D in FMLP-stimulated rabbit peritoneal neutrophils. Possible involvement of calmodulin/myosin L chain kinase pathway.

In the present study, we first investigated which of the factors, protein kinase C (PKC) or Ca2+, plays an important role in activation of phospholipase D (PLD) of rabbit peritoneal neutrophils stimulated by the chemoattractant FMLP. PLD activity was assessed by measuring [3H]phosphatidylethanol ([3H]PEt), the unambiguous marker of PLD, generated by [3H]lyso platelet-activating factor-prelabeled neutrophils in the presence of ethanol. PKC inhibitors, staurosporine and 1-(5-isoquinolinesulfonyl-2-methylpiperazine dihydrochloride, augmented the plateau level of [3H]PEt produced in FMLP-stimulated cells, although they had no effect on the initial rate of the formation. Furthermore, it was found that the FMLP-stimulated [3H]PEt formation was inhibited by pretreatment of cells with PMA, a PKC activator, and exposure of cells to staurosporine before PMA pretreatment moderately blocked the PMA inhibition. Ca2+ ionophore ionomycin, as well as FMLP, stimulated [3H]PEt formation, accompanied by a decrease in [3H]phosphatidylcholine, in a time- and concentration-dependent manner. Both FMLP and ionomycin absolutely required extracellular Ca2+ to increase [3H]PEt formation. These results imply that elevated intercellular Ca2+ by FMLP stimulation is the major factor for PLD activation and that PKC rather negatively regulates the enzyme activity. Interestingly, a calmodulin inhibitor, N-(6-aminohexyl)-5-chloro-1- naphthalenesulfonamide, and a myosin L chain kinase inhibitor, 1-(5-iodonaphthalene-1-sulfonyl)-1H-h exahydro-1,4-diazepine hydrochloride, both inhibited the ionomycin- and FMLP-stimulated [3H]PEt formation in a concentration-dependent manner. Results obtained in this study suggest that, in FMLP-stimulated rabbit peritoneal neutrophils, increased intracellular Ca2+ activates PLD through calmodulin/myosin L chain kinase pathway and, thereafter, the enzyme activation is turned off by simultaneously activated PKC.

Animals↗