Concurrent administration of monomethylaminoantipyrine (MAA) and CoCl2 caused a significant decrease of hepatic reduced glutathione and oxidized glutathione levels. Furthermore, the increase of glutathione S-transferase activity by combined treatment resulted in the decrease of Se-dependent glutathione peroxidase activity.
Two kinds of electrical stimulation, low frequency stimulation (5 Hz, 1 msec, 5 pulses, every 20 sec) and high frequency stimulation (30 Hz, 0.1 msec, 20 pulses, every 20 sec), produced contractions in isolated guinea-pig vas deferens. These responses were blocked by α, β-methylene-ATP, but not prazosin. Phentolamine potentiated the contractions produced by low frequency stimulation, while it had little or no effect on the contractions produced by high frequency stimulation. The effect of 5-methoxy-N, N-dimethyltryptamine (5-MeODMT), a potent short acting hallucinogen, on the contractile response to two kinds of electrical stimulation was examined. On the contraction produced by low frequency stimulation, 5-MeODMT showed a biphasic action. 5-MeODMT at concentrations of 3×10-8-10-6 M reduced the contractile response. 5-MeODMT at concentrations of 3×10-6-2×10-5 M potentiated the contractile response, and this potentiation was reversed by prazosin and ketanserin. Clonidine caused an inhibition of the contractile response to low frequency stimulation. This action of clonidine was reversed by 5-MeODMT. The reverse action of 5-MeODMT was greatly inhibited in the presence of prazosin and ketanserin. The results suggest that 5-MeODMT exerts two different kinds of modification on the contractile response to low frequency stimulation of isolated guinea-pig vas deferens: in one type of modification, 5-MeODMT at concentrations higher than 3×10-8 M exerts an action similar to that of 5-hydroxytryptamine on postganglionic sympathetic nerve terminals and reduces the release of transmitter presynaptically, and in the other type, 5-MeODMT at concentrations higher than 3×10-6 M causes the release of noradrenaline from postganglionic sympathetic nerve terminals.
Bradykinin (100 pM to 1 μM) contracted the rabbit urinary detrusor in vitro. The sensitivity to bradykinin was about 1000 times higher than that to acetylcholine (ACh) on a molar basis. The contractile response to bradykinin was unaffected by atropine, diphenhydramine, FPL-55712, methysergide, prazosin or tetrodotoxin, indicating that the contraction was not mediated via the release of ACh, histamine, peptide leukotrienes, serotonin or catecholamine. The bradykinininduced contraction was, however, inhibited by indomethacin (5 μM), a cyclooxygenase inhibitor. Caffeic acid (10 μM), a lipoxygenase inhibitor, did not affect the contraction. Bradykinin (1 nM to 100 nM) stimulated the release of prostaglandin E2 from the detrusor in a concentration-dependent manner, and the release was abolished by treatment with indomethacin (5 μM). Prostaglandin (PG) E2 contracted the urinary detrusor with an EC50 of about 0.1 μM. Adenosine 5'-triphosphate (ATP), a stimulator of PG synthesis, also contracted the muscle with an EC50 of about 100 μM. [14C]Arachidonic acid was converted to PGE2 and F2α when it was incubated with the 700×g supernatant of the muscle homogenate. However, neither bradykinin nor ATP stimulated the PG synthesis in the supernatant. These results showed that bradykinin and ATP did not affect the cyclooxygenase and/or PG degradation system. On the other hand, when the intact detrusor muscle was incubated with [14C]arachidonic acid, bradykinin and ATP stimulated the PG synthesis, and the stimulated synthesis was inhibited by indomethacin. Mepacrine, a phospholipase A2 inhibitor, more potently inhibited the bradykinin and ATP-induced contractions than the ACh-induced one. Therefore, bradykinin as well as ATP would stimulate phospholipase, probably the A2-type, after binding of its receptor, and contract rabbit urinary detrusor mediated via PGE2 converted from arachidonic acid.
The effects of hydralazine on the central nervous system were studied in rats. Administration of hydralazine (10 mg/kg, i.p.) transiently, but significantly suppressed the seizures elicited by pentylenetetrazol (PTZ). The suppressive actions were potentiated in the animals pretreated with either reserpine or pchlorophenylalanine, but not α-methyltyrosine. Methysergide, an antagonist of 5-hydroxytryptamine (5-HT) receptors, could abolish the effect of hydralazine on the tonic component of the seizures, but unlikely that on the clonic one. Although 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels in the brain were both significantly increased after the administration of hydralazine, the increased levels of 5-HIAA reached the peak level earlier than those of 5-HT did. In 5-HT turnover, hydralazine did not change the 5-HT synthesis rate, but the drug inhibited the elimination of 5-HIAA from the brain. The accumulation of 5-HIAA after the inhibition of the acid transport system by probenecid was transiently, but significantly increased in the animals treated with hydralazine. The potency of the suppressive effects of hydralazine on PTZ-induced seizures was in parallel with the rate of 5-HIAA formation in the brain. These results suggest that hydralazine might antagonize the PTZ-induced seizures at least partly by modulating the activation in the central 5-HT-ergic system.
The present studies were undertaken to determine whether the repeated administration of quinupramine caused down- or up-regulation of β-, α2-adrenergic, serotonin S2, imipramine and muscarinic cholinergic receptors, as had been demonstrated for tricyclic and atypical antidepressant drugs. Quinupramine administered at 10 mg/kg (p.o.) twice daily for 10 days caused a down-regulation of serotonin S2 receptors in the frontal cortex of the rat as determined by [3H]-ketanserin binding. However, quinupramine did not alter the binding populations of β-adrenergic, muscarinic cholinergic and α2-adrenergic receptors in the rat brain as determined by the Scatchard analysis of the [3H]-ligand binding data. Differing from quinupramine, imipramine caused down-regulation of β-adrenergic and serotonin S2 receptor bindings, and it caused sight but significant upregulation of muscarinic cholinergic receptor bindings. These results show that the antidepressant activity of quinupramine is associated with the central serotonin system, but not with the β-adrenergic system. Accordingly, quinupramine, chemically one of the typical tricyclic antidepressant drugs, seems to be pharmacologically one of the atypical antidepressant drugs, and it was suggested that the central serotonin system plays an important role in the antidepressant activity of quinupramine.
Hypotensive effects of SA446, an angiotensin converting enzyme (ACE) inhibitor, and effects on the renin-angiotensin system were evaluated in conscious normotensive and 2-kidney, 1-clip renal hypertensive dogs. SA446 (1 mg/kg, p.o.) remarkably inhibited the pressor response to angiotensin (Ang) I between 1 and 6 hr after the administration in normotensive dogs. SA446 significantly decreased blood pressure at 10 mg/kg, p.o., in normotensive dogs. During repeated administration of SA446 (100 mg/kg/day, p.o.) for 13 weeks, the blood pressure was lowered, and the pressor response to Ang I and plasma ACE activity were strongly inhibited. ACE activities in the aorta and kidney were also inhibited. Plasma renin activity and plasma Ang I concentration increased by repeated SA446 application, while plasma aldosterone concentration decreased. The hypotensive effect of SA446 (5 mg/kg, p.o.) was more potent in 2-kidney, 1 -clip renal hypertensive dogs than in normotensive dogs. SA446 had longer inhibitory effects on the pressor response to Ang I and more potent hypotensive effects than captopril. The hypotension caused by SA446 appears to be associated mainly with an inhibition of ACE in plasma and also in the vascular wall.
5 Dimethylsulfamoyl-6, 7-dichloro-2, 3-dihydrobenzofuran-2-carboxylic acid (S-8666) was studied as a possible new uricosuric diuretic agent using rats and chimpanzees. Various new compounds belonging to the 5-sulfamoyl-6, 7dichloro-2, 3-dihydrobenzofuran-2-carboxylic acids were clearly diuretic with uricosuric activity in intraperitoneally oxonate-treated rats. S-8666 was chosen as a favorable candidate because its uricosuric activity due to the effects of tubular transport of uric acid were apparently more marked than those of known uricosuric agents such as probenecid, benzbromarone, tienilic acid and indacrinone in oxonatetreated rats. S-8666 was also uricosuric in rats not given urate oxidase inhibitor. The diuretic effect of S-8666 in oxonate-treated rats was as high-ceilinged as that of furosemide, while those of tienilic acid, indacrinone and a known compound of a 5-carbonyl-6, 7-dichloro-2, 3-dihydrobenzofuran-2-carboxylic acid were rather low-ceilinged. These uricosuric and diuretic activities of S-8666 were manifested by two enantiomers, of which the (+)-enantiomer displayed predominantly uricosuric activity and the (-)-enantiomer, diuretic activity like furosemide. The new compound was also uricosuric and diuretic in chimpanzees, although the potency of the uricosuric activity was similar to that of probenecid and less than that of indacrinone. Thus, it seems that S-8666 is a different type of uricosuric diuretic from known agents which have already been tried in humans.
The uric acid-retaining effects of diuretics were studied using sodiumrestricted spontaneously hypertensive rats. Test agents were administered orally once a day for two weeks. Diuretic thiazides such as trichlormethiazide and hydrochlorothiazide and loop diuretics such as furosemide and indacrinone clearly reduced the renal function for uric acid excretion in treatment which produced major effects such as diuresis, saluresis and hypotension. However, a new diuretic with uricosuric activity, S-8666, developed in our laboratories, had no effect on the renal handling of uric acid at doses which showed major effects similar to those of other diuretics. The results should aid the understanding of the utility of S-8666 as a new diuretic antihypertensive which does not cause hyperuricemia during therapy.
Effects of sofalcone on the morphometrical glandular structure and the generative cell proliferation in the gastric mucosa of gastritis, induced in rats by the treatment of sodium taurocholate (TCA) for 3 and 6 months, were examined by means of 3H-thymidine autoradiography. Morphometrical observation revealed that the ratios of the length of the glandular portion/the total length of the gastric gland were generally decreased in both fundic and pyloric glands with TCA treatments, which may indicate mucosal atrophy. These atrophic changes were improved to the normal levels by the administration of sofalcone for 3 weeks after the treatment of TCA. On the other hand, cell proliferative activity, indicated by the labeling indexes in the generative cell zone of gastric mucosa, was increased in TCA induced gastritis rat, which seems to be the response to replace the increased cell loss. The administration of sofalcone to the gastritis rats further increased the labeling indexes, especially in pyloric gland with statistical significance in both TCA treated rats for 3 and 6 months. From these results, it is suggested that sofalcone stimulates the compensatory increase of proliferative activity of generative cells, which would be available to repair the gastric mucosa with gastritis.
Effects of intravenously administered clonidine and DJ-7141 on blood pressure and gastric acid output were studied in anesthetized rats. Both drugs caused a dose-dependent increase in blood pressure. Clonidine-induced increases in the blood pressure were attenuated by yohimbine and prazosin. DJ-7141-induced increases in blood pressure were also attenuated by yohimbine, but were little affected even by a large dose of prazosin. Splanchnic nerve stimulationinduced increases in blood pressure were attenuated by clonidine and DJ-7141. The inhibitory effects of DJ-7141 exceeded those of clonidine. On the other hand, these agonists had no effect on exogenously applied norepinephrine-induced increases in blood pressure. Vagally stimulated gastric acid output was inhibited by small doses of clonidine and large doses of DJ-7141. Clonidine-induced inhibition of acid output was abolished by yohimbine (5 mg/kg), but not by prazosin (5 mg/kg). In contrast, the DJ-7141-induced inhibition of acid output was not affected by yohimbine (5 mg/kg), but was attenuated by a small dose of prazosin (0.1 mg/kg). These results indicate that DJ-7141 had no effect on alpha-2 adrenoceptors in gastric parasympathetic nerves. Furthermore, the alpha-2 adrenoceptors on parasympathetic nerves in the gastric wall are probably pharmacologically different from those on sympathetic nerves and blood vessels in rats.
β-Lactam antibiotics, moxalactam (LMOX), cefotaxime (CTX), flomoxef (FMOX), cefamandole (CMD), carbenicillin (CBPC) and sulbenicillin (SBPC), suppressed colony formation from human megakaryocyte progenitors (CFU-M) and granulocyte-macrophage progenitors (CFU-GM) dose-dependently. The suppressive potencies for both progenitors were weakest for CBPC and SBPC, moderate for LMOX and FMOX, and strongest for CMD and CTX. The stainability of glycoprotein IIb/IIIa complex in the megakaryocyte colonies by the monoclonal antibody was decreased by LMOX and CTX. These data suggest that β-lactam antibiotics directly suppress proliferation of CFU-M and CFU-GM.
The effect of 16, 16-dimethyl prostaglandin E2 (dmPGE2) on gastric surface epithelial cell (SEC) damage induced by vagal nerve stimulation (VS) in urethane-anesthetized rats was studied using scanning electron microscopy. VS (1.25-10 Hz, 0.2 mA, 2 msec, 10 min) resulted in a graded increase in the SEC damage, increased gastric contractions, increased gastric acid secretion, and a decrease in heart rate. Pretreatment with dmPGE2 (0.3-30 μ, g/kg, s.c.) significantly protected the SEC from VS-induced damage, inhibited the increase in gastric contractions and acid secretion, but had no influence on the decrease in heart rate. Atropine (1 mg/kg, s.c.) also protected the SEC from VS-induced damage and inhibited the alterations in response to VS. Timoprazole (30 mg/kg, s.c.) had no protective effects on SEC from VS-induced damage, no effect on increased gastric contractions and heart rate, but did inhibit the increase in gastric acid secretion, in response to VS. These results suggest that: (A) VS-induced SEC damage was caused by increased gastric contractions and not by increased gastric acid secretion, and (B) dmPGE2 protects against SEC damage by inhibiting gastric contractions.
Subcutaneous injection of formaldehyde into mouse hind paw elicited pain responses consisting of licking or biting of the paw, which were observed biphasically. The first and second phases were enhanced by melatonin and melatonin, naloxone, prostaglandin E2, respectively. Mice kept in the dark also exhibited hyperalgesic response. When neurotropin was injected intraperitoneally 30 min prior to those treatments, hyperalgesia was suppressed to the control level. Aspirin inhibited only the second hyperalgesic phase.
The antagonistic potency, pA2, of several non-selective β-antagonists on presynaptic β-adrenoceptors was evaluated using a parallel line assay and MacKay's equation against isoproterenol-induced increases in 3H release in isolated guinea-pig pulmonary arteries preloaded with 3H-norepinephrine. Cumulatively applied isoproterenol at 10-9 M, 10-8 M and 10-7 M dose-dependently increased 3H release evoked by transmural field stimulation at 1 Hz. β-Antagonists tested dose-dependently antagonized the isoproterenol-induced increases. The order of pA2 was carteolol (11.23±0.09)>nadolol (9.78±0.05)>pindolol (9.59±0.03)>propranolol (9.26±0.17). Carteolol has the highest pA2 and is a useful tool for clarifying whether or not presynaptic β-adrenoceptors tonically function.
A single injection (s.c.) of prostaglandin biosynthesis inhibitors such as indomethacin (5 mg/kg), aspirin (200 mg/kg) and quinacrine (100 mg/kg) or a Na+·K+ ATPase inhibitor such as ouabain (10 mg/kg) significantly reduced the adaptive increase of HCO3-- output caused by acid in the duodenum of anesthetized rats. These agents had no effect on basal duodenal HCO3- secretion and histamine-stimulated gastric acid secretion. Either of these agents, when given alone, had no effect on the duodenal mucosa of conscious rats, but produced damage in the proximal duodenum within 8 hr when given together with histamine (40 mg/kg × 3, s.c., every 2.5 hr). A significant relationship was found between the degrees of inhibition of acid-induced HCO3- output and the severity of duodenal lesions induced by these drugs (r=0.8620, P<0.01). These results suggest that an impairment of the mechanisms related to acid-induced HCO3- secretion may be particularly relevant to the pathogenesis of duodenal lesions.
The activity of cyclic AMP-dependent protein kinase (protein kinase A) in the sensitized rat mast cell was decreased 2 min after antigen challenge when the histamine release exhibited a maximum. Drugs inhibiting allergic mediator release such as disodium cromoglycate, tranilast and theophylline significantly inhibited antigen-induced histamine release and reduced a decrease in the activity of protein kinase A. These results suggest that protein kinase A is involved in the histamine releasing process in the mast cell, and drugs inhibiting allergic mediator release cause their effects partially through the inhibition of protein kinase A.
Bay K 8644 caused no significant effects on the 3H overflow and contraction evoked by electrical stimulation in the canine saphenous vein preloaded with [3H]norepinephrine. Bay K 8644 significantly enhanced the 3H overflow evoked by 40 mM KCl in a concentration-dependent manner, which was antagonized by nisoldipine. Bay K 8644 failed to significantly augment the KCl-evoked contraction. These results suggest that there is a difference between the modes of action of Bay K 8644 on norepinephrine releases evoked by electrical stimulation and KCl.
Five mg/kg imipramine or desipramine was injected to infantile rats. L-5-Hydroxytryptophan-induced head shakes were assessed when rats were mature. The saline- and desipramine-treated adult male rats exhibited more sustained response to L-5-HTP than females. The time course of the head shake frequency in the imipramine-treated male and female rats showed a pattern between control males and females, resulting in no significant sex difference. The results suggest that infantile exposure to imipramine induces an alteration of the serotonergic neurons of the brain.
The depressant effect of indomethacin on contractions of isolated rat hearts was investigated under a constant heart rate. Ca2+ produced dose-dependent increases in myocardial contractile force and coronary perfusion pressure. Indomethacin-infusion significantly decreased myocardial contractile force and depressed increases in myocardial contractile force by Ca2+, but never affected both coronary perfusion pressure and increases in coronary perfusion pressure by Ca2+. Results suggest that indomethacin will depress myocardial contractile force with no involvement of any calcium antagonism.
Effects of acetaminophen against gastric mucosal lesions induced by three different necrotizing agents were studied. Acetaminophen (30, 100 mg/kg), given p.o. 0.5 hr before absolute ethanol, HCl· ethanol, or HCl· aspirin administration, afforded no cytoprotection against gastric mucosal lesions induced by the above agents in 24 hr fasted rats. However, 16, 16-dimethyl prostaglandin E2 (3 μg/kg), given p.o. 0.5 hr before these necrotizing agents, completely prevented development of these lesions.