Biomedical subjects

A Tobe

Publications and source records attributed to A Tobe.

At least 19 recordsLinked to original sources

PubMed1996

Effect of the novel high affinity choline uptake enhancer 2-(2-oxopyrrolidin-1-yl)-N-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b] quinolin-4-yl)acetoamide on deficits of water maze learning in rats.

The pharmacological properties of MKC-231 (2-(2-oxopyrrolidin-1-yl)-N- (2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl) acetoamide, CAS 135463-81-9) in comparison with an acetylcholinesterase (AChE) inhibitor, tacrine (CAS 1684-40-8) were studied. MKC-231(10(-10)-10(-6) moll) significantly increased high affinity choline uptake (HACU) when it was incubated with the hippocampal synaptosomes of ethylcholine mustard aziridinium ion (AF64A) treated rats, but not of normal rats. MKC-231 did not affect the AChE activity, [3H]- quinuclidinyl benzilate binding, and [3H]-pirenzepine binding. Oral administration of MKC-231 (1-10 mg/kg) significantly improved the learning deficits in the Morris' water maze of AF64A-treated rats, but it did not produce any significant side effects, like tremor, salivation or hypothermia, which were observed in rats treated with high doses of tacrine. Tacrine (0.1-3 mg/kg p.o.) failed to ameliorate the learning deficits in AF64A-treated rats. These results suggest that MKC-231 is a novel and quite unique compound, which improves the memory impairment induced by AF64A through the enhancement of HACU without any side effects at the effective doses.

Acetylcholinesterase↗

PubMed1994

Effects of a novel compound MCI-225 on impaired learning and memory in rats.

Effects of MCI-225, [4-(2-fluorophenyl)-6-methyl-2-(1-piperazinyl)thieno[2,3-d]pyrimidine monohydrate hydrochloride] on experimental amnesia were studied in rats and compared with those of THA [9-amino-1,2,3,4-tetrahydroacridine]. In the Morris-type water maze task, MCI-225 (1-10 mg/kg, PO) reduced the spatial learning impairment induced by scopolamine (0.5 mg/kg, IP). In a passive avoidance (PA) task, administration of MCI-225 prior to training (1-30 mg/kg, PO) lessened the carbon dioxide (CO2)-induced amnesia in a dose-dependent manner. MCI-225 (1-100 mg/kg) did not affect gross behavior. THA (0.1-3 mg/kg, PO) reduced scopolamine-induced learning deficits in the water maze task, but the effect was not significant. THA (0.3-3 mg/kg, PO) also ameliorated the CO2-induced amnesia, although slightly, in the PA task. THA (10 mg/kg, PO) increased locomotor activity and higher dose of THA (30 mg/kg, PO) induced tremor, hypersalivation, and muscle relaxation. These results suggest that MCI-225 lessens impairments in learning and memory without causing serious behavioral abnormalities.

Animals↗

PubMed1991

Improvement of postischemic contractile dysfunction of dog heart by MCI-154, a novel cardiotonic agent.

The effects of MCI-154, a cardiotonic agent which has direct effects on cardiac myofilaments, on postischemic contractile dysfunction were studied in dog heart subjected to a 30-min occlusion of the left anterior descending coronary artery followed by reperfusion, and compared with the effects of milrinone and dobutamine, that have largely cyclic AMP-dependent mechanisms of action. Regional myocardial contractility (segment shortening) and tissue ATP levels were severely depressed in reperfused myocardium. MCI-154 (0.3 and 1 microgram/kg per min) improved the regional function of postischemic myocardium and decreased left ventricular end-diastolic pressure and systemic aortic pressure when infused i.v. from 30 min after reperfusion. The improvement of regional function caused by MCI-154 (1 microgram/kg per min) was more pronounced than that caused by milrinone (1 microgram/kg per min) or dobutamine (1 microgram/kg per min), although the drugs produced an equal increase in cardiac performance (peak positive left ventricular dP/dt). These results suggest that MCI-154 produces a more pronounced improvement of regional myocardial function than milrinone and dobutamine, presumably by increasing the responses of the contractile protein system to Ca2+. In this respect, MCI-154 would be of much benefit for the treatment of postischemic left ventricular dysfunction.

Adenosine Triphosphate↗

PubMed1991

Fluoromethylated and hydroxymethylated derivatives of N-methyl-D-aspartate receptor antagonist 1-[1-(2-thienyl)cyclohexyl]piperidine.

Derivatives with fluoromethyl and hydroxymethyl groups on the cyclohexyl ring of 1-[1-(2-thienyl)cyclohexyl]piperidine (TCP), a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptor, were tested in a radioligand binding assay to evaluate their ability to inhibit [3H]TCP binding by rat brain homogenates. The potencies of these compounds as antagonists of NMDA and L-glutamate responses were also compared using a rat cortical slice preparation. One of the analogs, cis-2-hydroxymethyl-r-1-(N-piperidyl)-1-(2-thienyl) cyclohexane (5) was found to show a high affinity (IC50 = 16 nM) for the phencyclidine (PCP) binding sites, very close to that of TCP, and to be 38-fold more potent in binding than its trans isomer. Fluoromethyl and hydroxymethyl substitutions at C4 position of the cyclohexyl ring of TCP clearly reduced the affinity by at least one order of magnitude relative to TCP.

Animals↗

PubMed1991

Vascular effects of betaxolol, a cardioselective beta-adrenoceptor antagonist, in isolated rat arteries.

The effects of betaxolol on isolated rat arteries and the modes of action were investigated. Betaxolol (10(-5)-10(-3) M) relaxed the 80 mM K(+)-induced contraction of aortic strips concentration-dependently. The 50% inhibitory concentration of betaxolol in the K(+)-induced contraction was 3 times higher than that of papaverine and about 3 times lower than that of bunitrolol. The relaxations by betaxolol were also demonstrated in renal, mesenteric and femoral arteries. Betaxolol (3 x 10(-6) M-10(-4) M) produced rightward parallel shifts of the concentration-response curves for Ca2+ in the K(+)-depolarized aortic strips. On the other hand, betaxolol produced downward shifts as well as rightward shifts of the concentration-response curves for norepinephrine, 5-HT and angiotensin II. In K(+)-depolarized aortic strips, the cytosolic Ca2+ concentration measured with a fluorescent indicator, fura-2, was decreased by betaxolol (10(-4) M) almost concomitantly with the loss of tention. An elevation of external Ca2+ from 2.5 mM to 10 mM restored both the cytosolic Ca2+ concentration and tention. The relaxations of arteries induced by betaxolol were not influenced by glybenclamide, methylene blue, indomethacin or removal of the endothelium. These results suggest that betaxolol possesses a direct vasodilating action, and the action may be due to the inhibition of Ca2+ influx across the cell membrane.

Adrenergic beta-Antagonists↗

PubMed1991

Effects of MCI-727, a new antiulcer agent, on various gastric and duodenal lesions in experimental animals.

Effects of a new antiulcer drug, MCI-727, on gastric and duodenal lesions, gastric secretion and gastric motility were studied in comparison with cimetidine and teprenone. MCI-727 dose-dependently (3-100 mg/kg, p.o. or i.d.) inhibited the development of acute gastric or duodenal lesions such as pyrolus ligation-, water-immersion stress-, indomethacin-, HCl-, HCl-ethanol-induced gastric lesions and cysteamine-induced duodenal lesions in rats and histamine-induced duodenal lesions in guinea pigs. These antiulcer effects exceeded those of cimetidine or teprenone. Repeated administration of MCI-727 (0.3-3 mg/kg/day, p.o., for 10 days) significantly promoted the spontaneous healing of acetic acid-induced chronic gastric ulcers. Concerning gastric acid secretion, MCI-727 selectively inhibited tetragastrin-stimulated acid secretion without effecting basal acid secretion and acid secretion by other stimuli. Cimetidine and teprenone inhibited acid secretion in several cases. MCI-727 and teprenone had inhibitory effects on gastric motility, although cimetidine had no effect. These results suggest that MCI-727 has a wide spectrum of antiulcer activity, and its mode of antiulcer action is different from that of cimetidine or teprenone.

Animals↗

PubMed1991

Effects of MCI-727, a new anti-ulcer agent, on plasma secretin concentration in rats and dogs and pancreatic exocrine secretion in rats.

In the present study, we investigated the effects of MCI-727, a new anti-ulcer agent, on plasma immunoreactive secretin concentration in rats and dogs using secretin specific RIA with the ethanol extraction method. Plasma secretin levels were increased dose-dependently 10 min after oral administration of MCI-727 in rats (control: 5.5 +/- 0.6; MCI-727, 10 mg/kg: 10.4 +/- 2.6; 30 mg/kg: 15.3 +/- 1.5; 100 mg/kg: 20.7 +/- 2.6 pg/ml, n = 6). Teprenone also caused a significant increase of plasma secretin at 10 min after oral administration at the doses of 30, 100 and 300 mg/kg. Under the same conditions, MCI-727 and teprenone did not alter the plasma immunoreactive gastrin concentration in rats. From the results of the time course study, the increasing effect of MCI-727 (30 mg/kg, p.o.) on plasma secretin remained for at least 240 min after administration. On the other hand, the increasing effect of teprenone (200 mg/kg, p.o.) was only observed at 30 and 60 min after administration. Furthermore, MCI-727 had increasing effects on plasma secretin concentration in dogs, but teprenone had no effects in this species. The volume of pancreatic secretion and the pancreatic bicarbonate output increased after intra-duodenal administration of MCI-727 at 30 and 100 mg/kg in rats. Similar effects were also observed with teprenone (30-300 mg/kg, i.d.) or secretin (Secrepan, 0.1-1.0 unit/kg, i.v.).

Administration, Oral↗

PubMed1991

MCI-154, a novel cardiotonic agent, reverses the acidic pH-induced decrease in responses of cardiac myofilaments to Ca++: comparison with sulmazole and pimobendan.

In the present study, we have examined the effects of decreasing pH from 7.0 to 6.6 on the tension developed by direct activation of the myofilaments in chemically skinned fibers from guinea pig papillary muscles. We then compared the effects of the novel inotropic agents MCI-154, pimobendan and sulmazole, which have direct action on cardiac myofilaments, on the acidic pH-induced changes in responses of the contractile system to Ca++. The reduction of pH from 7.0 to 6.8 shifted the pCa (-log[Ca++] M)-tension relation curve to the right with no change in maximum tension. However, the reduction of pH from 7.0 to 6.6 shifted the pCa tension relation curve to the right and also depressed maximum force development. These effects were reversible by returning to neutral pH (pH 7.0), but were not overcome by increasing the free [Ca++] (decreasing pCa from 4.4 to 4.0). The amplitude of pMg-ATP (-log[MgATP]M)-tension curve in the absence of free Ca++ (Ca++ less than 1 nM, bell-shaped curve) was shifted downward by reducing pH from 7.0 to 6.6. MCI-154 (1-100 microM) reversed the acidic pH-induced decrease of tension development which was activated by pCa 5.8 in a concentration-dependent manner. Moreover, the acidosis induced reductions of maximum tension (pCa, 4.4) and pMgATP 6.0-activated tension (Ca++ less than 1 nM) were also reversed by MCI-154 (1-100 microM) in a concentration-dependent manner.(ABSTRACT TRUNCATED AT 250 WORDS)

Acidosis↗

PubMed1990

Effects of MCI-154, a novel cardiotonic agent, on mean circulatory filling pressure in anesthetized dogs.

The effects of MCI-154, a novel cardiotonic agent, on mean circulatory filling pressure (an index of total body venous tone), total peripheral resistance and the heart were examined in anesthetized dogs. The bolus injection of MCI-154 (10-100 micrograms/kg i.v.) caused a dose-dependent decrease in mean circulatory filling pressure and resistance to venous return. MCI-154 also decreased the mean blood pressure and total peripheral resistance, and increased cardiac output and heart rate. Right atrial pressure was reduced only by the lowest dose (10 micrograms/kg i.v.) of MCI-154. These hemodynamic effects of MCI-154, except those on mean circulatory pressure and resistance to venous return, reached a maximum with 30 micrograms/kg of the drug. Nitroglycerin (50 micrograms/kg i.v.), a venodilator, decreased mean circulatory filling pressure, resistance to venous return, mean blood pressure and total peripheral resistance, and increased heart rate. However, unlike MCI-154, nitroglycerin did not alter cardiac output and right atrial pressure. These results suggest that the venodilator effect of MCI-154, as well as the positive inotropic and vasodilator effects, could potentially benefit patients with congestive heart failure.

Anesthesia↗

PubMed1990

[Effects of betaxolol, a cardioselective beta-adrenoceptor antagonist, on ischemic myocardial energy and carbohydrate metabolism in dogs].

The effect of betaxolol, a beta 1-adrenoceptor antagonist, on ischemic myocardial metabolism was studied in dog hearts subjected to an occlusion of the left anterior descending coronary artery for 10 or 30 min. Betaxolol (0.1 or 0.3 mg/kg) was injected i.v. 5 min before ischemia. Betaxolol decreased heart rate, (+)dp/dt, coronary flow and blood pressure. Coronary occlusion decreased the levels of creatine phosphate, adenosine triphosphate, total adenine nucleotides and energy charge potential in the ischemic myocardium. Ten minutes after ischemia, betaxolol significantly diminished these impairments of energy metabolism. Even 30 min after ischemia, a higher dose of betaxolol significantly inhibited the depletion of total adenine nucleotides. Myocardial ischemia produced a breakdown of glycogen, an accumulation of lactate and an inhibition of glycolytic flux through the phosphofructokinase reaction. Betaxolol also reduced these alterations of carbohydrate metabolism 10 min after ischemia. These results indicate that betaxolol delays the onset of myocardial metabolic change from aerobic to anaerobic during ischemia and hence reduces the severity of myocardial ischemic injury.

Adenine Nucleotides↗

PubMed1990

[Antihypertensive effect of betaxolol, a cardioselective beta-adrenoceptor antagonist, in experimental hypertensive rats].

Betaxolol is a highly selective beta 1-adrenoceptor antagonist without intrinsic sympathomimetic activity. In this study, the antihypertensive effect of betaxolol was investigated in experimental hypertensive rats; and the antihypertensive mechanism was also studied. Betaxolol (1 and 10 mg/kg, p.o.) produced acute hypotensive effects in conscious spontaneously hypertensive rats (SHR), renal hypertensive rats, deoxycorticosterone/saline hypertensive rats and normotensive rats. The effect was particularly marked in SHR. Furthermore, daily oral administration of betaxolol to SHR for 3 weeks showed sustained antihypertensive effects without producing tolerance. In pithed rats, the pressor response induced by an electrical stimulation of the spinal cord was inhibited by both betaxolol and atenolol. However, only betaxolol reduced the pressor response to norepinephrine. These findings suggest that a certain relaxing effect on peripheral vascular beds in addition to inhibition of presynaptic beta-adrenoceptors may contribute to the antihypertensive mechanism of betaxolol.

Administration, Oral↗

PubMed1990

[Antihypertensive effect of betaxolol, a cardioselective beta-adrenoceptor antagonist, in renal hypertensive dogs].

The antihypertensive effect of betaxolol, a highly selective beta 1-adrenoceptor antagonist, was investigated in renal hypertensive dogs, and the mechanism was also studied. A single oral administration of betaxolol (1 and 10 mg/kg) lowered blood pressure dose-dependently. The hypotensive effect of betaxolol was enhanced by daily oral administration for 10 days. In anesthetized dogs, intraarterial injection of betaxolol produced a dose-dependent increase in femoral artery flow; and in this test, betaxolol was 3 times less potent than papaverine. The increase in blood flow with betaxolol was not affected by pretreatment with propranolol. These findings indicate that a certain vasodilating activity may contribute to the antihypertensive mechanism of betaxolol.

Adrenergic beta-Antagonists↗

PubMed1990

Betaxolol, a cardioselective beta-adrenoceptor antagonist, attenuates ischemic myocardial acidosis in dogs.

The effects of betaxolol, a cardioselective beta-adrenoceptor antagonist, on ischemic myocardial acidosis were studied in dog hearts, in which the left anterior descending coronary artery was partially occluded for 90 min, and were compared with those of atenolol and propranolol. Myocardial ischemia produced a decrease in myocardial pH (measured by a micro glass pH electrode) and an elevation of the ST segment of epicardial ECG (assessed by a surface electrode). Betaxolol (0.01, 0.03 or 0.1 mg/kg), atenolol (0.03 or 0.1 mg/kg) or propranolol (0.03 or 0.1 mg/kg), when injected i.v. 30 min after ischemia, restored myocardial pH and the ST segment of ECG that had been altered by partial occlusion. However, the effect of betaxolol on myocardial acidosis was more potent than that of atenolol or propranolol. The decrease in (+)dp/dt by betaxolol (0.03 mg/kg) was less potent than that by atenolol (0.1 mg/kg) and equivalent to that by propranolol (0.1 mg/kg), although the restorations of myocardial acidosis by the drugs were almost equivalent. These results have confirmed that beta-adrenoceptor antagonists attenuate the ischemia-induced myocardial acidosis and have shown that among three beta-adrenoceptor antagonists, betaxolol is the most effective in improving myocardial acidosis with a relatively weak effect on myocardial contractile function.

Acidosis↗

PubMed1990

Effects of betaxolol on cardiohemodynamics and coronary circulation in anesthetized dogs: comparison with atenolol and propranolol.

Effects of betaxolol, a cardioselective beta-adrenoceptor antagonist, on cardiohemodynamics and coronary circulation were investigated in two kinds of anesthetized open-chest dog preparations in comparison with those of atenolol and propranolol. When administered intravenously, betaxolol, atenolol and propranolol produced dose-dependent decreases in the heart rate (HR), maximum left ventricular dP/dt [+)dP/dt), cardiac output (CO) and mean arterial pressure (MAP). Although all three drugs were almost equipotent in decreasing HR, betaxolol was much less potent than atenolol and propranolol in decreasing (+)dP/dt. Betaxolol decreased the total peripheral resistance (TPR), whereas atenolol and propranolol increased it. In another series of experiments, when administered intravenously, betaxolol, atenolol and propranolol all produced a decrease in the myocardial oxygen consumption (MVO2) and an increase in the atrioventricular conduction time (AVCT). All three drugs were nearly equipotent in decreasing MVO2, although betaxolol was less potent than the other two drugs at higher doses (greater than 300 micrograms/kg). Prolongation of AVCT with propranolol was stronger than those with betaxolol and atenolol. These results suggest that, unlike atenolol and propranolol, the decrease in TPR as well as beta 1-adrenoceptor blockade may be responsible for both the hypotensive effect of betaxolol and the decrease in MVO2 with betaxolol. The result that the cardiodepressant effect of betaxolol was much less potent than those of atenolol and propranolol suggests that betaxolol would be more beneficial than the others in the treatment of ischemic heart disease.

Animals↗

PubMed1989

Agonist activity of a novel compound, 1-[3-(3,4-methylenedioxyphenoxy)propyl]-4-phenyl piperazine (BP-554), at central 5-HT1A receptors.

We used an in vitro radioligand receptor binding assay with rat cerebral cortex, hippocampus and striatum membrane preparations to show that 1-[3-(3,4-methylenedioxyphenoxy)propyl]-4-phenyl piperazine (BP-554) had much higher affinity for 5-HT1A recognition sites than for 5-HT1-non-A, 5-HT2, benzodiazepine, dopamine D-2 and alpha 2-adrenergic recognition sites. The compound inhibited the activity of forskolin-stimulated adenylate cyclase in rat hippocampal membranes. Intraperitoneal injection of BP-554 to mice decreased the concentration of only 5-hydroxy-indoleacetic acid of the amines and their metabolites in the brain and decreased the accumulation of 5-hydroxytryptophan in the brain after decarboxylase inhibition by 3-hydroxybenzylhydrazine. Furthermore, the administration of BP-554 caused hypothermia and increased serum corticosterone levels in mice. The observed effects of BP-554 were similar to those of 8-hydroxy-2-(di-n-propylamino)tetralin. These results suggest that BP-554 acts as a selective 5-HT1A receptor agonist in vivo.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1988

[Effects of terazosin on the blood pressure responses to tilting in conscious animals: comparison with prazosin].

Inhibitory effects of terazosin on the compensatory blood pressure responses to tilting were studied in conscious rabbits and spontaneously hypertensive rats (SHR). In rabbits, doses which reduced the mean blood pressure by 15 mmHg were 330 micrograms/kg, i.v., for terazosin and 42 micrograms/kg, i.v., for prazosin, while those which depressed the blood pressure responses to tilting by 30 mmHg were 180 micrograms/kg, i.v., for terazosin and 54 micrograms/kg, i.v., for prazosin. In SHR, almost equal decreases in the mean blood pressure (about 30%) were observed by 1 mg/kg prazosin, p.o., 20 mg/kg hexamethonium, i.p., 3 mg/kg hydralazine, p.o., or 3 mg/kg nicardipine, p.o. In these conditions, prazosin and hexamethonium markedly depressed the blood pressure responses to tilting, whereas hydralazine and nicardipine showed little effect. The results with these antihypertensive drugs closely paralleled the established orthostatic profiles seen clinically. In this SHR tilting model, when the mean blood pressure was reduced by 15%, prazosin significantly depressed the tilting reflexes; however, terazosin produced no depression. Considering the dose ratio of terazosin to prazosin for antihypertensive effects and inhibitory effects on the tilting reflexes, the orthostatic liability of terazosin was about 3 times as low as that of prazosin. On the basis of these results, it is expected that terazosin causes less orthostatic hypotension than prazosin in clinical use.

Adrenergic alpha-Antagonists↗

PubMed1988

Comparative tolerability of two formulations of Rhinalar (flunisolide) nasal spray in patients with seasonal allergic rhinitis.

This double-blind, randomized, crossover study compared the incidence of nasal burning and stinging, as well as overall tolerability of the currently marketed formulation of Rhinalar (original formulation) to a new formulation of Rhinalar containing less propylene glycol. In addition, patient and investigator subjective evaluations were used to compare the effectiveness of the test medications in controlling the nasal symptoms of seasonal allergic rhinitis. A total of 122 patients were enrolled in this 4-week trial. Each patient received one formulation of Rhinalar for 2 weeks and then crossed over to receive the alternate formulation for an additional 2 weeks. Eighteen patients withdrew from the trial prematurely. Ten patients were lost to follow-up and eight withdrew due to side effects and/or inadequate therapeutic response. Statistical comparisons of patient evaluations of nasal burning and stinging with the two formulations of Rhinalar showed a very significant difference in terms of severity (P less than .001), duration (P less than .001), and tolerability (P = .006) in favour of the new formulation. A reduction in severity of throat irritation with the new formulation was also shown to be statistically significant (P = .006). Nausea, headache, and other side effects including watery eyes, taste perversion, and runny nose were seldom reported with either test medication. Both formulations were shown to be equally effective in relieving the nasal symptoms of seasonal allergic rhinitis. The considerable reduction in nasal burning and stinging and throat irritation with the new formulation of Rhinalar was shown to enhance patient acceptability and may lead to better compliance.

Administration, Inhalation↗

PubMed1987

Effects of bifemelane hydrochloride on cortical neuronal activity in cats.

The effects of bifemelane hydrochloride on neuronal activity in the visual cortex of the cat were studied by microiontophoretic application under methoxyflurane anesthesia. Of 195 neurons examined with both acetylcholine (ACh) and bifemelane, 67 cells (34%) were excited and 7 cells (4%) were inhibited by ACh. The effect of bifemelane was excitatory on 122 neurons (63%), inhibitory on 20 (10%) and unchanged on the rest. In 60 cells out of the above 122 neurons, bifemelane showed a similar discharge pattern to ACh with a slow onset and delayed termination. The bifemelane-induced excitation was, in 18 out of 22 cells, antagonized by atropine (30-40 nA). Also, a potentiation in bifemelane-induced discharges by physostigmine (30-50 nA) was observed in 14 of the 32 cells tested. The firing evoked by ACh (80-100 nA) was potentiated during of after the application of bifemelane (30-40 nA) in 9 out of 29 neurons, which were not excited by bifemelane alone. These results suggest that neuronal discharges produced by bifemelane are induced at least in part, through a muscarinic ACh receptor, although other mechanisms may possibly be involved.

Acetylcholine↗