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Biomedical subjects

Y Kitada

Publications and source records attributed to Y Kitada.

At least 55 records · Page 3Linked to original sources
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↗
PubMed1990

Taste responses to electrolytes in the frog glossopharyngeal nerve: enhancement by Ni2+ ions.

In studies of whole-nerve recordings from the frog glossopharyngeal nerve, Kashiwagura et al. reported that Ni2+ enhances responses to MgCl2 and NaCl and that such enhanced responses are suppressed by Ca2+. In the present study, it was found that the responses to electrolytes of single water fibers of the frog glossopharyngeal nerve are enhanced by Ni2+. Ni2+ enhances the responses to MgCl2, NaCl, and CaCl2. The enhancement of the response to CaCl2 suggests that inhibition of the enhanced response by Ca2+ is not caused by the relationship between Ca2+ and Ni2+ ions on the receptor membrane. Kitada reported that, in the absence of Ni2+, Ca2+ competitively inhibits the responses to Na+ and Mg2+; and Kitada and Shimada reported that the response to Ca2+ is competitively inhibited by Na+ and Mg2+. The possibility is discussed that inhibition of the enhanced response by Ca2+ is due to competition between Ca2+ and Na+ and between Ca2+ and Mg2+ for multiple specific receptor sites.

Animals↗
PubMed1989

In vitro characterization of the effects of MCI-154, a novel cardiotonic agent, on cardiac tissues.

In vitro cardiac effects of a cardiotonic drug, MCI-154, for which the main action mechanism was proposed to be the enhancement of Ca2+ sensitivity of cardiac contractile proteins, were investigated. MCI-154 (3 x 10(-8)-3 x 10(-4) M) increased the developed tension in isolated ventricular muscles from cats, dogs, guinea pigs and rats and increased that of isolated left atrial muscles of guinea pigs and rats. However, species differences were observed in the responses to MCI-154. The positive inotropic potency of MCI-154 was stronger than those of amrinone and milrinone. In the isolated right atria from guinea pigs and rats, properties of the chronotropic effect of MCI-154 were different from those of amrinone and milrinone. The positive inotropic action of MCI-154 was not affected by phentolamine, propranolol, cimetidine and tetrodotoxin. MCI-154 did not inhibit cardiac Na+,K+-ATPase. MCI-154 moderately stimulated Ca2+-uptake of isolated cardiac sarcoplasmic reticulum (SR), but induced no release of Ca2+ from the SR. These results support the view that the main mechanism for the action of MCI-154 is the enhancement of Ca2+ sensitivity of cardiac contractile proteins.

Amrinone↗
PubMed1989

Comparison of the effects of MCI-154, a new cardiotonic agent, and some Ca2+-sensitizing agents on the response of the contractile system to Ca2+ in skinned cardiac muscle.

Several cardiotonic agents (MCI-154, sulmazole, pimobendan and adibendan) were examined for their ability to influence Ca2+-activated tension development and MgATP-activated tension development in the absence of free Ca2+ (rigor tension), using the chemically skinned fiber from guinea pig papillary muscles. MCI-154, sulmazole, pimobendan and adibendan all increased the tension development induced by pCa (-log[Ca2+]M) 5.8 in a concentration-dependent manner (10(-6) to 10(-4) M). The order of the potency was as follows: MCI-154 greater than pimobendan greater than adibendan greater than sulmazole. MCI-154 enhanced the maximum tension developed at pCa 4.4 but sulmazole, pimobendan and adibendan did not enhance it. MCI-154, but not sulmazole, pimobendan and adibendan, enhanced the tension development induced by pMgATP (-log[MgATP]M) 6.0 in the absence of free Ca2+. MCI-154, sulmazole, pimobendan and adibendan concentration-dependently (10(-7) to 10(-4) M) increased the force of contraction in isolated guinea pig papillary muscles. The order of the potency was as follows: MCI-154 greater than adibendan greater than pimobendan greater than sulmazole. These results demonstrated that the Ca2+-sensitizing action on the contractile system may be involved in the positive inotropic action of MCI-154, sulmazole, pimobendan and adibendan, and that MCI-154 is the most potent among these drugs. Furthermore, sulmazole, pimobendan and adibendan did not enhance the interaction of actin and myosin, suggesting that the mechanism of actions of these drugs are qualitatively different from that of MCI-154.

Adenosine Triphosphate↗
PubMed1989

Potent stimulation of myofilament force and adenosine triphosphatase activity of canine cardiac muscle through a direct enhancement of troponin C Ca++ binding by MCI-154, a novel cardiotonic agent.

In the present study we have analyzed a likely biochemical mechanism underlying the Ca++-sensitizing action of MCI-154 (6-[4-(4'-pyridyl)aminophenyl)-4,5-dihydro-3(2H)-pyridazinone hydrochloride), a novel cardiotonic agent, on the contractile protein system. MCI-154 (10(-7) to 10(-4) M) enhanced the tension development induced by -log molar-free Ca++ concentration (pCa) 5.8 in chemically skinned fiber from the canine right ventricular muscle in a concentration-dependent manner. At pCa 7.0, MCI-154 (10(-7) to 10(-4) M) markedly increased adenosine triphosphatase (ATPase) activities of canine myofibrils and reconstituted actomyosin. In myofibrils and reconstituted actomyosin, MCI-154 (10(-7) to 10(-4) M) caused a parallel shift of the pCa-ATPase activity relation curve to the left without affecting the maximum activity, suggesting an increase in Ca++ sensitivity. MCI-154 (10(-8) to 10(-4) M) had little effect on actin-activated, Mg++, Ca++ and (K+, EDTA)-ATPase activities of myosin. Ca++ binding to cardiac myofibrils or purified cardiac troponin was increased by 10(-4) M MCI-154. These results suggest that MCI-154 enhances Ca++ binding to cardiac troponin C to elevate the Ca++ sensitivity of myofilaments and thus may cause a positive inotropic action in cardiac muscle. MCI-154 may provide a valuable tool for studying the molecular mechanism by which Ca++ regulates the contractile system.

Actin Cytoskeleton↗
PubMed1988

Liquid chromatographic determination of alliin in garlic and garlic products.

A liquid chromatographic (LC) method is proposed for the determination of alliin in garlic and garlic products. The method involves heating of the sample with water in a bath of boiling water followed by homogenization and centrifugation. Interfering components are eliminated by use of a Sep-Pak C18 cartridge as a clean up step before injection. The LC system with ultraviolet detection at 210 nm consists of a separation on a Zorbax TMS column and isocratic elution with water as a mobile phase. Fluorometric determination by ion-pairing chromatography with tetra-n-butylammonium bromide on a Nucleosil 5C18 column is also described. The overall recoveries of alliin added to garlic products were greater than 90%. Thin-layer chromatography and enzymatic degradation of alliin were performed for the confirmation of alliin detected in garlic products.

Chromatography, Liquid↗
PubMed1987

Contractile proteins: possible targets for the cardiotonic action of MCI-154, a novel cardiotonic agent?

The effect on the contractile protein system of MCI-154, a novel and potent cardiotonic agent, was examined by using thin bundles of chemically skinned fibers from the guinea-pig papillary muscles. MCI-154 increased the Ca2+ sensitivity of the contractile protein system of the cardiac skinned fibers. Moreover, MCI-154 enhanced the maximum tension developed at pCa 4.4. These results suggest that an increase in responses of the contractile protein system to Ca2+ ion is, at least in part, responsible for the positive inotropic action of MCI-154.

Animals↗
PubMed1987

A novel class of cardiotonics. Synthesis and pharmacological properties of [4-(substituted-amino)phenyl]pyridazinones and related derivatives.

A series of [4-(substituted-amino)phenyl]pyridazinones and [4-(substituted-methyl)amino]phenyl]pyridazinones was synthesized and evaluated for inotropic activity in vitro and for cardiohemodynamic effects in vivo. Above all, 6-[4-(4-pyridylamino)phenyl]-4,5-dihydro-3(2H)-pyridazinone hydrochloride (4, MCI-154) and 6-[4-(4-pyridylamino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone hydrochloride (5) showed extremely potent positive inotropic activity along with vasodilating activity. Regarding dP/dtmax (an indicator for cardiac contractility), ED30's (doses that increased dP/dtmax by 30%) of compounds 4 and 5 were 8.5 +/- 1.9 and 4.4 +/- 0.6 micrograms/kg, respectively, where that of amrinone was 471.9 +/- 94.1 micrograms/kg. Structure-activity relationships of these series are presented, and a plausible model of receptor binding is discussed.

Animals↗
PubMed1987

Does the positive inotropic action of a novel cardiotonic agent, MCI-154, involve mechanisms other than cyclic AMP?

MCI-154 is a new positive inotropic agent with vasodilating property. Experiments were carried out in the canine isolated right ventricular muscle in order to elucidate whether or not cyclic AMP is involved in the positive inotropic effect (PIE) of MCI-154. MCI-154 (10(-7) to 10(-4) M) produced a concentration-dependent PIE amounting to 75% of the maximal effect of isoproterenol. MCI-154 did not affect the time to peak tension and had a tendency to shorten the relaxation time and total duration of contraction. Pindolol, reserpine-pretreatment or tetrodotoxin did not modify the PIE of MCI-154. MCI-154 increased the cyclic AMP levels only at 3 X 10(-4) M, whereas CI-914, of which chemical structure is similar to that of MCI-154, elevated definitely the cyclic AMP at the lower concentrations (10(-5) to 10(-4) M). Carbachol at a concentration known to decrease markedly the PIE of amrinone, milrinone and papaverine, did not affect the PIE of MCI-154. MCI-154 inhibited the activity of a crude phosphodiesterase (PDE) from the canine ventricular muscle and it enhanced the PIE of isoproterenol, which implied the involvement of cyclic AMP. However, the maximal inhibition of PDE by MCI-154 remained less than 18%. Amrinone, milrinone and papaverine inhibited more potently the PDE activity than MCI-154. These results suggest that the elevation of cyclic AMP levels is only partially involved in the PIE of MCI-154 in the canine right ventricular muscle, and that MCI-154 may have novel mechanisms of action different from those of amrinone, milrinone and CI-914 that are largely cyclic AMP-dependent.

Animals↗
PubMed1987

Increase in Ca++ sensitivity of the contractile system by MCI-154, a novel cardiotonic agent, in chemically skinned fibers from the guinea pig papillary muscles.

The effects of MCI-154, a novel cardiotonic agent, on the contractile protein system and the sarcoplasmic reticulum (SR) were investigated by using thin bundles of chemically skinned fibers from the guinea pig papillary muscles. In the skinned muscle fibers treated with 50 micrograms/ml of saponin, MCI-154 shifted the -log[Ca++]M-tension relation curve to the left and upward in the concentration-dependent manner (10(-7) to 10(-4) M). This was confirmed also in the skinned muscle fibers treated with 250 micrograms/ml of saponin which destroyed not only the surface membrane but also the function of SR. Sulmazole (10(-4) M) shifted the -log[Ca++]M-tension relation curve to the left but the effect was about 100 times less potent than that of MCI-154. Unlike MCI-154, sulmazole had little effect on the maximum tension development induced by -log[Ca++]M 4.4. Milrinone did not affect the Ca++-induced tension development in the skinned cardiac fibers. Higher concentration of MCI-154 (10(-4) M) also increased amplitude of -log[Mg-ATP]M-tension-curve in the absence of free Ca++ ion (bell-shaped curve) to the upward. Initial rate and plateau phase of Ca++ uptake by the SR in the skinned fibers treated with 50 micrograms/ml of saponin was increased slightly by MCI-154 at the concentrations of 10(-6) and 10(-4) M. MCI-154 had no effect on the Ca++-induced Ca++ release mechanism in the SR. These results suggest that an increase in Ca++ sensitivity of the contractile protein system is responsible for, at least in part, the mechanism of the positive inotropic action of MCI-154.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1987

Cardiovascular pharmacology of 6-[4-(4'-pyridyl)aminophenyl]-4,5-dihydro-3(2H)-pyridazinone hydrochloride, a novel and potent cardiotonic agent with vasodilator properties.

The cardiovascular profile of 6-[4-(4'-pyridyl)aminophenyl]-4,5-dihydro-3(2H)-pyridazinone hydrochloride (MCI-154), a novel cardiotonic agent structurally different from cardiac glycosides and beta-adrenoceptor agonists, was investigated in vivo. In anesthetized, open-chest dogs, MCI-154 (0.3-100 micrograms/kg i.v., bolus injection) produced dose-dependent increases in dP/dtmax and cardiac output, and decreases in arterial blood pressure and total peripheral resistance with a relatively small increase in heart rate. The positive inotropic effect of MCI-154 was more potent than those of amrinone and milrinone. In anesthetized, intact-chest dogs, infusion of MCI-154 (0.3-3 micrograms/kg/min i.v.) also exerted a positive inotropic effect. P.o. administrations of MCI-154 (10-300 micrograms/kg) increased dP/dtmax in conscious beagle dogs. The cardiotonic effect of MCI-154 was not attenuated by blockade of autonomic receptors, catecholamine depletion and prostaglandin synthesis inhibition. MCI-154 (0.3-30 micrograms i.a.) produced a direct vasodilator effect in the canine hind-limb. MCI-154 (3 and 30 micrograms/kg i.v.) was effective in heart failure models induced with high doses of propranolol or verapamil. The potent cardiotonic and vasodilator activities of MCI-154 revealed by the present study suggest that this agent would be an effective remedy for the treatment of heart failure.

Anesthesia↗
PubMed1986

Salt taste responses in the frog glossopharyngeal nerve: different receptor sites for Mg2+ and Na+.

The glossopharyngeal nerve of the frog responds to MgCl2 and NaCl applied to the tongue. To learn whether or not Mg2+ and Na+ react with different receptor sites, a proteolytic enzyme was topically applied to the tongue dorsum. Responses were recorded from the frog glossopharyngeal nerve during stimulation of the tongue with 100 mM MgCl2 and 500 mM NaCl. The magnitude of the MgCl2 response was selectively reduced after application of 0.1% pronase E to the dorsal tongue surface. The selective suppression of the MgCl2 response by the pronase treatment indicates that the receptor site responsible for the MgCl2 response differs from that for the NaCl response. The effect of pronase on the MgCl2 response was due to the proteolytic action. This suggests that the receptor site responsible for the MgCl2 response is composed of a protein or interacts secondarily with a protein affected by pronase treatment. It is suggested that there are multiple receptor sites for cations in salt taste reception of the frog.

Animals↗
PubMed1986

Different receptor sites for Ca2+ and Na+ in single water fibers of the frog glossopharyngeal nerve.

Unitary discharges were recorded from single water-sensitive fibers (water fibers) of the frog glossopharyngeal nerve during stimulation of the tongue with chemical stimuli. Low CaCl2 (1 mM CaCl2) and relatively high NaCl (500 mM NaCl) are effective stimuli which excite water fibers. To learn whether or not Ca2+ and Na+ react with different receptor sites, a proteolytic enzyme was topically applied to the tongue dorsum. After treatment of the tongue with 0.05% pronase E, the magnitude of the NaCl response remained unchanged, but the magnitude of the CaCl2 response markedly decreased. The selective elimination by the pronase E treatment indicates that there exist different receptor sites for Ca2+ and Na+ in single water fibers of the frog glossopharyngeal nerve. The effect of pronase E treatment was due to the proteolytic action. The results suggest that the Ca2+ receptor site may be composed of a protein.

Animals↗
PubMed1986

The significance of beta-adrenoceptor down regulation in the desipramine action in the forced swimming test.

The present studies were undertaken to clarify whether central beta-adrenoceptor down regulation is responsible for the greater effect of chronic treatment with desipramine (DMI) compared with acute treatment in the forced swimming test in rats. Repetitive administration of DMI activated the rat behaviour pattern and consequently reduced the duration of immobility. The degree of activation depended on the length of treatment, i.e. no effect when given in a single dose, moderate effect when given subchronically (3 doses) and marked activation after chronic (31 doses) treatment. Chronic treatment with DMI also produced a decrease in 3H-dihydroalprenolol (3H-DHA) binding site in the cerebral cortex. Acute stimulation of brain beta-adrenoceptors by intracerebroventricular (i.c.v.) isoprenaline significantly, though partially, attenuated the behavioural effect of chronic DMI by beta 1-adrenoceptor-related mechanisms. Similarly, chronic i.c.v. co-administration of atenolol or practolol, beta 1-adrenoceptor antagonists, together with DMI attenuated both beta-adrenoceptor down regulation and the behavioural activation by chronic DMI. On the other hand, chronic i.c.v. administration of isoprenaline, supposedly leading to down regulation of beta-adrenoceptors, facilitated the activating behavioural effect of DMI, as a single dose became effective. Changes, however, in 3H-DHA binding parameters in the cerebral cortex were not observed after chronic isoprenaline. These results suggest that down regulation of beta-adrenoceptors in brain is responsible, at least in part, for the marked activatory effect of chronic DMI in the forced swimming test, possibly by reducing an inhibitory function of beta 1-adrenoceptor mediated mechanisms.

Adrenergic beta-Antagonists↗
PubMed1986

[General pharmacological action of 4-(o-benzylphenoxy)-N-methylbutylamine hydrochloride (MCI-2016, bifemelane hydrochloride). Influence on respiratory and cardiovascular systems, renal function, autonomic nervous system, isolated smooth muscle and digestive organs].

MCI-2016 at 3 mg/kg, i.v., caused slight changes in systemic blood pressure (SBP), heart rate (HR), respiratory rate (RR) and ECG but at 10 mg/kg, i.v., it caused a significant increase in RR, decrease in SBP, increase or decrease in HR and a moderate change in ECG. Biphasic changes in SBP, HR and blood flow were sometimes observed after high doses. MCI-2016 also decreased SBP at 30 mg/kg, i.p., in SHR. MCI-2016 (50 mg/kg, p.o./day) showed little influence on SBP, HR and ECG in conscious beagle dogs. In isolated hearts, MCI-2016 decreased HR and contractility at the concentrations above 10(-5) g/ml, and 30 micrograms, i.a. MCI-2016 prolonged the AVCT at 10 mg/kg, i.v. MCI-2016 (i.v. or i.a.) moderately increased cerebral and femoral artery blood flows. MCI-2016 did not change CMRO2, but decreased MVO2. Coronary and renal artery flows were moderately increased by 10 mg/kg, i.v., of MCI-2016. Renal function was suppressed after 10 mg/kg, i.v., or 300 mg/kg, p.o., of MCI-2016. MCI-2016 potentiated the action of NE (increase in SBP, contractions of nictitating membrane and vas deferens), but showed little anti-cholinergic action. In contrast, MCI-2016 moderately increased gastrointestinal motility and salivatory response. As for the influence on isolated smooth muscles, MCI-2016 antagonized the contraction of blood vessels by high K+ at 10(-6) g/ml, or more, and it depressed the contractions by ACh, 5-HT, histamine and BaCl2 and also depressed spontaneous movements of uterus and ileum at 10(-5) M or more, in a nonspecific manner. MCI-2016 had no influence on liver damage and bile secretion, but inhibited stress ulcer and gastric acid secretion on the one hand, and caused gastric damage (125 mg/kg p.o., or more) on the other hand.

Animals↗
PubMed1986

[General pharmacological action of tritoqualine (TRQ; (+/-)-(R*)-7-amino-4, 5, 6-triethoxy-3-[(R*)-5, 6, 7, 8-tetrahydro-4-methoxy-6-methyl-1, 3-dioxolo [4, 5-g] isoquinolin-5-yl] phthalide].

The general pharmacological action of TRQ was investigated, and the following results were obtained: With regard to its influence on the central nervous system, TRQ moderately potentiated the actions of hexobarbital (sleeping time) and methamphetamine (stereotyped behavior) at doses above 100 mg/kg, p.o. TRQ, however, had little influence on behavioral changes, EEG and motor function. TRQ only had slight influence on the respiratory and cardiovascular system at doses ranging from 0.1 to 3 mg/kg, i.v. Significant decrease in SBP and increases of HR, FAF and respiratory rate were observed after high doses (10-30 mg/kg, i.v.) of TRQ. TRQ also had little influence on contractility and pacemaker in isolated hearts, but moderately increased the coronary flow. The inhibitory effect of TRQ on the isolated smooth muscle was observed at high concentration and was non-specific. Furthermore, TRQ exhibited little influence on the autonomic nervous system. Among the effects of TRQ on the gastrointestinal system, it was shown that TRQ moderately increased the outflow of bile after doses above 1 mg/kg, i.v. TRQ also showed no remarkable actions on other aspects of the gastrointestinal system and blood coagulation system. Considering the present results, it may be suggested that there should be no serious problems in the application of TRQ as a hepatoprotective agent.

Animals↗