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Biomedical subjects

K Tsuchida

Publications and source records attributed to K Tsuchida.

231 records · Page 13Linked to original sources
PubMed1980

Synthesis of naturally occurring uridine-alpha-amino acid derivatives by the application of Ugi reaction.

A simultaneous condensation (Ugi reaction) of four components (aldehyde, amine, isocyanide, and carboxylic acid) may be a useful reaction for the construction of N,N'-disubstituted alpha-aminocarboxamide structure. We have found that the reaction involving (2-picolyl 1-oxide) amine (op-amine) gave rise to a product, one of whose nitrogen-substituent could be easily removed to give mono-substituted derivative. Thus, the polyoxin skeleton as well as 3-(3-amino-3-carboxypropyl) uridine (a modified nucleoside in certain t-RNAs) were synthesized by the Ugi reaction by the use of the "op"-amine and appropriate aldehyde derived from uridine. Attempted synthesis of these nucleoside derivatives by the condensation involving (2-picolyl 1-oxide) isocyanide as well as the "op"-amine will be also touched on briefly.

Indicators and Reagents↗
PubMed1977

[A pharmacological study of chlorphenesin carbamate. Tolerance to chlorphenesin carbamate (author's transl)].

Tolerance to chlorphenesin carbamate (CPC) was investigated from the viewpoints of action of CPC, serum free CPC concentration, the activity of UDP-glucuronyltransferase and the content of cytochrome P-450. CPC was administered once daily for 7 or 14 days. In mice, the hypnotic action of hexobarbital injected 24 hours after the last administration of CPC and the motor incoordinating action of CPC significantly decreased on the 7th day, but slightly recovered on the 14th day. Serum free CPC concentration also decreased on the 7th day, but recovered on the 14th day. A significant relationship between the motor incoordinating action of CPC and serum free CPC concentration was observed. Therefore, the recovery of CPC effect on the 14th day was considered to be due to the recovery from the induction of drug-metabolizing enzymes. On the other hand, in rats, the weekly alteration of the motor incoordinating action of CPC was similar to that observed in mice. Serum free CPC concentration on the 7th and 14th days was lower than that on the 1st day, and enzyme induction was observed during CPC administration. Notwithstanding the low level of serum free CPC concentration, the recovery of CPC effect was observed on the 14th day and such was considered to be due to habituation to the rotarod. In mice and rats, it was demonstrated that the intensity of CPC effect was dependent on serum free CPC concentration to the extent that enzyme induction played an important role in the development of tolerance. From these results, the tolerance to CPC is attributed to induction of drug-metabolizing enzymes in liver microsomes.

Animals↗
PubMedDate not supplied

Hematopoietic tissues, as a playground of receptor tyrosine kinases of the PDGF-receptor family.

Three receptor tyrosine kinases of the PDGF receptor family (RTKP) that clustered within 1000 Kb of the mouse chromosome 5 constitute an interesting unit that are expressed in three distinct cell lineages essential for constructing hematopoietic tissues. Namely, the c-kit gene that is expressed in hematopoietic stem cells is flanked by pdgfr alpha and flk genes expressed respectively in stromal cells and vascular endothelial cells. In this article, we review our results on their expression in the embryonic hematopoietic tissues. We found that co-expression of Flkl and c-Kit was frequently detected either in vascular endothelial cells or hematopoietic cells in the early hematopoietic tissues. On the other hand, the three RTKPs are expressed in different cell lineages in the fetal liver. On the basis of this finding, we propose two modes of embryonic hematopoiesis; hematogenic angiopoiesis and hematopoiesis.

Animals↗
PubMedDate not supplied

Production and activation of hepatocyte growth factor in acute renal failure.

Hepatocyte growth factor (HGF) facilitates the regeneration of injured kidney in acute renal failure (ARF). HGF is produced as a single-chain precursor by cells of mesenchymal origin and is converted to a biologically active, heterodimeric molecule by proteolytic processing. We studied HGF mRNA and protein levels in systemic organs of glycerol-induced ARF rats, a model of crush syndrome. HGF protein concentration of tissue homogenate was measured by ELISA. Both mRNA and protein levels were increased in liver and spleen at 24 hours after the glycerol injection whereas HGF protein level was decreased in the injured kidney. Expression of HGF receptor/c-met mRNA was elevated only in the kidney. These results suggest that HGF supplied in an endocrine manner may play an important role in the regenerating process following ARF. Next, we measured serum HGF concentration by ELISA in 8 ARF patients caused by crush syndrome and the molecular size of serum HGF was determined by immunoblotting. Although serum HGF levels elevated in all patients, the HGF levels did not associate with their prognoses. While a single-chain molecule was predominantly observed in sera from chronic renal failure patients and healthy subjects, the majority of serum HGF was a heterodimeric form in 7 ARF patients. In one patient who developed disseminated intravascular coagulation syndrome and had a poor prognosis, a single-chain molecule was predominant although the serum HGF concentration was equivalent. These data suggest that the activity of proteolytic processing may be also an important factor for the expression of the biological function of HGF.

Acute Kidney Injury↗
PubMedDate not supplied

Impairment of endothelium-dependent relaxation of superior mesenteric artery in genetically diabetic WBN/Kob rats.

The endothelium-dependent relaxation of superior mesenteric arteries of Wistar and genetically diabetic WBN/Kob rats was compared. Endothelium-dependent relaxation induced by acetylcholine (ACh) and A23187 was depressed in WBN/Kob rats. Relaxation induced by sodium nitroprusside, an endothelium-independent agent, in strips from WBN/Kob rats was similar to that in strips from Wistar rats. Indomethacin (5 x 10(-6) M) enhanced the relaxation responses to ACh in strips from both WBN/Kob and Wistar rats; however, endothelium-dependent relaxation induced by ACh remained attenuated in WBN/Kob rats. These results show that endothelium-dependent relaxation is impaired not only in thoracic aorta but also in superior mesenteric arteries in genetically diabetic rats.

Animals↗
PubMedDate not supplied

Effect of CD349, a new dihydropyridine derivative Ca2+ antagonist, on the voltage-dependent Ca2+ currents in isolated mammalian brain neurons.

The effects of CD349 [2-nitratopropyl-3-nitratopropyl-2,6-dimethyl-4-(3- nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate], a dihydropyridine derivative Ca2+ antagonist, were studied on low and high voltage-activated Ca2+ currents in single pyramidal neurons isolated from the rat hippocampal CA1 region. CD349 inhibited the peak amplitude of the low voltage-activated Ca2+ current in a concentration-dependent manner with a threshold concentration of about 10(-7) M. The concentration for half-maximum inhibition was 1.5 x 10(-6) M. At 10(-5) M or more, a complete suppression of the low voltage-activated Ca2+ current was observed. There was no apparent effect on the current-voltage relationship and the current kinetics (rising and decaying phases of the current). The inhibitory potency of CD349 was similar to that of nicardipine. CD349, at a concentration of 10(-6) M (near the half-maximum inhibition concentration), delayed the reactivation and enhanced voltage- and time-dependently the inactivation of the low voltage-activated Ca2+ channel, suggesting that CD349 preferentially binds to the inactivated Ca2+ channel. CD349 also decreased the peak amplitude of the high voltage-activated Ca2+ current at half-maximum inhibition concentrations of 5.7 x 10(-6) M. The current kinetics of the high voltage-activated Ca2+ current were slightly accelerated without shifting the current-voltage relationship in the presence of 10(-5) M of CD349. The potency of CD349 in inhibiting both types of Ca2+ current was also similar to that of nicardipine. It is suggested that the blocking effect of CD349 on neuronal Ca2+ influx, in combination with a cerebral vasodilatory action, may contribute to a favorable effect on ischemic brain damage.

Animals↗
PubMedDate not supplied

Effects of a monovalent ionophore, lonomycin A, on the contractile force in canine cardiac Purkinje fibers.

The mechanism for the positive inotropic effects of a monovalent ionophore, lonomycin A, in the canine cardiac Purkinje fibers was examined. Lonomycin A increased developed and resting tensions in Tyrode solution containing 1.8 mM Ca2+. The per cent increase in contractile force induced by lonomycin A was more marked in Tyrode solution with lower Ca2+ than in that with higher Ca2+. Lonomycin A did not elicit marked positive inotropic effects in modified Tyrode solution containing 40.5 mM Na+ and 0.3-0.6 mM Ca2+, compared with the positive inotropy elicited in 1.8 mM Ca2+ Tyrode solution containing 152.7 mM Na+. In 40.5 mM Na+ Tyrode solution, the concentration of Ca2+ was adjusted so that the fibers would show roughly the same contractile force before replacement of Tyrode solution containing 1.8 mM Ca2+ and 152.7 mM Na+. Ouabain remarkably augmented the positive inotropic effect induced by lonomycin A. The increased contractile force induced by lonomycin A is thus mainly due to extracellular Na+ transport into cytosol, resulting in increased [Ca2+]i via a Na-Ca exchange.

Animals↗
PubMedDate not supplied

Effects of alpha-adrenoceptor agonists on cardiac output and blood pressure in spinally anesthetized ganglion-blocked dogs.

The alpha-adrenoceptor agonist ST-1059 (2-amino-1-(2,5-dimethoxyphenyl) ethanol), the alpha 1-adrenoceptor agonist methoxamine, the alpha 2-adrenoceptor agonist clonidine and a nonselective alpha-adrenoceptor agonist norepinephrine, all increase cardiac output and dose-dependently increase arterial blood pressure in spinally anesthetized ganglion-blocked dogs. The increase in cardiac output may be the result of an increased venous return via the contraction of capacitance vessels, and the vasopressor responses are attributed to an increase in total peripheral resistance. The increases in cardiac output and pressor responses induced by ST-1059 and methoxamine were antagonized by the alpha 1-adrenoceptor antagonist prazosin (0.3 mg/kg i.v.), but those induced by clonidine were not inhibited. In contrast, the alpha 2-adrenoceptor antagonist yohimbine (0.3 mg/kg i.v.) had little or no effects on the increase in cardiac output or the pressor responses induced by ST-1059 and methoxamine, but strongly attenuated those of clonidine. Prazosin and yohimbine inhibited the norepinephrine-induced increase in cardiac output and pressor responses. These results suggest that the increases in cardiac output and blood pressure induced by ST-1059 were mediated by postjunctional alpha 1-adrenoceptor stimulation, such as by methoxamine, but that those induced by clonidine were mediated by postjunctional alpha 2-adrenoceptor stimulation in dogs. Not only the postjunctional alpha 1-adrenoceptors but also the postjunctional alpha 2-adrenoceptors may play an important role in the constriction of venous beds, as well as of the arterioles in spinally anesthetized ganglion-blocked dogs.

Adrenergic alpha-Agonists↗
PubMedDate not supplied

Cardioselective effects of gallopamil compared with verapamil in the dog heart.

The cardiac and coronary vasodilator effects of gallopamil and verapamil were compared in isolated, blood-perfused papillary muscle, sinoatrial (SA) node and atrioventricular (AV) node preparations of the dog. Gallopamil and verapamil (0.3-100 micrograms) were injected intra-arterially. In all preparations, gallopamil produced an equipotent but longer-lasting increase in coronary blood flow compared to verapamil. In paced papillary muscle preparations, both drugs reduced the force of contraction. In spontaneously beating papillary muscle preparations, both drugs had virtually no effect on the ventricular rate. In SA node preparations, both drugs reduced the sinus rate and produced atrial standstill at medium and large doses. In AV node preparations, both drugs prolonged the AV conduction time and produced second- or third-degree AV block at medium and large doses only when injected into the artery supplying the AV node, but not when injected into the artery supplying the His-Purkinje-ventricular system. The cardiac effects of gallopamil described above were 2-3 times more potent and were longer-lasting than those of verapamil. These results suggest that gallopamil is more selective for myocardium (papillary muscle, SA node or AV node) than for coronary vasculature compared with verapamil in isolated, blood-perfused heart preparations of the dog.

Animals↗
PubMedDate not supplied

5-Hydroxytryptamine3 receptor and regulation of gastric emptying in rats.

We investigated the role of the 5-hydroxytryptamine3 (5-HT3) receptor in the regulation of gastric emptying in rats using various 5-HT3 receptor antagonists, including GK128, a novel and selective 5-HT3 receptor antagonist. GK128 dose-dependently accelerated gastric emptying in rats. The accelerating effect of GK128 on gastric emptying was more potent than that of the other 5-HT3 receptor antagonists used in this study. However, the rank order of potency of the selective 5-HT3 receptor antagonists, except for the benzamide derivatives, on the accelerating effect of gastric emptying, was not consistent with that of their 5-HT3 receptor-binding affinity in the rat cortex. GK128 improved the gastric emptying delayed by m-chlorophenylbiguanide, a 5-HT3 receptor agonist, and by cisplatin, which is known to cause damage to the small intestine and to release 5-HT from enterochromaffin cells. Furthermore, 5,7-dihydroxytryptamine, an indoleamine neurotoxin known to destroy 5-HT-containing neurons, significantly accelerated gastric emptying, and no further acceleration was observed after administration of GK128. These results may suggest that 5-HT3 receptor antagonists induce, at least in part, the acceleration of gastric emptying in rats via a peripheral mechanism, and that endogenous serotonin has an inhibitory regulatory effect on gastric emptying in rats. Furthermore, the difference in rank order between the accelerating effect of gastric emptying and the 5-HT3 receptor antagonistic potencies in the cortex suggests that the 5-HT3-like receptor, modulating gastric emptying, is not identical to the classically defined 5-HT3 receptor.

Animals↗