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T Sugaya

Publications and source records attributed to T Sugaya.

At least 55 records · Page 3Linked to original sources
PubMed1997

Bronchial anti-spasmogenic effects and selectivity of T-440, phosphodiesterase type 4 inhibitor, in the dog.

We investigated the selectivity of T-440 for the inhibition of phosphodiesterases (PDEs) in vitro and for bronchial anti-spasmogenic effects in vivo. Using a fast protein liquid chromatography system, five PDE isozymes, PDE 1, PDE 2, PDE 3, PDE 4 and PDE 5 were prepared from guinea pig and dog tissues. T-440 selectively inhibited PDE 4 with an IC50 of 0.071 microM and 0.13 microM for guinea pig lung and dog trachea, respectively. The IC50 values for all other PDE isozymes were over 20 microM. In contrast, theophylline nonselectively inhibited all the tested PDE isozymes, and the inhibition did not exceed 50%, even at 100 microM. T-440 inhibited the histamine-induced bronchoconstriction of anesthetized dogs in a dose-dependent manner with an ED50 of 0.029 mg/kg, indicating that T-440 is 600 times more potent than theophylline. Both T-440 and theophylline increased LV dp/dt/P (LVP; left ventricular pressure) in anesthetized dogs with ED50 values of 3.6 mg/kg and 4.4 mg/kg, respectively. This potency was 1/125 times the bronchial anti-spasmogenic effects for T-440 and 4.2 times that of theophylline. Rolipram, a PDE 4 inhibitor, also showed selective bronchial anti-spasmogenic effects in anesthetized dogs. These results suggest that T-440, which specifically inhibits PDE 4 activity, has potent and selective bronchial anti-spasmogenic effects.

Animals↗
PubMed1997

Location and action of angiotensin II type 1 receptor in the renal microcirculation.

To localize angiotensin II type 1a (AT-1a) receptor and to reveal the physiological roles of angiotensin II in the renal microcirculation, we investigated the AT-1a gene deficient mice, generated by a targeted replacement of the AT-1a receptor loci by the lacZ gene (Sugaya et al, J Biol Chem 270: 18719, 1995). Immunohistochemical localization of beta-galactosidase was performed in the heterozygous mutant mice to reveal the expression sites of AT-1a. The AT-1a receptor (that is, beta-galactosidase) was expressed both in the afferent and efferent arteriolar smooth muscles and also in the mesangial cells. The effect of angiotensin II on glomerular arterioles was directly observed using the hydronephrotic mice. Angiotensin II similarly constricted both the afferent and efferent arterioles in the wild-type and heterozygous mutant mice in a dose-dependent manner. This constriction was completely abolished by an AT-1 antagonist, CV-11974. In the homozygous null mutant mice, however, angiotensin II did not affect the arterioles at all. Electron microscopic studies revealed that the mesangial cells made contact with the glomerular basement membrane (GBM) at the capillary neck and also with each other in the wild-type mice. However, in the homozygous null mutant mice, the mesangial cells lost the contact either with GBM or with each other and thus the capillary neck became remarkably wider. The mesangial matrix area appeared loose and enlarged, suggesting impaired mesangial matrix formation. In conclusion, via the AT-1a receptor, angiotensin II equally constricts both the afferent and efferent arterioles and plays an essential role in maintaining the normal glomerular function and structure.

Angiotensin II↗
PubMed1996

Novel 5-aminoflavone derivatives as specific antitumor agents in breast cancer.

In the course of our search for new antitumor agents in breast cancer, novel amino-substituted flavone derivatives were synthesized and examined for antitumor activities. Among them, 5,4'-diaminoflavone and some of its congeners showed remarkable antiproliferative activity against the estrogen receptor (ER)-positive and estrogen-responsive human breast cancer cell line MCF-7. The activity was observed irrespective of the presence or absence of estrogen. The 5-aminoflavone derivatives (5-AFs) are not classical anti-estrogens because they did not compete with [3H]estradiol to bind the estrogen receptor. Moreover, 5-AFs showed antitumor activity highly selective to the ER-positive breast cancer cell line, and they showed no effects against the ER-negative human cancer cell lines HeLa S3, WiDr, and MDA-MB-453. Although the mechanism of their selective antitumor activity to ER-positive breast cancer cells is unclear, 5-AFs are expected to be a new type of antitumor agents in breast cancer.

Antineoplastic Agents↗
PubMed1996

Subcapsular hematoma of the liver and pylethrombosis in the setting of cholestatic liver injury.

We describe a subcapsular hematoma of the liver and pylethrombosis in a patient who developed cholestasis 4 days after severe burn injury. On the 44th hospital day, severe anemia suddenly appeared with no determinable cause. This was the initial manifestation of hepatic hematoma. Cholestatic liver injury of unknown cause lasted throughout the clinical course. The patient subsequently died of hepatic failure 27 months after the burn injury. An autopsy confirmed pylephlebitis and pylethrombosis, which were considered to have contributed to the hepatic failure. This was a rare case of hepatic hematoma and pylephlebitis and pylethrombosis that developed after burn injury.

Aged↗
PubMed1996

Sevoflurane and isoflurane impair edrophonium reversal of vecuronium-induced neuromuscular block.

PURPOSE: A dose-response relationship study for edrophonium to examine the modification of volatile anaesthetics on reversal of vecuronium block. METHODS: One hundred and twenty ASA (I-II) patients were anaesthetized with sevoflurane, isoflurane (1 minimum alveolar anaesthetic concentration [MAC] end-tidal concentration), or fentanyl-diazepam anaesthesia, in combination with 66% nitrous oxide (n = 40 for each group). The evoked electromyogram (EMG) response of the abductor digiti minimi was monitored at 20 sec intervals following train-of-four (TOF) stimulation of the ulnar nerve. The initial neuromuscular block was produced by vecuronium 100 micrograms.kg-1. When the amplitude of the first response (T1) had spontaneously recovered to 10% of the control, edrophonium (0, 125, 400, 700 or 1000 micrograms.kg-1; eight patients each) was randomly administered, and the ratio of the fourth TOF to the first response (TOFR) was monitored at one minute intervals for 10 min. RESULTS: Sevoflurane and isoflurane impaired the edrophonium-assisted TOFR recovery in an edrophonium dose and time dependent manner. The dose-response curves at 10 min exhibited a greater shift to the right in the sevoflurane and isoflurane groups than in the fentanyl-diazepam-nitrous oxide group (P < 0.05). Higher ED50 values (the edrophonium dose required to obtain TOFR value of 50%) in the sevoflurane (> 1000 micrograms.kg-1) and isoflurane groups (851 micrograms.kg-1) were observed than in the fentanyl-diazepam-nitrous oxide group (339 micrograms.kg-1) (P < 0.05). CONCLUSION: One MAC sevoflurane and isoflurane anaesthesia impair edrophonium reversal of vecuronium block to a similar degree.

Adult↗
PubMed1996

Hypertensive and hypotensive mice produced by the introduction and disruption of genes on the renin-angiotensin system.

We constructed in mice the chimeric renin-angiotensin cascade comprising human renin, human angiotensinogen, and the endogenous angiotensin-converting enzyme and angiotensin II (A II) receptors by crossmating separate lines of transgenic mice carrying either gene. Although hypertension did not develop in the single-gene carriers despite the observed tissue-specific expression of the transgenes, dual-gene strains exhibited a chronically sustained increase in blood pressure (BP). The systolic BP was 130 +/- 7 mmHg, which is about 30 mmHg higher than that of control mice. Administration of a selective antagonist directed at the A II receptor decreased the basal BP in both single-gene and dual-gene mice. In addition, we generated two lines of knockout mice by homologous recombination in mouse embryonic stem cells. One line consisted of angiotensionogen-deficient mice, which failed to produce angiotensinogen in the liver, resulting in the complete loss of plasma angiotensin 1. The systolic BP of the mice was 66.9 +/- 4.1 mmHg, significantly lower than that of the controls (100.4 +/- 4.4 mmHg). The second line consisted of A II-receptor type la-deficient mice, which also exhibited hypotension (24 mmHg lower than that of controls). These results demonstrated that the renin-angiotensin system plays an indispensable role in maintaining normal BP in vivo, and cannot be replaced by other hormonal and neuronal systems.

Animals↗
PubMed1995

Angiotensin II type 1a receptor-deficient mice with hypotension and hyperreninemia.

Angiotensin (AT) II, the bioactive octapeptide in the renin-angiotensin system that plays a key role in cardiovascular homeostasis, exerts its multiple effects through the different types of AT receptors, AT1a, AT1b, and AT2. Previously, we showed chronic hypotension in angiotensinogen (the precursor of AT)-deficient mice and a dramatic increase in renin mRNA levels in its kidney, but it remains unclear which types of AT receptors regulate the blood pressure and renin gene expression. In order to elucidate the physiological roles of AT1a receptor, we generated mutant mice with a targeted replacement of the AT1a receptor loci by the lacZ gene. In the heterozygous mutant mice, the strong lacZ staining was found in the glomerulus and juxtaglomerular apparatus of the renal cortex, which coincided with that of the signals detected by in situ hybridization. Chronic hypotension was observed in the heterozygous and homozygous mutant mice, with 10 and 22 mm Hg lower systolic blood pressure, respectively, than that of wild-type littermates. Both levels of renin mRNA in the kidney and plasma renin activity were markedly increased only in the homozygous mutant mice. These results demonstrated that an AT1a-mediated signal transduction pathway is, at least in part, involved in the regulation of blood pressure and renin gene expression.

Angiotensin II↗
PubMed1995

Inadequate antagonism of vecuronium-induced neuromuscular block by neostigmine during sevoflurane or isoflurane anesthesia.

To examine the effects of discontinuing sevoflurane or isoflurane anesthesia (1 minimum alveolar anesthetic concentration [MAC] of end-tidal concentrations, together with 66% N2O/O2) on the reversal of vecuronium-induced neuromuscular blockade (an initial dose = 100 micrograms/kg), the electromyographic response of the abductor digiti minimi was monitored at 20-s intervals after train-of-four (TOF) stimulation of the ulnar nerve in 192 ASA grades I and II patients. When the amplitudes of the first response (T1) had recovered to 10% of the control, neostigmine (0;spontaneous recovery, 10, 20, 30, 40, or 55 micrograms/kg, eight patients each) was given and the ratio of the fourth TOF to the first response (TOFR) was monitored at 1-min intervals for 15 min in the presence of the volatile anesthetics, or after discontinuation of anesthetic administration. Spontaneous TOFR recovery was also assessed in another eight patients who were anesthetized with 66% N2O/O2-fentanyl-diazepam. Adequate antagonisms (TOFR > 75%) were achieved after discontinuation of both administrations, but not during anesthetic administration at the neostigmine doses tested. The dose-response curves for neostigmine (10, 20, 30, and 40 micrograms/kg) were constructed using the TOFR values at 5-11 min, from which the ED50 values (a neostigmine dose required for a TOFR value of 50%) were derived. Sevoflurane impaired neostigmine antagonism more than isoflurane, as demonstrated by the significantly higher ED50 values at 7-11 min (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

[Atrophic gastritis in Sjögren's syndrome].

In patients with Sjögren's syndrome (SJS), it has been found that chronic atrophic gastritis is often associated with low HCl secretion or achlorhydria. However, the role of autoimmune injuring mechanism in the pathogenesis of the atrophic gastritis in SJS is unclear. In recent studies, Helicobacter pylori (HP) infection is accepted as the major cause of chronic gastritis. In our studies, HP infection was present in the half of SJS patients with atrophic gastritis. We also determined HP specific IgG antibody levels by enzyme-linked immunosorbent assay (ELISA). In SJS patients with gastric inflammatory cell infiltration, the IgG levels were high. We determined gastric parietal cell antibody (PCA) levels by ELISA, using a recombinant fusion protein of the alpha subunit of gastric H+, K(+)-ATPase. Our observation suggests that atrophic gastritis in SJS is caused by HP infection associated with gastric mucosal injury due to PCA.

Autoantibodies↗
PubMed1994

Isolation and characterization of two alternatively spliced complementary DNAs encoding a Xenopus laevis angiotensin II receptor.

We have isolated two cDNAs of 1.7 and 3.0 kb, produced by alternative splicing, that encode a angiotensin II (AII) receptor from a Xenopus laevis heart cDNA library. The two clones had identical coding regions with each other and were found to belong to the G protein-coupled receptor superfamily like the mammalian type 1 AII receptors (AT1); their amino acid sequence was 68.7% homologous with the human AT1 receptor sequence. However, there was a 1.3 kb insertion at the 3'-untranslated region of the longer clone. The insertion contained 9 repeats of an ATTTA motif, suggesting that the two mRNAs undergo distinct post-transcriptional regulation by virtue of a difference in their stability. Although the Xenopus receptor exhibited distinct specificities for AII receptor antagonists compared with mammalian AII receptors, several common characteristics, including the effect of dithiothreitol and guanosine 5'-O-(3-thiotriphosphate), demonstrated that the cloned receptor is a counterpart of the mammalian AT1 receptor. Moreover, the cloned receptor was expressed most abundantly in the Xenopus heart, which is inconsistent with the tissue distribution of mammalian AII receptors. This indicated that the Xenopus heart, unlike that of mammals, plays a major role in the AII-dependent regulation of blood pressure and extracellular fluid volume.

Alternative Splicing↗
PubMed1994

6H-pyrazolo[4,5,1-de]acridin-6-ones as a novel class of antitumor agents. Synthesis and biological activity.

The 7-substituted 6H-pyrazolo[4,5,1-de]acridin-6-ones with (aminoalkyl)amino and/or (hydroxyalkyl)amino groups in the side chains were synthesized by bromination using N-bromosuccinimide and the subsequent reaction with amines from the 7-substituted 5-bromo-2-methyl-6H-pyrazolo-[4,5,1-de]acridin-6-one. The substitution reaction of the amines with alkyl bromide (the C2 position) and aryl bromide (the C5 position) was accomplished by choosing the proper reaction conditions. These compounds show DNA intercalating ability in ethidium fluorescence assay and antiproliferative activity against Hela S3 cells. Impressive antitumor activity in vivo against murine P388 leukemia and murine sarcoma 180 solid tumor in mice was demonstrated for the 7-hydroxy analogs. In addition, some of these showed excellent antitumor activity against adriamycin-resistant murine P388 leukemia (P388/ADM) in mice.

Aminoacridines↗
PubMed1994

The effects of sevoflurane are similar to those of isoflurane on the neuromuscular block produced by vecuronium.

We have examined the interactions of 1 MAC of isoflurane and sevoflurane (and 66% nitrous oxide in oxygen) with vecuronium, using the EMG response of the abductor digiti minimi to train-of-four (TOF) stimulation of the ulnar nerve. We constructed dose-response curves for vecuronium in 54 patients. The curves for both isoflurane and sevoflurane had a significant leftward shift compared with that for fentanyl-nitrous oxide anaesthesia (P < 0.01). When the amplitudes of the first response (T1) had recovered to 50% of control in another 32 patients, subsequently we compared the spontaneous recovery rate of the ratio of the fourth to the first TOF response (T4:T1) at 3-min intervals during the 15-min period, in the presence of two volatile anaesthetics or after discontinuation of administration of anaesthetic. The rate of recovery of T4:T1 was significantly greater when both anaesthetics were discontinued. However, this rate was similar for both anaesthetics, suggesting that the mechanism of action of the two anaesthetics is similar.

Adult↗
PubMed1994

[Studies on angiotensin I converting enzyme (ACE): inhibitory effect of imidapril, a novel ACE inhibitor (II). Inhibition of various tissue ACEs ex vivo].

The antihypertensive mechanism of imidapril was investigated in relation to its inhibition of ACE activities in the serum, thoracic-abdominal aorta, lung, kidney, heart and brain from adult spontaneously hypertensive rats (SHRs). In comparison with normotensive rats (NTRs), the ACE activities in the aorta, heart, brain and lung were higher, while those in the serum and kidney were considerably lower. Imidapril (2 mg/kg) showed remarkable inhibitions within 6 hr in all tissues, except for the brain, after a single oral administration. Consecutive administration of imidapril (2 mg/kg/day) for 30 days produced inhibitions in all tissues. The inhibitions in the serum, aorta and lung were greater, and the duration of inhibition in the aorta, brain and lung were longer. Blood pressure declined gradually until 6 hr, and the reductions were significant at 24 hr after the single and chronic administrations. Imidapril (0.5 mg/kg, ineffective on normal blood pressure) inhibited ACE activities in NTRs similarly. Enalapril at the same dose exhibited less ACE inhibition and antihypertension. These results suggest that the ACE inhibition in the serum, lung and aorta by imidapril correlate with the antihypertension in SHRs; especially, the lung and vascular ACE inhibitions play an important role in the duration of antihypertension in SHRs.

Administration, Oral↗
PubMed1994

[Effects of volatile anesthetics on microtubule-associated protein 2 degradation during forebrain ischemia in the rat].

One of the most prominent phenomena that occurs during the early phase of cerebral ischemia has been shown to be the immunohistochemical collapse of cytoskeletal proteins. Among these, microtubule-associated protein 2 (MAP 2) has been shown to be vulnerable to ischemic injuries. In order to select a suitable volatile anaesthetic from the standpoint of cytoskeletal protein breakdown during cerebral ischemia, we compared the effect of isoflurane, halothane and sevoflurane on MAP 2 degradation during 20 min of forebrain ischemia in the rat. Under 1 MAC of three volatile anesthetics, forebrain ischemia was induced by the occlusion of the bilateral common carotid artery combined with a lowering of mean arterial pressure to 50 mmHg. Immediately after cerebral ischemia, four regions of the brain, the frontoparietal cortex, brainstem, hippocampus and cerebellum, were removed separately and homogenized. Subsequently, MAP 2 from each region was quantitatively measured using an enzyme-linked immunosorbent assay. MAP 2 in the frontoparietal cortex and hippocampus was significantly protected from degradation with isoflurane anaesthesia more than with halothane and sevoflurane anaesthesia.

Anesthetics, Inhalation↗
PubMed1993

Isoflurane reduces microtubule-associated protein 2 degradation compared with halothane during forebrain ischaemia in the rat.

One of the most prominent features of the early phase of cerebral ischaemia is the immunohistochemical collapse of cytoskeletal proteins. Among these proteins, microtubule-associated protein 2 (MtP2) has been shown to be vulnerable to ischaemic injuries. In order to identify a suitable volatile anaesthetic on the basis of cytoskeletal protein breakdown during cerebral ischaemia, we have compared the effects of isoflurane and halothane on MtP2 degradation in rats. Under equipotent isoflurane or halothane anaesthesia, forebrain ischaemia was induced by occlusion of the bilateral common carotid artery, combined with a decrease in mean arterial pressure to 50 mm Hg. After 20 min of ischaemia, the frontoparietal cortex, brainstem, hippocampus and cerebellum were removed separately and homogenized. MtP2 from each region was measured using an enzyme-linked immunosorbent assay. MtP2 degradation in the frontoparietal cortex and hippocampus was significantly (P < 0.05 and P < 0.01) less with isoflurane anaesthesia (75.6 (SD 10.7)% and 72.3 (12.8)%, respectively) than with halothane (65.0 (13.1)% and 54.7 (13.9)%, respectively).

Animals↗
PubMed1993

Enzymatic optical resolution of dibenzoxepins and its application to an optically active antiallergic agent with thromboxane A2 receptor antagonistic activity.

Methyl (+/-)-11-(2-hydroxyethyl)thio-6,11-dihydrodibenz[b,e]oxepin- 2- carboxylate (5) was enantio-selectively acylated with acetic anhydride in an organic medium by Lipase Amano P to give methyl (-)-11-(2-acetoxyethyl)thio-6,11-dihydrodibenz[b,e]oxepin-2- carboxylate (8), and the (+)-enantiomer by Lipase Sigma Type VII. Using Lipase Amano P, (+)- and (-)-(5) could be prepared with high optical purity (84-94% e.e.). These products were respectively converted to (+)- and (-)-KW-4099, which had antiallergic activity with complete retention of the optical purity.

Acylation↗
PubMed1992

[Studies on angiotensin I converting enzyme (ACE) inhibitory effect of imidapril. (I). Inhibition of various tissue ACEs in vitro].

Imidapril is a newly synthesized non-sulfhydryl-containing angiotensin I converting enzyme (ACE) inhibitor. The present study describes the inhibitory effects of imidapril and its active metabolite 6366A on ACEs from various tissues and compares its effects to those of captopril, enalapril and enalaprilat in vitro. 6366A inhibited swine renal and human serum ACEs with an inhibition constant (Ki) of 0.067 nM and 0.04 nM, respectively. These values were 3 to 18 times more potent than those of the other inhibitors. The kinetic study showed that 6366A exerted competitive type inhibition. The ACE inhibition (IC50 values) of 6366A, enalaprilat and the structurally related compounds (6366DM and 6366PY) were compared in homogenates of lung, aorta, heart, brain and kidney from spontaneously hypertensive rats (SHRs) and Wistar Kyoto rats (WKYs). The inhibitory effects of 6366A on all tissue ACEs from SHRs and WKYs were the most potent among these compounds. And the inhibitory potencies of these compounds were correlated with their chemical structure. The present results suggest that 6366A may show a strong inhibitory effect on ACEs from several tissues and species due to its chemical characteristics.

Angiotensin-Converting Enzyme Inhibitors↗