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K Aisaka

Publications and source records attributed to K Aisaka.

At least 37 records · Page 2Linked to original sources
PubMed2000

Distribution of alpha1L-adrenoceptors in canine prostate: characterization by quantitative autoradiography.

Our aim was to determine the distribution of alpha1L-adrenoceptors in canine prostate by an autoradiographic technique using [3H]JTH-601 (an alpha1L-adrenoceptor antagonist) and [3H]JTH-601-G1 (an active metabolite of JTH-601). Prostates were removed from three male beagle dogs. Several slices of the specimens were incubated with 5 nM of [3H]JTH-601, [3H]JTH-601-G1 and [3H]tamsulosin (an alpha1A-adrenoceptor antagonist). For macroscopic autoradiography, visualization was performed using an imaging plate and image-analyser. To examine microscopic localization of binding sites, preparations were exposed, developed and fixed. Specific binding of [3H]JTH-601 and [3H]JTH-601-G1 was observed diffusely throughout the entire interstitium on macroscopic autoradiography. Specific binding of [3H]tamsulosin was also recognized although the binding was weaker than that of [3H]JTH-601. On microscopic autoradiograms, the grains of each ligand were mainly distributed on smooth muscle. These results indicate morphologically that specific binding sites of JTH-601 and JTH-601-G1 exist in canine prostate, suggesting the distribution of alpha1L-adrenoceptors in this tissue, in addition to alpha1A-adrenoceptors.

Adrenergic alpha-Antagonists↗
PubMed2000

Disposition and alpha(1)-adrenoceptor binding characteristics of JTH-601 and its metabolites in rat tissues.

The present study was performed to characterize the disposition and alpha(1)-adrenoceptor binding of JTH-601, a novel alpha(1L)-adrenoceptor antagonist, and its metabolites (beta-D-glucopyranosyl uronic acid, JTH-601-G1; hydrogen sulfate, JTH-601-S1) in the rat prostate and other tissues. JTH-601, JTH-601-G1, and JTH-601-S1 inhibited competitively specific [(3)H]tamsulosin binding in the prostate, submaxillary gland, and spleen of rats in vitro, and the inhibitory effect of JTH-601 was 2. 5 to 6.4 times more potent than that of its metabolites. JTH-601 and its metabolites inhibited dose dependently in vivo specific [(3)H]tamsulosin binding in the particulate fraction of the prostate, aorta, submaxillary gland, and spleen of rats. Compared with that of JTH-601, the in vivo inhibitory effect of JTH-601-G1 was 1.9 to 2. 9 times more potent, and the effect of JTH-601-S1 was 1.3 to 3.2 times less potent. Based on the ratios of ID(50) values, JTH-601 and JTH-601-G1 appeared to be 4.0 to 6.9 times more selective than prazosin as far as the alpha(1)-adrenoceptors in the prostate and submaxillary gland versus the spleen or aorta were concerned. The total radioactivity in rat tissues after i.v. injection of [(3)H]JTH-601-G1 was considerably lower than that of [(3)H]JTH-601. The plasma concentration of [(3)H]JTH-601-G1 at 10 min after i.v. injection in rats was 3 times higher than that of [(3)H]JTH-601, and conversely, the concentration in the prostate was 3 times lower. Although in vivo [(3)H]JTH-601-G1 binding at 10 min was significantly lower than that of [(3)H]JTH-601 in most rat tissues, there was comparable binding between these radioligands in the prostate and vas deferens. Specific binding of [(3)H]JTH-601, at 60 min after i.v. injection compared with that at 10 min, was considerably reduced in rat tissues except the prostate and vas deferens, both of which showed relatively sustained binding. In conclusion, the present study has shown that JTH-601 and its metabolites bind to alpha(1)-adrenoceptors in rat tissues in vivo and that JTH-601-G1 retains the prostatic alpha(1)-adrenoceptor subtype selectivity of its parent compound.

Adrenergic alpha-Antagonists↗
PubMed1999

Effect of JTH-601, a novel alpha1-adrenoceptor antagonist, on the function of lower urinary tract and blood pressure.

In the present study, we investigated the effect of JTH-601 (3-{N-[2-(4-hydroxy-2-isopropyl-5-methylphenoxy)ethyl]-N-methylaminomethyl}-4-methoxy-2,5,6-trimethylphenol hemifumarate), a novel alpha1-adrenoceptor antagonist, in vitro and in vivo. JTH-601 (10(-9)-3 x 10(-8) M) competitively antagonized phenylephrine-induced contraction in lower urinary tract tissues (prostate, urethra and bladder trigon) in a concentration-dependent manner. The mean pA2 values for JTH-601 were 8.59+/-0.14, 8.74+/-0.09 and 8.77+/-0.11 for prostate, urethra and bladder trigon, respectively. In anesthetized rabbits, intraduodenal administration of JTH-601 (0.3-3 mg/kg), prazosin (0.03-0.3 mg/kg) and tamsulosin (0.03-0.3 mg/kg) dose dependently inhibited the phenylephrine-induced increase in urethral pressure for 3 h. Although these drugs also decreased mean blood pressure, JTH-601 was less potent than prazosin or tamsulosin. In conscious rabbits, administered JTH-601 (0.01-1 mg/kg, i.v.) had a tendency to augment orthostatic hypotension, but dose dependency was not evident. Prazosin (0.01-1 mg/kg) and tamsulosin (0.001-1 mg/kg) dose dependently augmented orthostatic hypotension. These results indicate that JTH-601 antagonized alpha1-adrenoceptor-mediated contractile responses more potently than prazosin or tamsulosin in rabbit lower urinary tract both in vitro and in vivo. JTH-601 is therefore expected to be effective in the treatment of urinary outlet obstruction in benign prostatic hypertrophy.

Adrenergic alpha-Antagonists↗
PubMed1999

Effects of red blood cells on the coagulation of blood in normal and preeclamptic pregnancies.

OBJECTIVE: The objective of this study was to determine the cellular effects of whole blood, especially of red blood cells, on the hypercoagulability of blood from patients with preeclampsia. STUDY DESIGN: The time elapsed between mixing and the onset of coagulation was measured by means of a highly sensitive rheometer for whole blood, platelet-rich plasma (in which red blood cells had been removed from whole blood), and platelet-free plasma from 3 groups of subjects: 25 nonpregnant women, 25 women with normal pregnancies, and 10 patients with preeclampsia. RESULTS: Time to coagulation for whole blood from patients with preeclampsia was significantly shorter than that for whole blood from women with normal pregnancies. However, there was no significant difference in time to coagulation for platelet-rich plasma between women with preeclampsia and those with normal pregnancies. CONCLUSION: Hypercoagulability of blood in preeclampsia appears to be strongly related to red blood cell alterations.

Adult↗
PubMed1999

The role of alpha 1L-adrenoceptor in rat urinary bladder: comparison between young adult and aged rats.

We examined the role of the alpha1L-adrenoceptors in the urinary bladder of young adult and aged rats in vitro. In the isolated body of the urinary bladder (corpus vesicae), phenylephrine-induced contractions were significantly facilitated in aged rats. Either prazosin, a non-selective alpha1-adrenoceptor antagonist, or JTH-601, an alpha1L-adrenoceptor antagonist, competitively inhibited the phenylephrine-induced contraction of isolated body of the urinary bladder. The antagonistic effect of JTH-601 was almost equipotent between young adult and aged rats (pA2 values were 9.61+/-0.12 and 9.79+/-0.07, respectively), although a statistically significant difference was noted for that of prazosin (pA2 values were 9.49+/-0.09 and 9.19+/-0.06, respectively). In macroscopic autoradiographic studies, specific binding of [3H]JTH-601 (5nM) was seen widely in the muscle layer of urinary bladder, but no differences were noted between young adult and aged rats. In the present study, there was no evidence to suggest a role of the alpha1L-adrenoceptors in the body of rat urinary bladder. On the other hand, alpha1A-adrenoceptors may play an important role in an age-related increase of alpha1-adrenoceptors response in this tissue. These results suggest that a facilitation of contractile response mediated by alpha1A-adrenoceptors may be a cause of unstable bladder in aged persons.

Adrenergic alpha-Agonists↗
PubMed1999

Age-related change of the role of alpha1L-adrenoceptor in canine urethral smooth muscle.

To examine age-related alteration of the role of alpha1L-adrenoceptor in the urethra, young non-parous and aged parous female dogs were used. In a functional study, we evaluated phenylephrine-induced contraction and antagonistic effects of JTH-601, a newly synthesized alpha1-adrenoceptor antagonist, and prazosin; in a localization survey using autoradiographic technique, we investigated specific [3H]JTH-601 and [3H]tamsulosin binding. Concentration-response curves were obtained for phenylephrine (pD2 = 5.0-5.3). JTH-601 and prazosin antagonized this contraction with pA2 values of 8.2-8.3 and 8.0-8.1, respectively. Specific binding of both [3H]JTH-601 and [3H]tamsulosin were observed in the bladder neck and proximal section of urethra. There were no significant differences of the pD2, pA2, and radio ligand binding between young non-parous and aged parous dogs.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed1999

Effects of the new potassium channel opener JTV-506 on coronary vessels in vitro and in vivo.

The vascular effects of JTV-506 ((-)-(3S,4R)-2.2-bis(methoxymethyl)- 4-[(1,6-dihydro-l-methyl-6-oxo-3-pyridazinyl)amino]-3-hydroxychroman+ ++-6- carbonitrile hemihydrate, CAS 170148-29-5), a new potassium channel opener, was evaluated in isolated coronary arteries and anesthetized dogs. JTV-506 (1 nmol/l-3 mumol/l) produced a concentration-dependent relaxation in porcine isolated epicardial large coronary arteries precontracted with KCl (30 mmol/l), phenylephrine (3 mumol/l), histamine (3 mumol/l), serotonin (5-HT; 300 nmol/l), prostaglandin F2 alpha (PGF2 alpha; 10 mumol/l), U-46619 (100 nmol/l), endothelin-1 (ET-1; 30 nmol/l) and Bay K-8644 (100 nmol/l). JTV-506 was 2.5-8.5 and 13.3-81.5 times more potent than levcromakalim (CAS 94535-50-9) and nicorandil (CAS 65141-46-0), respectively, but was less potent than nifedipine (CAS 21829-25-4). JTV-506 and levcromakalim produced almost a complete relaxation in arteries precontracted with various kinds of vasoconstrictor, except for KCl. In contrast, nifedipine produced about 80-90% relaxation in arteries, precontracted with PGF2 alpha, U-46619 and ET-1. Thus, this potassium channel opener can be characterized as an agonist-nonselective vasorelaxant. The relaxing effects of JTV-506 and levcromakalim on coronary arteries precontracted with 30 mmol/l KCl was competitively antagonized by 3 mumol/l glibenclamide, an ATP-sensitive potassium (KATP) channel blocker. In canine isolated epicardial large coronary arteries, 10 mumol/l JTV-506, 10 mumol/l levcromakalim, 100 mumol/l nicorandil and 0.1 mumol/l nifedipine eliminated 10 mmol/l 3,4-diaminopyridine-induced rhythmic contractions. In anesthetized dogs, when administered directly into the coronary artery, JTV-506 induced dose-dependent increases in coronary arterial diameter and coronary blood flow. These results suggest that JTV-506 elicits coronary vasorelaxation through activation of the KATP channel. It is expected that JTV-506 might be useful in the treatment of coronary vasospasm in angina pectoris.

Anesthesia↗
PubMed1999

Ex vivo and in vivo alpha1-adrenoceptor binding characteristics of a novel alpha1L-adrenoceptor antagonist, JTH-601, in rat tissues.

In vitro, ex vivo and in vivo alpha1-adrenoceptor binding of JTH-601 (3-[N-[2-(4-hydroxy-2-isopropyl-5-methylphenoxy)ethyl]-N-methylaminometh yl]-4-methoxy-2,5,6-trimethyl-phenol hemifumarate), a novel alpha1L-adrenoceptor antagonist, in rat tissues was investigated. JTH-601 competed in a concentration-dependent manner with [3H]prazosin for binding sites in the prostate, submaxillary gland and spleen of rats in vitro, and the inhibitory effect was not largely different among these tissues, as shown by the Ki values of 2-3 nM. At 0.25, 0.5 and 3 h after oral administration of JTH-601 (6.5 micromol/kg) in rats, there was a significant (57, 64 and 28%, respectively) increase in the apparent dissociation constant (Kd) for prostatic [3H]prazosin binding, compared to the control value. The administration of a higher dose (21.8 micromol/kg) of this agent produced greater (67-99%) increases in Kd values for prostatic [3H]prazosin binding at 0.5-12 h later. Similar significant increases in Kd values, as with the prostate, were seen in the submaxillary gland and heart 0.25-12 h after the oral administration of JTH-601 (6.5 and 21.8 micromol/kg), but significant increases in the spleen and cerebral cortex were seen only at 0.25-3 h and 0.5 h, respectively. At 10 min of i.v. injection of [3H]JTH-601 in rats, in vivo specific binding was observed in the prostate, cerebral cortex, submaxillary gland, spleen and heart but not in the aorta. The binding in the prostate, submaxillary gland and heart, but not in the cerebral cortex and spleen, lasted until 120 min. It is concluded that JTH-601 may exert a considerably sustained blockade of alpha1-adrenoceptors in the prostate of rats. This finding may be important in characterizing the therapeutic effect of JTH-601 for bladder outlet obstruction in patients with benign prostatic hyperplasia.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed1998

Effect of JTV-506, a novel vasodilator, on experimental angina model in rats.

The antianginal effects of JTV-506, a newly synthesized 2,2-bis-methoxymethyl benzopyran-derivative potassium channel opener, were evaluated in experimental angina models in rats and compared with those of levcromakalim, nicorandil, and nifedipine. JTV-506 (0.01-0.1 mg/kg, i.d.) dose-dependently inhibited S-wave elevation induced by injection of methacholine but caused almost no changes in blood pressure or heart rate. Other vasodilators including levcromakalim, nicorandil, and nifedipine, when administered intraduodenally, also inhibited the S-wave elevation and elicited a decrease in blood pressure. Oral administration of JTV-506 (1 and 3 mg/kg), levcromakalim (1 and 3 mg/kg), and nicorandil (30 mg/kg) significantly inhibited the S-wave depression induced by intravenous administration of arginine vasopressin (AVP). Thus JTV-506 exerts a potent protective effect on angina pectoris models to an extent similar to those of levcromakalim, nicorandil, and nifedipine, whereas its action on systemic blood pressure is different from that of other vasodilators, including reference potassium channel openers. These results suggest that JTV-506 may clinically be useful as an antianginal agent.

Administration, Oral↗
PubMed1998

Purification and characterization of trehalose phosphorylase from Catellatospora ferruginea.

Trehalose phosphorylase was purified from the cell extracts of Catellatospora ferruginea. The enzyme had an apparent molecular weight of 400,000 by gel filtration and 98,000 by SDS-PAGE, suggesting that the enzyme was a tetramer. The enzyme was specific for trehalose in phosphorolysis and specific for beta-D-glucose 1-phosphate in synthesis. In addition to D-glucose, D-xylose and D-fucose were also possible sugar acceptors during synthesis. Phosphate ions were a key to the activity and stability of the enzyme, controlling the equilibrium of the reversible reaction and the heat stability of the enzyme. The enzyme was strongly inhibited by p-chloromercuribenzoate and pyridoxal phosphate. The enzyme was inactivated by heat or by storage frozen with ammonium chloride and lithium chloride.

Actinomycetaceae↗
PubMed1997

Human PEG1/MEST, an imprinted gene on chromosome 7.

The mouse Peg1/Mest gene is an imprinted gene that is expressed particularly in mesodermal tissues in early embryonic stages. It was the most abundant imprinted gene among eight paternally expressed genes (Peg 1-8) isolated by a subtraction-hybridization method from a mouse embryonal cDNA library. It has been mapped to proximal mouse chromosome 6, maternal duplication of which causes early embryonic lethality. The human chromosomal region that shares syntenic homology with this is 7q21-qter, and human maternal uniparental disomy 7 (UPD 7) causes apparent growth deficiency and slight morphological abnormalities. Therefore, at least one paternally expressed imprinted gene seems to be present in this region. In this report, we demonstrate that human PEG1/MEST is an imprinted gene expressed from a paternal allele and located on chromosome 7q31-34, near D7S649. It is the first imprinted gene mapped to human chromosome 7 and a candidate for a gene responsible for primordial growth retardation including Silver-Russell syndrome (SRS).

Animals↗
PubMed1997

Effect of JTV-506, a novel vasodilator, on coronary blood flow in conscious dogs.

Coronary vasodilator and hemodynamic profiles of JTV-506, a newly synthesized 2,2-bis-methoxymethyl benzopyran-derivative potassium channel opener, were evaluated in conscious dogs. JTV-506 (2.5-10 microg/kg, i.v.) elicited dose-dependent increases in coronary blood flow (CBF) and heart rate (HR) but only slight changes in mean blood pressure (MBP). Other vasodilators such as levcromakalim, nicorandil, diltiazem, and nitroglycerin, when administered intravenously, elicited increases in CBF and HR and a decrease in MBP. When dosed orally JTV-506 (0.01-0.1 mg/kg), levcromakalim (0.01-0.1 mg/kg), nicorandil (1-10 mg/kg), and nifedipine (3-30 mg/kg) also elicited increases in CBF and HR and a decrease in MBP. JTV-506 caused a marked increase in CBF with slight changes in HR and MBP. In contrast to JTV-506, however, the changes caused by levcromakalim, nicorandil, and nifedipine were accompanied by a marked increase in HR and a marked decrease in MBP. These results suggest that the action of JTV-506 on hemodynamics is different from that of other vasodilators, including reference potassium channel openers, and that the profile of cardiovascular action of JTV-506 may be useful in the treatment of angina pectoris.

Administration, Oral↗
PubMed1997

[Female sterility].

Recent progress in female sterility of Japanese women is reported in this study. The causes of sterility in the female side, the most popular sterile factor is a tubal factor due to the increase of the endometriosis and pelvic inflammatory disease. The main treatment of the tubal factor is an IVF-ET technique. The ovulatory disturbances occupy the second position of the female sterile factor. The precise endocrinological examinations must be done for the diagnosis of the ovulatory disturbances. In case of the hypergonadotropic hypogonadism, the ovulation induction is almost impossible. Generally, clomiphene citrate is used for moderate hypothalamic anovulations, and bromocriptine or terguride is for prolactin related diseases (hyperprolactinemia, occult hyperprolactinemia, galactorrhea) and endocrinological PCO (LH/FSH > 1) in the beginning. If these treatments are not effective, hMG-hCG therapy will be performed. During hMG-hCG therapy, we must take care for the occurrence of the ovarian hyperstimulation syndrome. For the treatment toward the cervical factor, the artificial insemination with husband semen will be done, however, if it is not effective, IVF-ET must be performed. For the uterine factor (such as after hysterectomy state, adhesion of uterine cavity, etc.) surrogate mothers are hired in some foreign countries, however, it is prohibited in Japan. If patients have anti-phospholipid antibodies, low dose aspirin and/or heparin administration will be done for the treatment of infertility. Recently, the assisted reproductive technology (ART) have made much progress. IVF-ET is performed widely in Japan. Cryopreservation of the fertilized ovum and intracytoplasmic sperm injection (ICSI) are also performed. However, the legal and ethical problems are occurring, and much discussion must be done for the acceptance of such new technologies.

Anovulation↗
PubMed1996

Synthesis and selective coronary vasodilatory activity of 3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol derivatives: novel potassium channel openers.

A variety of compounds having a benzopyran such as levcromakalim generally exhibit potent antihypertensive activity. During extensive investigations aimed toward identifying K+ channel openers having selective coronary vasodilation without potent hypotensive and tachycardiac effects, we synthesized a series of 3,4-dihydro-2H-1-benzopyran-3-ol derivatives modified at positions 2, 4, and 6 in the benzopyran ring. Initially, compounds having two methoxymethyl groups at position 2 were found to show a selective effect on coronary blood flow (CoBF) relative to mean arterial pressure (MAP) in anesthetized dogs. To find more potent vasodilators, various benzopyran derivatives modified at position 4 were synthesized and structure-activity relationships were examined by evaluation of the extent and duration of the increase in CoBF in anesthetized dogs. As a result, compounds having a (1,6-dihydro-6-oxopyridazin-3-yl)amino group at position 4, in addition to the two methoxymethyl groups at position 2, were found to be more potent and to have an improved duration of action. Among these compounds, JTV-506, (-)-(3S,4R)-6-cyano-3,4-dihydro-4-[(1,6-dihydro-1-methyl-6-oxopyridaz in-3-yl)amino]-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol, exhibited good selectivity for its effect. Administration of this compound (0.03 mg/kg, p.o.) elicited an increase of CoBF without a change of systemic blood pressure and heart rate (HR) in conscious dogs. Further evaluation was performed with respect to (i) the selectivity of its action on the coronary artery versus the aorta and (ii) its effects on MAP, HR, and electrocardiographic ST elevation. As a result, JTV-506 was selected as a potent and selective coronary vasodilator with various pharmacological features favoring clinical development.

Animals↗
PubMed1996

Substitutions of Ser for Asn-163 and Pro for Leu-264 are important for stabilization of lipase from Pseudomonas aeruginosa.

The lipase gene from Pseudomonas aeruginosa was randomly mutated by error-prone PCR to obtain thermostable mutants, followed by screening for thermostable mutant lipases. Out of about 2,600 transformants, four thermostable clones were obtained. Their nucleotide sequences showed that they had two or three amino acid substitutions. Analysis of the thermal stabilization of these mutant lipases indicated that Asn-163 to Ser and Leu-264 to Pro mutations were essential for the increased stability of the lipase. We expressed a mutant lipase (StLipA-5) having only the Asn-163 to Ser mutation and another (StLipA-6) having only the Leu-264 to Pro mutation in P. aeruginosa PAO1161, purified them, and then confirmed that the temperature which causes a 50% decrease in the activity of the non-treated enzyme on treatment for 30 min was increased by 1.5 and 3 degrees C, respectively, compared to the wild-type enzyme. However, the thermal stability of the mutant lipase (StLipA-7) having both mutations was increased only by 2.5 degrees C. These mutant lipases were stabilized through a decrease in activation entropy. Kinetic studies showed that the Kcat/K(m) values of StLipA-5, StLipA-6, and StLipA-7 were decreased by 14.4, 52.9, and 26.0%, respectively. Interestingly, the pH-stabilities of StLipA-6 and StLipA-7 were also increased, especially at alkaline pH. Based on these results, the tertiary structure and mechanism of stabilization of the lipase were discussed.

Aspartic Acid↗
PubMed1996

Acetylpolyamine amidohydrolase from Mycoplana ramosa: gene cloning and characterization of the metal-substituted enzyme.

We have cloned a gene (aphA) encoding acetylpolyamine amidohydrolase from Mycoplana ramosa ATCC 49678, (previously named Mycoplana bullata). A genomic library of M. ramosa was screened with an oligonucleotide probe designed from a N-terminal amino acid sequence of the enzyme purified from M. ramosa. Nucleotide sequence analysis revealed an open reading frame of 1,023 bp which encodes a polypeptide with a molecular mass of 36,337 Da. This is the first report of the structure of acetylpolyamine amidohydrolase. The aphA gene was subcloned under the control of the trc promoter and was expressed in Escherichia coli MM294. The recombinant enzyme was purified, and the enzymatic properties were characterized. Substrate specificities, Km values, and Vmax values were identical to those of the native enzyme purified from M. ramosa. In the analysis of the metal-substituted enzymes, we found that the acid limb of pH rate profiles shifts from 7.2 for the original zinc enzyme to 6.6 for the cobalt enzyme. This change suggests that the zinc atom is essential for the catalytic activity of the enzyme similarly to the zinc atom in carboxypeptidase A.

Actinomycetales↗