Language：English   Publishing type：Research paper (scientific journal)  

The response of basilar arteries to noradrenaline varies among many animal species, but remains little studied in poultry. Accordingly, we aimed to characterize the adrenergic receptor (AR) subtypes that modulate vascular response in basilar arteries in the chicken, with isometric recording of arterial ring tension using an organ bath. We demonstrated the presence of both alpha and beta (α and β) receptor subtypes through evaluating the response to noradrenaline, with and without a range of β-AR and α-AR antagonists. The concentration-dependent relaxations then induced by a range of β-AR agonists indicated a potency ranking of isoproterenol > noradrenaline > adrenaline > procaterol. We then investigated the effects of β-AR antagonists that attenuate the effect of isoproterenol (propranolol for β1,2,3-ARs, atenolol for β1-ARs, butoxamine for β2-ARs, and SR 59230A for β3-ARs), with Schild regression analysis, ascertaining multiple β-AR subtypes, with neither the β1-AR nor the β2-AR as the dominant subtype. SR 59230A was the only antagonist to yield a pA2 value (7.52) close to the reported equivalent for the relevant receptor subtype. Furthermore, treatment with SR 58611 (a β3-AR agonist) induced relaxation, which was inhibited (P < 0.01) by L-NNA and SR 59230A. Additionally, treating basilar arterial strips (containing endothelium) with SR 58611 induced nitric oxide (NO) production, which was inhibited (P < 0.01) by L-NNA and SR 59230A. Based on this first characterization of AR subtypes in chicken basilar arteries (to our knowledge), we suggest that α- and β-ARs are involved in contraction and relaxation, and that β3-ARs, especially those on the endothelium, may play an important role in vasodilation via NO release.

DOI： 10.1016/j.psj.2023.102633

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Language：English   Publishing type：Research paper (scientific journal)  

Cytochromes P450 (P450s or CYPs) are important drug-metabolizing enzymes. Because dogs are frequently used in drug metabolism studies, knowledge of dog CYP2C enzymes is essential because in humans these enzymes are abundant and play major roles in liver and intestine. The present study identified and characterized novel dog CYP2C94 along with previously identified dog CYP2C21 and CYP2C41. Dog CYP2C21, CYP2C41, and CYP2C94 cDNAs, respectively, contained open reading frames of 490, 489, and 496 amino acids and shared high-sequence identities (70%, 75%, and 58%) with human CYP2Cs. Dog CYP2C94 mRNA was preferentially expressed in liver, just as dog CYP2C21 and CYP2C41 mRNAs were. In dog liver, CYP2C21 mRNA was the most abundant, followed by CYP2C94 and CYP2C41 mRNAs. Moreover, the hepatic expressions of all three dog CYP2C mRNAs varied in four individual dogs, two of which did not express CYP2C41 mRNA. The three dog CYP2C genes had similar gene structures, and CYP2C94, although located on the same chromosome, was in a genomic region far from the gene cluster containing CYP2C21 and CYP2C41 Metabolic assays with recombinant proteins showed that dog CYP2C94, along with CYP2C21 and CYP2C41, efficiently catalyzed oxidations of diclofenac, warfarin, and/or omeprazole, indicating that dog CYP2C94 is a functional enzyme. Novel dog CYP2C94 is expressed abundantly in liver and encodes a functional enzyme that metabolizes human CYP2C substrates; it is, therefore, likely responsible for drug clearances in dogs. SIGNIFICANCE STATEMENT: Novel dog cytochrome P450 2C94 (CYP2C94) was identified and characterized along with dog CYP2C21 and CYP2C41. Dog CYP2C94, isolated from liver, had 58% sequence identity and a close phylogenetic relationship with its human homologs and was expressed in liver at the mRNA level. Dog CYP2C94 (and CYP2C21 and CYP2C41) catalyzed oxidations of diclofenac and omeprazole, human CYP2C9 and CYP2C19 substrates, respectively, but CYP2C41 also hydroxylated warfarin. CYP2C94 is therefore a functional drug-metabolizing enzyme likely responsible for drug clearances in dogs.

DOI： 10.1124/dmd.122.001236

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Language：English   Publishing type：Research paper (scientific journal)  

People who drink naturally hardened water may experience longevity-enhancing effects. In this study, we investigated water hardness and longevity from both geological and epidemiological perspectives in Japan's Amami islands, where drinking water is drawn from coralline or non-coralline bedrock. We investigated drinking water hardness, limestone bedrock occupancy, and the centenarian rate (number per 10,000 population) by municipality across four adjacent islands (Amami-Oshima (non-coralline), Tokunoshima, Okinoerabu, and Yoron (predominantly coralline)). Limestone was strongly correlated with water hardness (r = 0.99; p < 0.01), occupying more than 80% of the bedrock where the water was the hardest (Tokunoshima's Isen municipality: 86.5%; Yoron: 82.9%) and being scarcely detectable in Amami-Oshima (0.0 to 0.2%), where the water was the least hard. The centenarian rate was also strongly correlated with water hardness (r = 0.84, p < 0.01), with the highest figures in Yoron (29.7) and Isen (29.2), and the lowest in Amami-Oshima (0.0 to 12.2). Therefore, we hypothesize a potentially beneficial effect of hard water on longevity when that water is drawn from coralline limestone. Water hardness is determined by the water content of calcium and magnesium and may plausibly influence life expectancy through a preventative effect against cardiovascular disease. Our findings are of interest to current debates about future global access to drinking water and its quality.

DOI： 10.3390/nu15071569

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Language：English   Publishing type：Research paper (scientific journal)  

Pigs are an important species used in drug metabolism studies; however, the cytochromes P450 (P450s or CYPs) have not been fully investigated in pigs.In this study, pig CYP2C32, CYP2C33, CYP2C34, CYP2C36, CYP2C42, and CYP2C49 cDNAs were isolated and found to contain open reading frames of 490 or 494 amino acids that shared 64-82% sequence identity with human CYP2C8/9/18/19.Pig CYP2C genes formed a gene cluster in a genomic region that corresponded to that of the human CYP2C cluster; an additional gene cluster was formed by pig CYP2C33a and CYP2C33b distant from the first cluster but located in the same chromosome.Among the tissues analysed, these pig CYP2C mRNAs were preferentially expressed in liver, small intestine, and/or kidney; pig CYP2C49, CYP2C32, CYP2C34, and CYP2C33 mRNAs were the most abundant CYP2C mRNAs in liver, jejunum, ileum, and kidney, respectively.Metabolic assays showed that pig CYP2C proteins (heterologously expressed in Escherichia coli) metabolised typical human CYP2C substrates diclofenac, warfarin, and/or omeprazole.The results suggest that these pig CYP2Cs are functional enzymes able to metabolise human CYP2C substrates in liver and small intestine, just as human CYP2Cs do.

DOI： 10.1080/00498254.2022.2148139

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Language：Japanese   Publishing type：Research paper (scientific journal)  

Arylamine N-acetyltransferases (NATs) are drug-metabolizing enzymes that are essential for the metabolism of endogenous substrates and xenobiotics. The molecular characteristics of NATs have been extensively investigated in humans but remain to be investigated in common marmosets and pigs, animal species that are often used in drug metabolism studies. In this study, marmoset NAT1 and pig NAT1 cDNAs were isolated from liver samples and were characterized by molecular analyses and drug-metabolism assays. These NAT genes were intronless and formed gene clusters with one other NAT gene in the genome, just as human NAT genes do. Marmoset NAT1 and pig NAT1 amino acid sequences showed high sequence identities (94% and 85%, respectively) to human NAT1. Phylogenetic analysis indicated that marmoset NAT1 and pig NAT1 were more closely clustered with human NATs than with rat or mouse NATs. Marmoset NAT1 and pig NAT1 mRNAs were expressed in all the tissue types analyzed, with the expression levels being highest in the small intestine. Metabolic assays using recombinant proteins found that marmoset NAT1 and pig NAT1 metabolized human NAT substrates p-aminobenzoic acid, 2-aminofluorene, sulfamethazine, and isoniazid. Marmoset NAT1 and pig NAT1 substantially acetylated p-aminobenzoic acid and 2-aminofluorene relevant human NAT1, but their activities were lower toward sulfamethazine and isoniazid than those of the relevant human NAT2. Therefore, marmoset and pig NATs are functional enzymes with molecular similarities to human NAT1, but their substrate specificities, while similar to human NAT1, differ somewhat from human NAT2. SIGNIFICANCE STATEMENT: Marmoset N-acetyltransferase NAT1 and pig NAT1 were identified and showed high sequence identities to human NAT1. These NAT mRNAs were expressed in various tissues. Marmoset and pig NAT1s acetylated typical human NAT substrates, although their substrate specificities differed somewhat from human NAT2. Marmoset NAT1 and pig NAT1 have similarities with human NAT1 in terms of molecular and enzymatic characteristics.

DOI： 10.1124/dmd.122.000919

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Language：Japanese   Publishing type：Research paper (scientific journal)  

Cytochrome P450s (P450s) have been identified and analyzed in dogs and pigs, species that are often used in preclinical drug studies. Moreover, P450s are clinically important for drug therapy not only in humans, but also in species under veterinary care, including dogs and cats. In the present study, seven P450s homologous to human CYP2J2, namely, dog CYP2J2; cat CYP2J2; and pig CYP2J33, CYP2J35, CYP2J91, and CYP2J93, were newly identified and characterized, along with pig CYP2J34 previously identified. The cDNAs of these CYP2Js contain open reading frames of 502 amino acids, except for CYP2J35 (498 amino acids), and share high sequence identity (77%-80%) with human CYP2J2. Phylogenetic analysis revealed that dog and cat CYP2J2 were closely related, whereas pig CYP2Js formed a cluster. All seven CYP2J genes contain nine coding exons and are located in corresponding genomic regions, with the pig CYP2J genes forming a gene cluster. These CYP2J2 mRNAs were predominantly expressed in the small intestine with additional expression in the kidney and brain for dog CYP2J2 and pig CYP2J91 mRNAs, respectively. All seven CYP2Js metabolized human CYP2J2 substrates terfenadine, ebastine, and astemizole, indicating that they are functional enzymes. Dog CYP2J2 and pig CYP2J34 and CYP2J35 efficiently catalyzed ebastine primary hydroxylation and secondary carebastine formation at low substrate concentrations, just as human CYP2J2 does. Velocity-versus-substate plots exhibited sigmoidal relationships for dog CYP2J2, cat CYP2J2, and pig CYP2J33, indicating allosteric interactions. These results suggest that dog, cat, and pig CYP2Js have similar functional characteristics to human CYP2J2, with slight differences in ebastine and astemizole oxidations. SIGNIFICANCE STATEMENT: Dog CYP2J2; cat CYP2J2; and pig CYP2J33, CYP2J34, CYP2J35, CYP2J91, and CYP2J93, homologous to human CYP2J2, were identified and characterized by sequence, phylogenetic, and genomic structure analyses. Intestinal expression patterns of CYP2J mRNAs were characteristic in dogs, cats, and pigs. Dog, cat, and pig CYP2Js likely play roles as drug-metabolizing enzymes in the small intestine, similar to human CYP2J2.

DOI： 10.1124/dmd.122.000930

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE SOCIETY OF VETERINARY SCIENCE  

<p>Bovine lactoferrin (BLF) reportedly lowers blood pressure and induces vasorelaxation, but its effect on nitric oxide (NO) production has not been established. Accordingly, we aimed to determine whether BLF induces NO production in bovine aortic endothelial cells, and the effects of extracellular free magnesium (Mg) ion concentrations on this NO production. BLF induced NO production time-dependently. NO production was markedly inhibited by the NO synthase inhibitor, <i>N^G</i>-nitro-L-arginine methyl ester, in an effect abolished by L-arginine, but not D-arginine. NO production was suppressed at low concentrations, and enhanced at high concentrations, of Mg ions in culture medium. These results suggest that BLF has an important role in hypotensive effects. Mg ions may affect BLF-induced NO production.</p>

DOI： 10.1292/jvms.22-0368

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Language：English   Publishing type：Research paper (scientific journal)  

Noxious stimuli on the colorectum cause colorectal contractions through activation of descending monoaminergic pathways projecting from the supraspinal defecation center to the spinal defecation center. Since it is known that substance P is involved in the response to peripheral noxious stimuli in the spinal cord, we investigated the effects of intrathecally administered substance P at L6-S1 levels on colorectal motility in rats that were anesthetized with alpha-chloralose and ketamine. Intrathecally administered substance P enhanced colorectal motility, even after transection of the thoracic spinal cord at the T4 level. Severing the pelvic nerves, but not the colonic nerves, abolished substance P-enhanced colorectal motility. In the spinal cord at L6-S1 levels, expression of mRNA coding NK1-3 receptors was detected by RT-PCR. Immunohistochemical experiments revealed that preganglionic neurons of the pelvic nerves express NK1 receptors, while expression of NK2 receptors was not found. In addition, substance P-containing fibers densely innervated around the preganglionic neurons expressing NK1 receptors. An intrathecally administered NK1 receptor antagonist (spantide) attenuated capsaicin-induced colorectal contractions. These results suggest that the colokinetic action of substance P is mediated by the NK1 receptor in the spinal defecation center. Our findings indicate that substance P may function as a neurotransmitter in the spinal defecation center.

DOI： 10.1152/ajpgi.00342.2021

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

Objectives : To characterise the clinical signs of suspected cerebrovascular disease in dogs. Materials and Methods : Medical records of one hospital were searched from November 2009 to December 2016 for dogs that suffered of cerebrovascular disease. We diagnosed cerebrovascular disease based on acute onset, clinical signs and magnetic resonance imaging findings. The medical history, clinical signs, concurrent disease, area of infarction, cerebrospinal fluid results, month at onset and outcome were investigated in the cerebrovascular disease group and in a control group (dogs with brain disorders other than cerebrovascular disease). Results : A total of 122 CVD cases were extracted from the 5312 patients that visited during the study period. Of these 122 cases, 66 (1.2%) matched the subject selection criteria of our study and were included in the analysis. Forebrain infarction was observed in 51 of 66 cases, of which 24 (47.1%) suffered from seizures. The number of dogs diagnosed with cerebrovascular disease was disproportionately high in August (nine of 59 cases) and December (13 of 59 cases). In the outcome survey, deterioration was observed in 11 of 55 cases. Clinical Significance : Seizure is an important clinical sign of cerebrovascular disease in dogs. There was a significant seasonal variation in the number of dogs diagnosed with cerebrovascular disease in Japan. Clinical features observed in this report differ from those of previous reports and highlight the need for additional research in this area.

DOI： 10.1111/jsap.13422

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Language：English   Publishing type：Research paper (scientific journal)  

The responsiveness of the basilar artery to intrinsic vasoactive substances is species-specific and can be a unique characteristic. We investigated the responsiveness of the bat (Rhinolophus ferrumequinum) basilar artery to noradrenaline (NA), 5-hydroxytryptamine (5-HT), angiotensin (Ang) II, bradykinin (BK), histamine (His), and acetylcholine (ACh). NA, 5-HT, Ang II, and BK induced contraction, whereas His and ACh induced relaxation, in a concentration-dependent manner. The NA cumulative concentration-response curve was shifted to the right in parallel with phentolamine (an α-antagonist). However, propranolol, a β-antagonist, had no significant effect. The 5-HT curve was shifted to the right in parallel by ketanserin (a 5-HT2 antagonist) and methiothepin (a 5-HT1 and 5-HT2 antagonist). Losartan (an AT1 antagonist) shifted the Ang II curve to the right, whereas PD123319 (an AT2 antagonist) had no significant effect. L-NA, indomethacin, and des-Arg9-[Leu8]-BK (a B1 antagonist) did not significantly affect BK-induced contractions. HOE140 (a B2 antagonist) shifted the BK concentration-response curve to the right. The His curve was shifted to the right weakly by diphenhydramine (an H1 antagonist) and strongly by cimetidine (a H2 antagonist). ACh-induced relaxation was significantly inhibited by L-NA, atropine, and pFHHSiD (a muscarinic M3 antagonist), whereas pirenzepine and methoctramine (muscarinic M1 and M2 antagonists, respectively) showed no significant effects. At a resting vascular tone, L-NA-induced contraction and indomethacin induced relaxation. These results suggest that α-adrenergic, 5-HT1, 5-HT2, AT1, and B2 receptors might be important in arterial contraction, whereas M3 and H2 (>H1) receptors might modify these contractions, inducing relaxation.

DOI： 10.1016/j.cbpc.2021.109190

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE SOCIETY OF VETERINARY SCIENCE  

<p>Microparticles (MPs) are released from budding plasma membranes into body fluids. The use of flow cytometry for the measurement of MP in canines has not been standardized. In this fundamental study, we compared the effect of anticoagulant agents, such as acid-citrate-dextrose (ACD) and heparin on the measurement of canine MPs in platelet-free plasma (PFP) using flow cytometry. In addition, we used annexin V, carboxyfluorescein succinimidyl ester (CFSE), or calcein tetraacetoxymethyl ester (calcein-AM), and explored the characteristics of the staining reagents in MP detection using flow cytometry. We were able to measure canine MPs in PFP prepared from ACD-anticoagulated blood using flow cytometry, in which the highest positive rate for fluorescent staining was observed when CFSE was used.</p>

DOI： 10.1292/jvms.21-0448

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Language：English   Publishing type：Research paper (scientific journal)  

The central nervous system is involved in regulation of defaecation. It is generally considered that supraspinal regions control the spinal defaecation centre. However, signal transmission from supraspinal regions to the spinal defaecation centre is still unclear. In this study, we investigated the regulatory role of an anorexigenic neuropeptide, α-MSH, in the spinal defaecation centre in rats. Intrathecal administration of α-MSH to the L6-S1 spinal cord enhanced colorectal motility. The prokinetic effect of α-MSH was abolished by severing the pelvic nerves. In contrast, severing the colonic nerves or thoracic cord transection at the T4 level had no impact on the effect of α-MSH. RT-PCR analysis revealed MC1R mRNA and MC4R mRNA expression in the L6-S1 spinal cord. Intrathecally administered MC1R agonists, BMS470539 and SHU9119, mimicked the α-MSH effect, but a MC4R agonist, THIQ, had no effect. These results demonstrate that α-MSH binds to MC1R in the spinal defaecation centre and activates pelvic nerves, leading to enhancement of colorectal motility. This is, to our knowledge, the first report showing the functional role of α-MSH in the spinal cord. In conclusion, our findings suggest that α-MSH is a candidate for a neurotransmitter from supraspinal regions to the spinal defaecation centre.

DOI： 10.1038/s41598-020-80020-x

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Language：English   Publishing type：Research paper (scientific journal)  

From an evolutionary aspect, dolphins share a very close phylogenetic relationship with pigs. Previously, we characterized porcine cerebral artery responsiveness to intrinsic vasoactive substances. Therefore, here, we investigated dolphin (Tursiops truncatus) cerebral artery responsiveness to 5-hydroxytryptamine (5-HT), histamine (His), angiotensin (Ang) II, acetylcholine (ACh), noradrenaline (NA), and bradykinin (BK) to characterize their related receptor subtypes. We also compared dolphin cerebral artery responsiveness with porcine cerebral artery responsiveness. We found that 5-HT and His induced concentration-dependent contraction of the dolphin cerebral artery. Ketanserin (a 5-HT2 antagonist) and methiothepin (a 5-HT1 and 5-HT2 antagonist) shifted the concentration-response curve for 5-HT to the right. Although diphenhydramine (an H1 antagonist) shifted the concentration-response curve for His to the right, cimetidine (an H2 antagonist) had no such effect. Ang II and ACh did not produce any vasomotor actions. NA induced concentration-dependent relaxation. Propranolol (a β antagonist) shifted the concentration-response curve for NA to the right, whereas phentolamine (an α antagonist) had no significant effect. BK induced relaxation followed by contraction in pre-contracted arteries with intact endothelium. HOE140 (a B2 antagonist) shifted the concentration-response curve for BK to the right, whereas des-Arg9-[Leu8]-BK (a B1 antagonist) had no significant effect. These results suggest that 5-HT1, 5-HT2, and H1 receptor subtypes are important in arterial contraction and that β and B2 receptor subtypes modify these contractions to relaxations. The responsiveness of the dolphin cerebral artery is very similar to that of porcine cerebral artery, supporting their evolutionary linkage.

DOI： 10.1292/jvms.20-0351

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Mercury (Hg) and cadmium (Cd) are the major toxic heavy metals and are known to induce neurotoxicity. Although many studies have shown that several heavy metals have neurotoxic effects, the cellular and molecular mechanisms thereof are still not clear. Oxidative stress is reported to be a common and important mechanism in cytotoxicity induced by heavy metals. However, the assays for identifying toxic mechanisms were not performed under the same experimental conditions, making it difficult to compare toxic properties of the heavy metals. In this study, we investigated the mechanisms underlying neurotoxicity induced by heavy metals and H2O2, focusing on cell death, cell proliferation, and oxidative stress under the same experimental condition. Our results showed that MeHg caused lactate dehydrogenase (LDH) release, caspase activation and cell-cycle alteration, and ROS generation in accordance with decreased cell viability. HgCl2 caused LDH release and cell-cycle alteration, but not caspase activation. CdCl2 had a remarkable effect on the cell cycle profiles without induction of LDH release, caspase activation, or ROS generation. Pretreatment with N-acetyl-l-cysteine (NAC) prevented the decrease in cell viability induced by MeHg and HgCl2, but not CdCl2. Our results demonstrate a clear difference in neurotoxic mechanisms induced by MeHg, HgCl2, CdCl2 or H2O2 in SH-SY5Y cells. Elucidating the characteristics and mechanisms of each heavy metal under the same experimental conditions will be helpful to understand the effect of heavy metals on health and to develop a more effective therapy for heavy metal poisoning.

DOI： 10.1292/jvms.19-0059

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： https://doi.org/10.1292/jvms.17-0473

Language：English   Publishing type：Research paper (scientific journal)  

Angiotensin (Ang) II is known to promote vascular disease and hypertension, partly through its effect on vascular endothelium. Bradykinin (BK) is an endothelium-dependent agonist that induces relaxation followed by contraction of the porcine basilar artery through release of NO and PGF2α, respectively. In this study, we evaluated the effect of Ang II-induced hypertension on basilar artery responsiveness to BK in the Microminipig (MMPig). Ang II (200ng/kg/min) or vehicle was infused into MMPigs for 14days using an osmotic mini-pump and blood pressure was monitored regularly. The responsiveness of subsequently isolated basilar arteries was then measured using a micro organ bath system. MMPig basilar artery endothelial cells were cultured and stimulated with Ang II or vehicle for 48h. Mean blood pressure was significantly (P<0.05; n=5) higher in Ang II-infused MMPigs than in vehicle-infused MMPigs. In vitro, BK-induced endothelium-dependent dilation of isolated basilar artery specimens was abolished and BK-induced contraction was significantly increased (Emax: 15.85±2.42% and 56.54±2.71% of 60mM KCl in control and Ang II group respectively at 10-7M concentration of BK; P<0.01; n=5) in Ang II-infused MMPigs. Ang II stimulation of the endothelial cells significantly decreased (54.15% at 24h; P<0.05; n=three independent experiment performed in triplicate) the amount of BK-elicited NO and increased (44.27% at 24h; P<0.05; n=three independent experiment performed in triplicate) the amount of BK-elicited PGF2α. These results suggest that the decrease of NO and increase of PGF2α production from endothelial cells are responsible for cerebrovascular dysfunction in hypertension, possibly causing cerebrovascular contraction and thus increasing the risk of brain infarction.

DOI： 10.1016/j.mvr.2017.06.001

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Diabetes mellitus comprises a heterogeneous group of metabolic disorders with underlying hyperglycemia and secondary cardiovascular complications. Growing evidence suggests that vascular dysfunction is among the most important causes of diabetic cardiovascular disease. Therefore, we determined whether streptozotocin (STZ)-induced diabetes in mice affects blood pressure and cerebral arterial responsiveness to angiotensin (Ang) II and acetylcholine (ACh), which are important modulators of cerebrovascular autoregulation. Diabetes was induced using a single intraperitoneal injection of STZ (50 mg/kg). Blood pressure was measured in conscious mice using the indirect tail-cuff method. Functional studies of the isolated arteries' response to vasoactive substances were performed using a micro-organ-bath system at 60 days after STZ injection. Systolic, diastolic, and mean blood pressures significantly increased at days 45 and 60 in the STZ-induced diabetic mice. In the isolated basilar arteries, ACh-induced relaxation, which is dependent on nitric oxide (NO) production from endothelial cells, decreased. In contrast, Ang II-induced contraction, mediated via rho-kinase activation in the smooth muscle, increased in the diabetic mice. There was significantly greater relaxation in the precontracted isolated basilar arteries of diabetic mice that had been treated with Y27632, a rho-kinase inhibitor, than in the control mice arteries. Pretreatment with Nω-nitro-L-arginine (L-NAME), an NO synthase inhibitor, significantly enhanced Ang II-induced contraction and Y27632-induced relaxation in the control basilar arteries but not in the STZ-induced diabetic mice arteries. These results suggest that decreased NO bioavailability and enhanced rho-kinase activity in basilar arteries contribute to altered reactivity to ACh and Ang II, respectively, in STZ-induced diabetic mice.

DOI： 10.1007/s00210-017-1396-x

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1292/jvms.16-0249

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DOI： 10.1142/S0192415X16500907

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DOI： 10.1292/jvms.15-0620

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DOI： 10.1016/j.jep.2016.02.009

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DOI： 10.1016/j.lfs.2016.01.033

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DOI： 10.1016/j.bmc.2015.09.011

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DOI： 10.4236/abb.2015.68060

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Event date： 2023.8

Language：Japanese   Presentation type：Oral presentation (general)  

Event date： 2022.9

Language：Japanese   Presentation type：Oral presentation (general)  

Event date： 2022.9

Language：Japanese   Presentation type：Symposium, workshop panel (nominated)  

Event date： 2022.9

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Event date： 2022.9

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Venue：Cairns Convention Centre   Country：Australia  

Event date： 2022.8

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Venue：岐阜大学 柳戸キャンパス  

Other Link： http://31st-pathophysiology.kenkyuukai.jp/images/sys/information/20220720133221-0D6DDB2185BE343443736EA0F05E67C1AB13F8CEDA321C0D982C01327B7FD039.pdf

Event date： 2022.3

Language：English   Presentation type：Oral presentation (general)  

Other Link： https://pharmacology.main.jp/jps95/download/pdf/oral_0309.pdf

Event date： 2022.1

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：京都大学医学部　芝蘭会館別館  

Event date： 2021.9

Event date： 2021.9

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Event date： 2021.3

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Event date： 2020.3

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Event date： 2019.11

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Event date： 2019.9

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Event date： 2017.11

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Event date： 2017.11

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Event date： 2017.11

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Event date： 2017.9

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Venue：鹿児島  

Event date： 2017.8

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Venue：福岡  

Event date： 2017.7

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Event date： 2016.12

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Venue：東京  

Event date： 2016.9

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Venue：神奈川  

Event date： 2016.3

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Venue：神奈川  

Event date： 2016.1

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Venue：東京  

Event date： 2015.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：青森  

Event date： 2015.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：青森  

Event date： 2015.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：青森  

Event date： 2015.3

Language：Japanese  

Venue：愛知  

Event date： 2015.3

Language：Japanese  

Venue：愛知  

Event date： 2014.11

Language：Japanese  

Venue：神奈川  

Event date： 2014.11

Language：Japanese  

Venue：京都  

Event date： 2014.11

Language：Japanese  

Venue：茨城  

Event date： 2014.9

Language：Japanese  

Venue：北海道  

Event date： 2014.3

Language：Japanese  

Venue：宮城  

Event date： 2014.3

Language：Japanese  

Venue：宮城  

Event date： 2014.3

Language：Japanese  

Venue：宮城  

Event date： 2013.9

Language：Japanese  

Venue：北海道  

Event date： 2013.9

Language：Japanese  

Venue：岐阜  

Event date： 2013.9

Language：Japanese  

Venue：神奈川  

Event date： 2013.9

Language：Japanese  

Venue：神奈川  

Event date： 2013.9

Language：Japanese  

Venue：岐阜  

Event date： 2013.7

Language：English  

Venue：韓国  

Event date： 2013.6

Language：English  

Venue：愛知  

Event date： 2013.3

Language：Japanese  

Venue：神奈川  

Event date： 2013.3

Language：Japanese  

Venue：福岡  

Event date： 2013.3

Language：Japanese  

Venue：福岡  

Event date： 2013.3

Language：Japanese  

Venue：東京  

Event date： 2012.12

Language：Japanese  

Venue：福岡  

Event date： 2012.9

Language：Japanese  

Venue：岩手  

Event date： 2012.9

Language：Japanese  

Venue：岩手  

Event date： 2011.9

Language：Japanese  

Venue：大阪  

Event date： 2011.9

Language：Japanese  

Venue：大阪  

Event date： 2011.9

Language：Japanese  

Venue：宮崎  

Event date： 2011.3

Language：Japanese  

Venue：東京  

Event date： 2010.11

Language：Japanese  

Venue：鹿児島  

Event date： 2010.11

Language：Japanese  

Venue：鹿児島  

Event date： 2010.9

Language：Japanese  

Venue：北海道  

Event date： 2009.10

Language：Japanese  

Venue：兵庫  

Event date： 2009.9

Language：Japanese  

Venue：鳥取  

Event date： 2009.9

Language：Japanese  

Venue：鳥取  

Event date： 2009.9

Language：Japanese  

Venue：鳥取  

Event date： 2008.12

Language：Japanese  

Venue：兵庫  

Event date： 2008.9

Language：Japanese  

Venue：宮崎  

Event date： 2008.9

Language：English  

Venue：宮崎  

Event date： 2008.9

Language：Japanese  

Venue：宮崎  

Event date： 2007.10

Language：Japanese  

Venue：東京  

Event date： 2007.9

Language：Japanese  

Venue：北海道  

Event date： 2007.9

Language：Japanese  

Venue：神奈川  

Event date： 2007.3

Language：Japanese  

Venue：三重  

Event date： 2007.3

Language：Japanese  

Venue：富山  

Event date： 2006.7

Language：English  

Venue：カナダ  

Event date： 2006.6

Language：English  

Venue：京都  

Event date： 2005.9

Language：Japanese  

Venue：鹿児島  

Event date： 2004.9

Language：Japanese  

Venue：北海道  

Event date： 2003.10

Language：English  

Venue：カナダ  

Event date： 2003.3

Language：English  

Venue：アメリカ合衆国  

Event date： 2002.8

Language：English  

Venue：イギリス  

Event date： 2002.4

Language：English  

Venue：アメリカ合衆国  

Event date： 2001.3

Language：Japanese  

Venue：神奈川  

Event date： 2001.3

Language：Japanese  

Venue：神奈川  

Event date： 2000.8

Language：English  

Venue：カナダ  

Event date： 1999.11

Language：Japanese  

Venue：鹿児島  

Event date： 1998.11

Language：Japanese  

Venue：宮崎