Yamaki Fumiko

INTRODUCTION: The National Database of Health Insurance Claims and Specific Health Checkups (NDB) Open Data Japan provides a nationwide health-related dataset based on region. This study aimed to identify lifestyle habits that correlated with the prevalence of hypertension, diabetes, and dyslipidemia by analyzing a dataset. METHODS: Data from 28.9 million respondents regarding lifestyle habits were collected in the fiscal year 2020 and provided in the 8th NDB Open Data Japan. Medication status for hypertension, diabetes, and dyslipidemia was used to determine the prevalence of each disorder. Responses to lifestyle habit questions were used as lifestyle variables. Pearson's correlation coefficient (r) was calculated to determine the relationships between variables. RESULTS: Lifestyle habits that had a moderate or larger correlation with the prevalence of each disorder were identified by setting the criterion |r| > 0.5. Smoking, weight gain, chewing condition, eating speed, snacking, and alcohol consumption were associated with the prevalence of hypertension. Smoking, weight gain, and chewing conditions correlated with the prevalence of diabetes. No single lifestyle habit showed correlations above the set criterion for dyslipidemia prevalence. CONCLUSION: Due to the diversity of lifestyle habits of residents within each of the 47 Japanese prefectures, the prefecture-based dataset in NDB Open Data Japan is pragmatic and useful for epidemiologically investigating the association between lifestyle habits and the prevalence of disorders of interest. It would be important to raise the alarm about the lifestyle habits identified in the present study to reduce the risk of developing the corresponding disorders.

Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are n-3 polyunsaturated fatty acids (PUFAs), and are abundant in fish oil. These n-3 PUFAs have been reported to improve the lower gastrointestinal (LGI) disorders such as ulcerative colitis and Crohn's disease through their anti-inflammatory effects. However, there are few studies on the effect of n-3 PUFAs on motility of the LGI tract, such as the ileum and colon, the parts frequently affected by these inflammatory disorders. To elucidate the effects of DHA and EPA on the LGI tract motility, we performed comparative evaluation of their effects and linoleic acid (LA), an n-6 PUFA, on contractions in the ileal and colonic longitudinal smooth muscles (LSMs) isolated from guinea pigs. In the ileal and colonic LSMs, DHA and EPA (3 × 10-5 M each) significantly inhibited contractions induced by acetylcholine (ACh), histamine, and prostaglandin (PG) F2α (vs. control), and these effects are stronger than that of LA (3 × 10-5 M). In the colonic LSMs, DHA and EPA also significantly inhibited contractions induced by PGD2 (vs. control). In addition, DHA and EPA significantly inhibited CaCl2-induced ileal and colonic LSM contractions in Ca2+-free 80 mM-KCl solution (vs. control). Any ileal and colonic LSM contractions induced by ACh, histamine, PGF2α, and CaCl2 were completely suppressed by verapamil (10-5 M), a voltage-gated/dependent Ca2+ channel (VGCC/VDCC) inhibitor. These findings suggest that DHA and EPA could improve the abnormal contractile functions of the LGI tract associated with inflammatory diseases, partly through inhibition of VGCC/VDCC-dependent ileal and colonic LSM contractions.

The clinical applications of antipsychotics for symptoms unrelated to schizophrenia, such as behavioral and psychological symptoms, in patients with Alzheimer's disease, and the likelihood of doctors prescribing antipsychotics for elderly people are increasing. In elderly people, drug-induced and aging-associated urinary disorders are likely to occur. The most significant factor causing drug-induced urinary disorders is a decrease in urinary bladder smooth muscle (UBSM) contraction induced by the anticholinergic action of therapeutics. However, the anticholinergic action-associated inhibitory effects of antipsychotics on UBSM contraction have not been sufficiently assessed. In this study, we examined 26 clinically available antipsychotics to determine the extent to which they inhibit acetylcholine (ACh)-induced contraction in rat UBSM to predict the drugs that should not be used by elderly people to avoid urinary disorders. Of the 26 antipsychotics, six (chlorpromazine, levomepromazine (phenothiazines), zotepine (a thiepine), olanzapine, quetiapine, clozapine (multi-acting receptor targeted antipsychotics (MARTAs))) competitively inhibited ACh-induced contractions at concentrations corresponding to clinically significant doses. Further, 11 antipsychotics (perphenazine, fluphenazine, prochlorperazine (phenothiazines), haloperidol, bromperidol, timiperone, spiperone (butyrophenones), pimozide (a diphenylbutylpiperidine), perospirone, blonanserin (serotonin-dopamine antagonists; SDAs), and asenapine (a MARTA)) significantly suppressed ACh-induced contraction; however, suppression occurred at concentrations substantially exceeding clinically achievable blood levels. The remaining nine antipsychotics (pipamperone (a butyrophenone), sulpiride, sultopride, tiapride, nemonapride (benzamides), risperidone, paliperidone (SDAs), aripiprazole, and brexpiprazole (dopamine partial agonists)) did not inhibit ACh-induced contractions at concentrations up to 10-5 M. These findings suggest that chlorpromazine, levomepromazine, zotepine, olanzapine, quetiapine, and clozapine should be avoided by elderly people with urinary disorders.

Certain catecholamine metabolites exert significant pharmacological effects. Herein, we evaluated the pharmacological activities of catecholamine metabolites in the rat thoracic aorta, prostate, and spleen to determine whether these metabolites affect the contractile functions of smooth muscle tissue via direct action on α-adrenoceptors and α-adrenoceptor subtypes. Among the catecholamine metabolites examined, normetadrenaline and metadrenaline (10-4 M each) produced relatively strong contractions in the rat thoracic aorta. Maximum aortic contractions induced by normetadrenaline (≈70% of phenylephrine (3 × 10-7 M)-induced contractions) and metadrenaline (≈45%) were significantly smaller than those induced by phenylephrine (≈95%). Normetadrenaline and metadrenaline (10-4 M each) inhibited phenylephrine (3 × 10-7 M)-induced aortic contractions, which were not affected by propranolol (10-6 M), by 5-20%. Normetadrenaline- and metadrenaline (3 × 10-5 M each)-induced aortic contractions were strongly inhibited by prazosin (10-8 M; an α1-adrenoceptor antagonist) and BMY 7378 (10-8-10-7 M; a selective α1D-adrenoceptor antagonist). Metadrenaline (3 × 10-5 M)-induced aortic contractions were also significantly inhibited by silodosin (10-9 M; a selective α1A-adrenoceptor antagonist). Normetadrenaline and metadrenaline (3 × 10-5 M each) caused silodosin (10-9 M)-sensitive prostate contractions but did not cause a prominent spleen contraction. Maximum prostate contractions induced by metadrenaline (≈100% of phenylephrine (3 × 10-5 M)-induced contractions) were nearly identical to those induced by phenylephrine (≈100%) but were significantly larger than those induced by normetadrenaline (≈80%). These findings suggest that normetadrenaline and metadrenaline act as a partial α1D/α1A-adrenoceptor agonist and partial α1D-adrenoceptor/full α1A-adrenoceptor agonist, respectively, functioning as adrenaline system stabilizers in α1D/α1A-adrenoceptor-abundant smooth muscle tissues.

The β-adrenoceptor (β-AR)-mediated pharmacological effects of catecholamine (CA) metabolites are not well known. We examined the effects of seven CA metabolites on smooth muscle relaxation in mouse and guinea pig (GP) tracheas and rat thoracic aorta. Among them, metadrenaline (MA) significantly relaxed GP trachea (β2-AR dominant), even in the presence of clorgiline, a monoamine oxidase-A inhibitor. In mouse trachea (β1-AR dominant), normetadrenaline (NMA) and MA (10-4 M each) apparently did not affect isoprenaline (ISO)-induced relaxation, but significantly inhibited it in the presence of clorgiline. ISO-induced relaxation was also unaffected by 3,4-dihydroxyphenylglycol (DHPG) (10-4 M), but significant suppression was observed with the addition of 3,5-dinitrocatechol, a catechol-O-methyltransferase inhibitor. In GP trachea, NMA, MA, 3,4-dihydroxymandelic acid (DOMA), and DHPG (10-4 M each) significantly augmented ISO-induced relaxation. However, in the presence of clorgiline plus 3,5-dinitrocatechol, both NMA and MA (10-4 M) significantly suppressed ISO-induced relaxation. DHPG (10-4 M) also significantly suppressed ISO-induced relaxation in the presence of 3,5-dinitrocatechol. In rat thoracic aorta, DHPG (10-4 M) significantly suppressed relaxation induced by CGP-12177 A (a β3-AR partial agonist) in the presence of 3,5-dinitrocatechol plus propranolol. Our findings indicate that 1) MA may possess β2-AR agonistic action; 2) NMA and MA augment β2-AR-mediated tracheal relaxation in the absence of CA metabolic inhibitors, though themselves possessing β1-, β2-AR antagonistic action (β2 > β1); 3) DHPG exhibits β1-, β2-, β3-AR antagonistic action, and this is particularly marked for β3-AR. Our observations may help explain some of the pathologies associated with pheochromocytoma, which is characterized by increased CA metabolite levels.

INTRODUCTION: Benzodiazepine anxiolytics are believed to cause urination disorders due to their anticholinergic effects. OBJECTIVE: This study was carried out to investigate the potential inhibitory effects of 15 clinically available anxiolytics in Japan on acetylcholine (ACh)-induced contractions in rat detrusor smooth muscle (DSM) to predict whether these anxiolytics could induce urination disorders. METHODS: -Effects of anxiolytics on contractions induced by ACh and 80 mmol/L KCl solution in rat DSM and effects of anxiolytics on specific binding of [N-methyl-3H]scopolamine ([3H]NMS) in mouse cerebral cortex were investigated. RESULTS AND CONCLUSIONS: ACh-induced contractions in rat DSM were inhibited by clotiazepam and diazepam (benzodiazepine anxiolytics) at concentrations that were clinically relevant. These contractions were also significantly inhibited by paroxetine, escitalopram (selective serotonin reuptake inhibitors -[SSRIs]), and hydroxyzine (a histamine H1 receptor antagonist), albeit at concentrations that substantially exceeded clinically achievable blood levels. At a concentration of 10-5 mol/L, paroxetine, escitalopram, and hydroxyzine inhibited 80 mmol/L high-KCl solution-induced rat DSM contractions but not clotiazepam and diazepam. Paroxetine, escitalopram, and hydroxyzine also inhibited specific binding of [3H]NMS in mouse cerebral cortex but clotiazepam and diazepam did not. In contrast to the effects of the abovementioned anxiolytics, ACh-induced contractions were not significantly affected by tofisopam, alprazolam, lorazepam, bromazepam, oxazolam, chlordiazepoxide, clonazepam, ethyl loflazepate (benzodiazepine anxiolytics), fluvoxamine (an SSRI), or tandospirone (a serotonin 5-HT1A receptor agonist). These findings suggest that most clinically used anxiolytics are not likely to result in anticholinergic-induced urination disorders within their clinically achievable blood concentration ranges. However, clotiazepam and diazepam may induce urination disorders within their clinical dose ranges via nonanticholinergic inhibition of DSM contractility.

β-Adrenoceptors are subclassified into 3 subtypes (β1-β3). Among these, β3-adrenoceptors are present in various types of smooth muscle and are believed to play a role in relaxation responses of these muscles. β3-Adrenoceptors are also present in urinary bladder smooth muscle (UBSM), although their expression varies depending on the animal species. To date, there has been little information available about the endogenous ligand that stimulates β3-adrenoceptors to produce relaxation responses in UBSM. In this study, to determine whether noradrenaline is a ligand of UBSM β3-adrenoceptors, noradrenaline-induced relaxation was analyzed pharmacologically using rat UBSM. We also assessed whether noradrenaline metabolites were ligands in UBSM. In isolated rat urinary bladder tissues, mRNAs for β1-, β2-, and β3-adrenoceptors were detected using RT-PCR. In UBSM preparations contracted with methacholine (3 × 10-5 M), noradrenaline-induced relaxation was not inhibited by the following antagonists: atenolol (10-6 M; selective β1-adrenoceptor antagonist), ICI-118,551 (3 × 10-8 M; selective β2-adrenoceptor antagonist), propranolol (10-7 M; non-selective β-adrenoceptor antagonist), and bupranolol (10-7 M; non-selective β-adrenoceptor antagonist). In the presence of propranolol (10-6 M), noradrenaline-induced relaxation was competitively inhibited by bupranolol (3 × 10-7-3 × 10-6 M) or SR59230A (10-7-10-6 M; selective β3-adrenoceptor antagonist), with their pA2 values calculated to be 6.64 and 7.27, respectively. None of the six noradrenaline metabolites produced significant relaxation of methacholine-contracted UBSM. These findings suggest that noradrenaline, but not its metabolites, is a ligand for β3-adrenoceptors to produce relaxation responses of UBSM in rats.