It is often noted that the collaboration of hospital-to-hospital, hospital-to-clinic and clinic-to-clinic in medical care for patients with headache is important. However, the role of community pharmacies in the medical network for consultation of patients with headache is not clear. Here, we investigated the role of pharmacists in a community pharmacy in encouraging patients with headache to undergo medical examination and elucidated their future needs using a questionnaire intended for doctors and pharmacists. About 70% of pharmacists had experience with recommending that patients with headache consult a hospital. However, only 17% of doctors had experience with referral of patients with headache by pharmacists in a community pharmacy. About 22% of pharmacists had experiences in which the patient with headache refused to consult a hospital despite the recommendation, suggesting that many patients did not think that their headache symptoms were severe. In addition, 90% of doctors and 84% of pharmacists felt the need for collaboration between hospitals or clinics and community pharmacies. Doctors needed information from pharmacists on the "current state of drugs" taken by patients. However, pharmacists considered that they needed to provide not only "current state of drugs being taken" but also "symptoms of headache" to doctors. Although 67% of doctors considered the medication notebook to be useful for pharmacists to provide patient information to doctors, pharmacists preferred to provide the information by telephone. Moreover, 56% of pharmacists did not know how to search a website for medical specialists in headache. A medical network including not only hospitals or clinics but also community pharmacies might be useful for patients with headache.
This study examined whether intravenous administration of tetrahydrobiopterin (BH4) reduces myocardial infarct size following ischemia/reperfusion (I/R) in rats, and the mechanisms of its protective effect were also investigated. Rats were subjected to 30 minutes of ischemia by ligation of the left coronary artery and 2 hours of reperfusion. The infarct size was determined as a percentage of the area at risk by triphenyltetrazolium staining. Intravenous administration of BH4 (0.01 mg/kg-1 mg/kg) significantly reduced the myocardial infarct size. Nitrite plus nitrate (NOx) and cGMP levels in the hearts were significantly increased by the treatment with BH4, and the infarct size-limiting effect of BH4 was abolished by the co-administration of NG-nitro-L-arginine methyl ester, a specific inhibitor of nitric oxide synthase, or 5-hydroxydecanoic acid, a specific inhibitor of mitochondrial ATP-sensitive potassium channel (mitoKATP channel). These findings suggest that BH4 has a cardioprotective effect against I/R in vivo, and its protective effect appeared to be involved in the opening of mitoKATP channels through increased nitric oxide production.
The aim of the present study was to characterize the increase in tetrahydrobiopterin (BH4), which is a cofactor for nitric oxide synthase (NOS), by carboxy-PTIO, a scavenger of nitric oxide (NO), in vascular endothelial cells. BH4 level was determined by oxidation under acidic conditions as biopterin. Addition of lipopolysaccharide (LPS) to endothelial cells increased mRNA levels of inducible NOS (iNOS) and GTP-cyclohydrolase I (GTPCH), which is a rate-limiting enzyme for BH4 synthesis, and the biopterin level. NOS inhibitors, NO-donors and L-arginine, a substrate of NOS, did not affect the increase in the biopterin level induced by LPS, suggesting that BH4 synthesis is unlikely to be modulated by NO produced by iNOS during LPS treatment. However, carboxy-PTIO increased the biopterin level in the absence and the presence of LPS. Carboxy-PTIO did not affect the expression of GTPCH mRNA level. Moreover, 2,4-diamino-6-hydroxypyrimidine, an inhibitor of GTPCH, inhibited only about 30% of the carboxy-PTIO-induced increase in the biopterin level. Whereas, N-acetylserotonin, an inhibitor of sepiapterin reductase, strongly inhibited the increase in biopterin level. Carboxy-PTIO inhibited the accumulation of pterin, a decomposition product of BH4 in endothelial cells. These findings suggest that carboxy-PTIO accumulates BH4 under basal and LPS-treated conditions in vascular endothelial cells due to both inhibition of the decomposition of BH4 to pterin and activation of the salvage pathway of BH4 synthesis via sepiapterin reductase.
Abstract We examined the effect of immunosuppressant cyclosporin A (CsA) on the synthesis of tetrahydrobiopterin (BH 4 ), which is a cofactor for nitric oxide synthase (NOS), during treatment with lipopolysaccharide (LPS) in mouse brain microvascular endothelial cells. Addition of LPS to the endothelial cells increased the BH 4 content and the mRNA level of GTP-cyclohydrolase I (GTPCH), the rate-limiting enzyme of BH 4 synthesis, and the LPSínduced increases in both the BH 4 content and expression of GTPCH mRNA were further stimulated by the cotreatment with CsA. 2,4-Diamino-6-hydroxypyrimidine, an inhibitor of GTPCH, blocked the increase in BH 4 content induced by CsA during the LPS treatment. Moreover. CsA stimulated the expression of inducible NOS (iNOS) mRNA during the LPS treatment. These findings suggest that CsA stimulates LPS-induced BH 4 synthesis through the induction of GTPCH, and iNOS expression. CsA may increase NO production during LPS treatment in brain microvascular endothelial cells.
Abstract Transient receptor potential melastatin 2 (TRPM2) assembles into tetramers to function as an oxidative stress‐sensitive Ca 2+ channel at the surface membrane. Limited information is currently available on the 10 protein isoforms of mouse TRPM2 ( m TRPM2) identified. This study investigated whether these isoforms function as Ca 2+ channels and examined their effects on full‐length m TRPM2 activity using the HEK 293 cell exogenous expression system. Only full‐length m TRPM2, isoform 1 localized to the surface membrane and was activated by oxidative stress. Isoform 7 was clearly recognized by protein quality control systems and degraded by endoplasmic reticulum‐associated degradation after transmembrane proteolysis. In the co‐expression system, the activation and expression of full‐length m TRPM2 were attenuated by its co‐expression with isoform 7, but not with the other isoforms. This decrease in the expression of full‐length m TRPM2 was recovered by the proteasomal inhibitor. The present results suggest that isoforms other than isoform 1 did not function as oxidative stress‐sensitive channels and also that only isoform 7 attenuated the activation of full‐length m TRPM2 by targeting it to endoplasmic reticulum‐associated degradation. The present study will provide important information on the functional nature of m TRPM2 isoforms for the elucidation of their roles in physiological and patho‐physiological responses in vivo using mouse models.
