Kei Hara

Voltage-gated sodium channel expressed in cultured human smooth muscle cells: involvement of SCN9A

Voltage‐gated Na+ channel (INa) is expressed under culture conditions in human smooth muscle cells (hSMCs) such as coronary myocytes. The aim of this study is to clarify the physiological, pharmacological and molecular characteristics of INa expressed in cultured hSMCs obtained from bronchus, main pulmonary and coronary artery. INa, was recorded in these hSMCs and inhibited by tetrodotoxin (TTX) with an IC50 value of approximately 10 nM. Reverse transcriptase/polymerase chain reaction (RT‐PCR) analysis of mRNA showed the prominent expression of transcripts for SCN9A, which was consistent with the results of real‐time quantitative RT‐PCR. These results provide novel evidence that TTX‐sensitive Na+ channel expressed in cultured hSMCs is mainly composed of Nav1.7.

Thromboxane inhibition and monocrotaline-induced pulmonary hypertension in rats.

Abstract Monocrotaline (MCT)‐induced pulmonary hypertension (PH) is a useful model for the investigation of this disorder in humans. The role of thrombocytes in the genesis of PH has already been addressed; however, the exact mechanism by which they induce PH remains to be elucidated. We investigated the effects of a thromboxane A2 (TXA2) synthase inhibitor (OKY‐046) and a TXA2/ prostaglandin H2 (PGH2) receptor antagonist (ONO‐8809) on the development of MCT‐induced PH. A single dose of MCT (60 mg/kg bodyweight; BW) was injected subcutaneously in Wistar rats 24 h after the administration of OKY‐046 or ONO‐8809. The TXA2 inhibitors were administered by gavage daily for 3 weeks. Urinary excretion of eicosanoids was determined by radioimmunoassay. At the end of the treatment period, the lungs, heart and kidneys were morphologically examined. The per cent medial thickness of the muscular pulmonary arteries (%MT) and the ratio of the right to the left ventricular mass including the septum (RV/LV+S) increased significantly in MCT‐treated rats compared with the control rats. The %MT was attenuated by the administration of ONO‐8809. Either OKY‐046 or ONO‐8809 attenuated the increase in RV/LV+S. In addition, both TXA2 inhibitors reduced urinary excretion of 11‐dehydro‐TXB2, particularly during the early phase of PH, suggesting that platelet aggregation was reduced. These findings suggest that the inhibition of TXA2 by synthase inhibition or receptor antagonism reduces or delays the development of MCT‐induced PH in rats, probably by inhibiting platelet aggregation.

Activation of cyclin D1-related kinase in human lung adenocarcinoma

Cyclin D1 gene amplification is an important event in many cancers, but it is rarely found in non-small-cell lung cancer (NSCLC). This study was conducted in an attempt to clarify any other mechanisms related to cyclin D1 involvement in the malignant transformation of NSCLC, and we clearly showed for the first time that cyclin D1-related kinases are activated in NSCLC, especially in adenocarcinoma but not in squamous cell carcinoma. The results of this study strongly suggest that enhanced cyclin D1-related kinase activity could contribute to a progression of adenocarcinoma in NSCLC.