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Abstract: The effect of low-intensity resistance exercise with external limb compression (100 [EC100] and 160 [EC160] mm Hg) on limb blood flow and venous blood gas-metabolite response was investigated and compared with that of high-intensity resistance exercise (no external compression). Unilateral elbow flexion muscle contractions were performed at 20% (75 repetitions, 4 sets, 30-second rest intervals) and 70% of 1-repetition maximum (1-RM; 3 sets, each set was until failure, 3-minute rest intervals). Precontraction brachial arterial blood flow (Doppler ultrasound) was reduced with EC100 or EC160 (56% and 39% of baseline value, respectively) compared with no external compression (control). At 20% 1-RM, brachial arterial blood flow increased after contractions performed with EC160 (190%), but not with the others. Decreases in venous oxygen partial pressure (PvO2) and venous oxygen saturation (SvO2) were greater during EC100 and EC160 than control (mean [SE]: PvO2, 28 [3] vs 26 [2] vs 33 [2] mm Hg; SvO2, 41% [5%] vs 34% [4%] vs 52% [5%], respectively). Changes in venous pH (pHv), venous carbon dioxide partial pressure (PvCO2), and venous lactate concentration ([L−]v) were greater with EC160 than EC100 and/or control (pHv, 7.19 [0.01] vs 7.25 [0.01] vs 7.27 [0.02]; PvCO2, 72 [3] vs 64 [2] vs 60 [3] mm Hg; [L−]v, 5.4 [0.6] vs 3.7 [0.4] vs 3.0 [0.4] mmol/L, respectively). Seventy percent 1-RM contractions resulted in greater changes in pHv (7.14 [0.02]), PvCO2 (91 [5] mm Hg), and [L−]v (7.0 [0.5] mmol/L) than EC100 and EC160, but PvO2 (30 [4] mm Hg) and SvO2 (40% [3%]) were similar. In conclusion, changes in pHv, PvCO2, and [L−]v, but not in PvO2 and SvO2, are sensitive to changes in relative, “internal” intensity of low-intensity muscle contractions caused by reduced blood flow (EC160) or high-intensity muscle contractions. Given the magnitude of the changes in pHv, PvCO2, and [L−]v, it appears plausible that they may be involved in stimulating the observed increase in muscle activation via group III and IV afferents. [Copyright &y& Elsevier]

Abstract: Endothelin-1 is known to be implicated in the pathogenesis of hepatobiliary diseases such as cirrhosis, especially in portal hypertension. This study aimed to investigate the effects of ursodeoxycholic acid on endothelin-1 production in human endothelial cells. The effects of ursodeoxycholic acid and its conjugates (tauroursodeoxycholic and glycoursodeoxycholic acids) on endothelin-1 production as well as nitric oxide (NO) in human umbilical vein endothelial cells (HUVECs) were examined. The production of endothelin-1 and nitric oxide in culture medium was measured using enzyme-linked immunosorbent assay (ELISA) and the Griess method, respectively. Endothelin-1 and endothelial nitric oxide synthase (eNOS) mRNA expression were investigated by real-time quantitative reverse transcriptase/polymerase chain reaction (RT-PCR). Ursodeoxycholic acid (30–1000 μM) inhibited endothelin-1 production in a concentration-dependent manner, and ursodeoxycholic acid at concentrations higher than 300 μM increased nitric oxide production in culture medium. The conjugates of ursodeoxycholic acid also increased nitric oxide production and decreased endothelin-1 production, which was less effective than ursodeoxycholic acid. N-nitro-l-arginine-mythel-ester (l-NAME), a nitric oxide synthase (NOS) inhibitor, suppressed the ursodeoxycholic acid-induced nitric oxide production, but it did not antagonize the inhibitory effects of ursodeoxycholic acid on endothelin-1 production. Ursodeoxycholic acid also induced a concentration-dependent decrease in endothelin-1 mRNA expression without significant changes in eNOS mRNA expression. These results provide novel evidence that ursodeoxycholic acid inhibits endothelin-1 production in human endothelial cells, but nitric oxide is not responsible for the inhibitory effect of ursodeoxycholic acid on endothelin-1. Thus, ursodeoxycholic acid therapy may prevent the development of several pathogenesis such as portal hypertension observed in patients with cirrhosis due to the improvement of endothelial function. [Copyright &y& Elsevier]

The expression of inducible nitric oxide synthase (iNOS) and the resultant increased nitric oxide production are associated with endotoxemia and atherosclerotic lesions observed in transplant hearts or balloon-injured artery. Ursodeoxycholic acid has been shown to have cardiovascular protective effects, such as inhibition of the development of transplant arteriosclerosis, but its mechanism remains unclear. Here, we investigated the effects of ursodeoxycholic acid on nitric oxide production and the expression of iNOS in vascular smooth muscle cells isolated from adult rat aorta and rabbit coronary artery. Nitrite released from cells in the culture medium was measured with the Griess reaction. iNOS mRNA and protein were measured by Northern and Western blot analyses. Treatment with ursodeoxycholic acid (30–1000 μM) significantly inhibited lipopolysaccharide plus interferon-γ-induced nitric oxide production in a concentration-dependent manner, but ursodeoxycholic acid showed only small inhibitory effects on nitric oxide production that had already been induced by lipopolysaccharide plus interferon-γ. Ursodeoxycholic acid by itself did not affect basal nitric oxide production. Ursodeoxycholic acid also suppressed lipopolysaccharide plus interferon-γ-induced expression of iNOS mRNA and protein. Ursodeoxycholic acid had the most potent inhibitory effect among various kinds of bile acids examined, i.e. chenodeoxycholic acid, deoxycholic acid, cholic acid and conjugated bile acids such as tauroursodeoxycholic acid. These results suggest that ursodeoxycholic acid inhibits the induction of iNOS and then nitric oxide production in aortic and coronary artery smooth muscle cells, suggesting a possible mechanism for the cardiovascular protective effect of ursodeoxycholic acid under various pathophysiological conditions such as endotoxemia and atherosclerosis. [Copyright &y& Elsevier]

Abstract: Voltage-gated Na+ channel (I Na) encoded by SCN9A mRNA is expressed in cultured human bronchial smooth muscle cells. We investigated the effects of dexamethasone on I Na, by using whole-cell voltage clamp techniques, reverse transcriptase/polymerase chain reaction (RT-PCR), and quantitative real-time RT-PCR. Acute application of dexamethasone (10−6 M) did not affect I Na. However, the percentage of the cells with I Na was significantly less in cells pretreated with dexamethasone for 48 h, and the current-density of I Na adjusted by cell capacitance in cells with I Na was also decreased in cells treated with dexamethasone. RT-PCR analysis showed that α and β subunits mRNA of I Na mainly consisted of SCN9A and SCN1β, respectively. Treatment with dexamethasone for 24–48 h inhibited the expression of SCN9A mRNA. The inhibitory effect of dexamethasone was concentration-dependent, and was observed at a concentration higher than 0.1 nM. The effect of dexamethasone on SCN9A mRNA was not blocked by spironolactone, but inhibited by mifepristone. The inhibitory effects of dexamethasone on SCN9A mRNA could not be explained by the changes of the stabilization of mRNA measured by using actinomycin D. These results suggest that dexamethasone inhibited I Na encoded by SCN9A mRNA in cultured human bronchial smooth muscle cells by inhibiting the transcription via the glucocorticoid receptor. [Copyright &y& Elsevier]