Cigarette smoking is one of the main risk factors in the development of chronic obstructive pulmonary disease (COPD). It has been suggested that an augmented agonist-induced, RhoA mediated Ca2+ sensitization is responsible for the enhanced bronchial smooth muscle contraction induced by cigarette smoking. In the present study, to determine whether or not these phenomena are dependent on the degree of exposure to the components of cigarette smoke, we examined the effects of exposure to mainstream smoke derived from either light or heavy cigarettes on both the contractile responsiveness and the expression of RhoA in bronchial smooth muscle. Male Wistar rats were exposed to mainstream cigarette smoke for 2 hr/day for 2 weeks. Twenty-four hr after the last cigarette smoke exposure, we measured isometrical contractions of the bronchial smooth muscle. The concentration-response curve to ACh was significantly shifted upward after heavy cigarette smoke (HCS) exposure, whereas no significant difference was observed in the case of light cigarette smoke (LCS) exposure compared with control rats. No significant difference in K+ responsiveness was observed between the groups. The expression of RhoA protein in bronchial preparations from rats repeatedly exposed to HCS, but not to LCS, was significantly increased as compared with that of the control animals. On the other hand, inhalation of nicotine had no effect on either the ACh- and high K+ depolarization-induced contractions or the expression of RhoA protein. The increased expression of RhoA seems to have an important role in the augmented contractile responses of the airways in rats, a characteristic feature of early COPD.
Purpose: To measure the effects of levormeloxifene on vaginal smooth muscle cell (SMC) proliferation, tropoelastin and transforming growth factor (TGF)-β1 production. Methods: Primary SMC cultures were performed from vaginal wall biopsies. SMC were incubated with levormeloxifene (0.1 μM, 1 μM), in 96-well plates and cell proliferation was assessed by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazoliumbromide (MTT) assay at 24 hours. Tropoelastin production was measured by the Fastin Assay kit and TGF-β1 levels were assessed by ELISA. Results: SMC proliferation was significantly increased by levormeloxifene [relative cell number, mean ± SE, levormeloxifene 0.1 μM 130 ± 13% of control (P=NS), 1 μM 151 ± 19% of control (P<0.05)]. Tropoelastin production was significantly decreased by levormeloxifene [mean ± SE, levormeloxifene 0.1 μM 75 ± 4% of control (P=NS), 1 μM 64 ± 2% of control (P<0.05)]. In addition, TGF-β1 production was significantly decreased [mean ± SE, levormeloxifene 0.1 μM 79 ± 11% of control (P=NS), 1 μM 72 ± 14% of control (P<0.05)]. Conclusions: Levormeloxifene increases vaginal SMC proliferation, inhibits tropoelastin and TGF- β1 production.
A novel intermittent vasomotion induced by potassium in rat pulmonary artery was investigated with a view to characterize the ion channel mechanisms governing such secondary oscillatory activity. Isometric force was recorded from ring preparations of rat isolated pulmonary arteries incubated in a modified Krebs buffer containing K+ 15–18 mM and nitro-L-arginine methyl ester (10 μM). Tissues exhibited a stable pattern of on-off vasomotion consisting of intermittent contractile wave (ICW) activity with a periodicity of 7–8/hr and a rising phase of oscillatory ramping-up of contractile tone at 7 cycles/min. L-channel antagonists arrested (nicardipine; 3nM) or retarded (verapamil, 30 nM) ICW activity with a concomitant wave asynchronization or decrease in amplitude. Mibefradil (30–100 nM) inhibited ICW ramping-up without affecting ICW period. Niflumic acid (1.0–3.0 μM) exerted dual actions on ICW amplitude but arrested ICW cycling at 10 μM. K+-channel blockers produced shortening of ICW period (4-aminopyridine, Ba2+ 30 μM; Cs+ 3.0–6.0 mM) and increase (tetraethylammonium; 1.0 mM) or decrease (Ba2+, 100 μM) in amplitude. Cyclopiazonic acid caused ICW asynchronization (0.3 μM) or cessation (1.0 μM) of ICW cycling. Fasudil retarded ramping-up contractile oscillations without changing ICW period. The inhibitory effects of nicardipine, niflumic acid and cyclopiazonic acid were partially surmounted by small additional increments in [K+]e. Our findings support the concept that a secondary vasomotive oscillator operates in rat pulmonary artery which enables the activity of the primary oscillator to be regulated in a cyclic manner via sarcolemmal L-type Ca2+ channels and an array of K conductances.
Purpose: Tissue dysoxia is thought to be a fundamental cause of the organ failure that occurs as a result of shock. Plasma lactate has been frequently measured as an indicator of the state of systemic tissue metabolism. On the other hand, tissue lactate levels can directly indicate a disorder in the state of cytological tissue metabolism. The continuous monitoring of lactate levels in subcutaneous tissue will reflect the state of tissue dysoxia more precisely than levels of lactate in the plasma lactate. We have investigated the differences in the levels of plasma and tissue lactate using a microdialysis (MD) technique in an animal septic shock model. Method: Male 8-week-old Wistar/ST rats were used. We prepared an animal model by injection of lipopolysaccharide (LPS) into the abdominal cavity. LPS was given to 9 animals in the experimental group while physiological saline was given to 6 animals in the control group. A MD probe was used to quantify the lactate levels in the subcutaneous tissue. The mean arterial pressure, blood gas content and lactate levels were measured every 50 min up to 400 min after injection and compared between both groups. Result: The MAP of both groups showed similar changes after injection. Plasma lactate levels in the LPS group showed a significant increase after 100 min and reached a plateau from 150 min to 250 min. Subcutaneous lactate in the LPS group showed a significant increase after 150 min. Subcutaneous pyruvate in the LPS group showed a significant increase after 100 min. The lactate/pyruvate (L/P) ratio in the subcutaneous tissue showed a sustained increase from 300 min in the LPS group. Conclusion: Monitoring plasma lactate levels is useful for the early assessment of anaerobic metabolism before hypotension. Plasma lactate levels did not increase during some periods. This phenomenon was due to the balance between production and utilization. However, tissue lactate showed a chronological increase. These results suggest that the measurement of tissue lactate levels is reliable for assessing local energy metabolic disturbances. Under conditions of septic shock, an increase in lactate levels was found to be a sensitive marker of tissue metabolism disorder.
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