Effect of chloride channel blocker on pulmonary hypertension induced by high pulmonary blood flow in rats / 中华实用儿科临床杂志

Objective To study the effect of chloride channel blocker(niflumic acid,NFA) on pulmonary hypertension induced by high pulmonary blood flow in rats.Methods Fifty male or female Sprague-Dawley rats were randomly divided into 5 groups:normal group,sham group,model group,drug 1 group,and drug 2 group,with 10 rats in each group.After subjected to an abdominal aorta-inferior vena cava shunt,all the rats were reared under the same condition for 11 weeks.Then,mean pulmonary artery pressure(mPAP) and right ventricular hypertrophy index(RVHI) of each rat were measured.In addition,arterial wall area/vessel area (W/V) and arterial wall thickness/vessel external diameter(T/D) of each rat were also measured.Results 1.The mPAP of model group [(25.79 ± 4.03) mmHg,1 mmHg =0.133 kPa] was significantly higher than those of normal group [(16.48 ± 1.70) mmHg],sham group [(17.03 ± 2.01) mmHg],drug 1 group [(21.78 ± 2.77) mmHg] and drug 2 group [(20.31 ± 2.15) mmHg] (F =18.983,P ＜0.01).Although the mPAP of drug 1 group was a little higher than drug 2 group,there was no significant difference (P ＞ 0.05).Compared with normal group and sham group,the mPAP of drug 1 group and drug 2 group increased(P ＜0.01,respectively).2.The W/V and T/D of model group were significantly higher than those of normal group,sham group,drug 1 group and drug 2 group (F =26.135,15.527,all P ＜ 0.001).The W/V and T/D of two drug groups showed no significant difference,but they were higher than those of normal group and sham group (P ＜ 0.01,respectively).Conclusions Chloride channel blocker NFA partly decrease mPAP of pulmonary hypertension indnced by high pulmonary blood flow in rats,and inhibit proliferation of vascular smooth muscle cells.These results suggest that NFA had part of therapeutic effect to pulmonary hypertension induced by high pulmonary blood flow.

Effect of the chloride channel activity on vascular tone in the spontaneously hypertensive rats / 中国病理生理杂志

AIM: To study the chloride channel activity [ICl_(Ca)] in vascular smooth cells of the spontaneously hypertensive rats (SHR). METHODS: The vascular beds of mesenteric arteries were isolated from the pentobarbital anesthetized rats and perfused with 37 ℃ PSS at a constant flow rate. The vasoconstriction response to norepinphrine (NE) was determined by changes in perfused pressure. The strips of the rat arteries were mounted in an organ chamber filled with 37 ℃ PSS and the vascular tension was measured. RESULTS: (1) The contractile responses of mesenteric arteries to NE in SHR were greater than that in Wistar rats. (2) The inhibitory magnitude of the contractile response by niflumic acid in SHR was significantly less than that in Wistar rats and showed dose-dependent manner. (3) Decreasing the extracellular Cl~- concentration increased the contractile response to NE significantly and the amplitude of enhanced contractile response in SHR was greater than that in Wistar rats. CONCLUSION: It can be concluded that NE-induced contraction is enhanced in SHR, which is partly due to an increase in Cl~- efflux through the Ca~(2+)-activated Cl~- channels. The chloride channel activity may increase in association with the elevation of vascular tone and blood pressure.

Inhibitory effect of niflumic acid on the proliferation of airway smooth muscle cells / 中国病理生理杂志

AIM: Niflumic acid (NFA) is known as a kind of inhibitor of calcium-activated chloride channel. The inhibition and mechanism of NFA on the proliferation of airway smooth muscle cells (ASMCs) were investigated. METHODS: Using [ 3H]-TdR incorporation method, we examined the effect of NFA (at concentration of 10 and 50 ?mol/L) on the proliferation of primarily ASMCs from BALB/c mouse. With confocal laser scanning microscope the [Ca 2+ ]i in ASMCs exposed to histamine was observed, and the opposed effects of NFA and nifedipine on histamine were also checked. Finally the effect of NFA on expression of MAPK in ASMCs was examined by indirect immunofluorescent assay. RESULTS: Compared with control group, the proliferation of NFA group was reduced markedly with dependent concentration. Histamine significantly improved the [Ca 2+ ]i in ASMCs, but NFA and nifedipine showed the inhibition on the effect of histamine. NFA reduced the level of MAPK expression in ASMCs. CONCLUSION: It is demonstrated that NFA inhibits the proliferation of ASMCs by reducing [Ca 2+ ]i and the expression level of MAPK. [

Effects of Cl- channel blockers on the cardiac ATP-sensitive K+ channel

To explore whether Cl- channel blockers interact with the ATP-sensitive K+ (KATP) channel, I have examined the effect of two common Cl- channel blockers on the KATP channel activity in isolated rat ventricular myocytes using patch clamp techniques. In inside-out patches, 4,4'-diisothio-cyanatostilbene-2,2'-disulfonic acid (DIDS) and niflumic acid applied to bath solution inhibited the KATP channel activity in a concentration-dependent manner with IC50 of 0.24 and 927 muM, respectively. The inhibitory action of DIDS was irreversible whereas that of niflumic acid was reversible. Furthermore, DIDS-induced block was not recovered despite exposure to ATP (1 mM). In cell-attached and inside-out patches, DIDS blocked the pinacidil- or 2,4-dinitrophenol (DNP)-induced KATP channel openings. In contrast, niflumic acid did not block the pinacidil-induced KATP channel openings in inside-out patches, but inhibited it in cell-attached patches. DIDS and niflumic acid produced additional block in the presence of ATP and did not affect current-voltage relationship and channel kinetics. All these results indicate that DIDS among Cl- channel blockers specifically blocks the cardiac KATP channel.