Niflumic acid (NFA) is a novel gap junction (GJ) inhibitor. The aim of the present study was to investigate the effect of NFA on GJ communication and the expression of connexin (Cx) in vascular smooth muscle cells (VSMCs) of mesenteric arterioles of spontaneously hypertensive rats (SHR). Whole-cell patch clamp recording demonstrated that NFA at 1×10–4 M significantly inhibited the inward current and its effect was reversible. The time for charging and discharging of cell membrane capacitance (Cinput) reduced from 9.73 to 0.48 ms (P<0.05; n=6). Pressure myograph measurement showed that NFA at 3×10-4 M fully neutralized the contraction caused by phenylephrine. The relaxation responses of normotensive control Wistar Kyoto (WKY) rats were significantly higher, compared with those of the SHRs (P<0.05; n=6). Western blot and reverse transcription-quantitative polymerase chain reaction analyses showed that the mRNA and protein expression levels of Cx43 of the third-level branch of mesenteric arterioles of the SHRs and WKY rats were higher, compared with those of the first-level branch. The mRNA and protein expression levels of Cx43 of the primary and third-level branches of the mesenteric arterioles in the SHRs were higher, compared with those in the WKY rats (P<0.05; n=6). The mRNA levels of Cx43 in the mesenteric arterioles were significantly downregulated by NFA in a concentration-dependent manner (P<0.01; n=6). The protein levels of Cx43 in primary cultured VSMCs isolated from the mesenteric arterioles were also significantly downregulated by NFA in a concentration-dependent manner (P<0.01; n=6). These results showed that the vasorelaxatory effects of GJ inhibitors were reduced in the SHRs, which was associated with a higher protein expression level of Cx43 in the mesenteric arterioles of the SHRs. NFA also relaxed the mesenteric arterioles by reducing the expression of Cx43, which decreased blood pressure. Therefore, regulation of the expression of GJs may be a therapeutic target for the treatment of hypertension.

The aim of the present study was to examine whether single-nucleotide polymorphisms (SNPs) of β1 subunit of large-conductance Ca2+-activated K+ channel (KCNMB1) and inwardly rectifying K+ channel, subfamily J, member-11 (KCNJ11) are associated with essential hypertension (EH) in Xinjiang Kazak Chinese patients. A polymerase chain reaction-restriction fragment length polymorphism technique was applied to detect the distribution of selected alleles and genotype frequencies in a cohort of Xinjiang Kazak Chinese patients. Samples from 267 patients with EH and 259 normotensive (NT) controls were analyzed. An unconditional logistic regression analysis was used to estimate the odds ratio and 95% confidence interval of the risk factors that are associated with the development of EH. Genotype and allele frequency analyses revealed that the frequency of genotypes KCNJ11-rs2285676 and KCNMB1-rs11739136 was not significantly different between the EH and NT groups. Individuals carrying the GG genotype of KCNJ11-rs5219 had a 2.08 times higher risk of having EH than individuals carrying the GA+AA genotype of KCNJ11-rs5219. Furthermore, the G allele frequency of KCNJ11-rs5219 in the EH group was significantly higher than that of the NT group (P=0.048). Additionally, logistic regression analysis revealed that the body weight and GG genotype of KCNJ11-rs5219 were positively associated with EH in Xinjiang Kazak Chinese patients (P<0.01).

Niflumic acid (NFA) is a type of non-steroidal anti-inflammatory drug. Neuropathic pain is caused by a decrease in presynaptic inhibition mediated by γ-aminobutyric acid (GABA). In the present study, a whole-cell patch-clamp technique and intracellular recording were used to assess the effect of NFA on GABA-induced inward current in dorsal root ganglion (DRG) neurons of a chronic constriction injury (CCI) model. It was observed that 1–1,000 µmol/l GABA induced a concentration-dependent inward current in DRG neurons. Compared with pseudo-operated rats, the thermal withdrawal latency (TWL) of CCI rats significantly decreased (P<0.01); however, the TWLs of each NFA group (50 and 300 µmol/l) were significantly longer than that of the CCI group (P<0.01). In the CCI group, the response evoked by GABA (10−6-10−3 mol/l) was reduced in a concentration dependent manner compared with a normal control group (P<0.01), and the current amplitudes of CCI rats activated by the same concentrations of GABA (10−6-10−3 mol/l) were significantly decreased compared with the control group (P<0.05). The inward currents activated by 100 µmol/l GABA were suppressed by treatment with 1, 10 and 100 µmol/l NFA (5.32±3.51, 33.8±5.20, and 52.2±6.32%, respectively; P<0.05). The inverse potentials of GABA-induced currents were 9.87±1.32 and 9.64±1.24 mV with and without NFA, respectively (P<0.05). Pre-treatment with NFA exerted a strong inhibitory effect on the peak value of GABA-induced current, and the GABA-induced response was inhibited by the same concentrations of NFA (1, 10 and 100 µmol/l) in the control and CCI groups (P<0.05). The results suggest that NFA reduced the primary afferent depolarization (PAD) associated with neuropathic pain and mediated by the GABAA receptor. NFA may regulate neuropathic pain by inhibiting dorsal root reflexes, which are triggered PAD.