[Regulatory role of calcium activated chloride channel in pulmonary vascular structural remodeling in rats with pulmonary arterial hypertension induced by high pulmonary blood flow].

OBJECTIVE: To explore the regulatory role of calcium activated chloride channel (CaCC) in vascular structural remodeling in pathogenesis of pulmonary arterial hypertension (PAH) induced by high pulmonary blood flow. METHOD: An abdominal aorta and inferior vena cava shunting operation was used to induce high pulmonary blood flow and establish a PAH rat model.Seventy-five SD rats were randomly divided into normal, sham, shunt, niflumic acid (NFA) 1(0.2 mg/(kg·d))and NFA 2 (0.4 mg/(kg·d)) groups. There were 15 rats in each group. Pulmonary artery pressure and vascular structural remodeling were measured, arteriole contraction ratio among these groups were compared using vascular tone analysis system, and the electrophysiology of pulmonary artery smooth muscle cell (PASMC) was recorded using patch clamp technology. Differences between multiple groups were compared through variance analysis and that between groups with q test. RESULT: Compared with normal ((14.4±1.3 ) mmHg, 1 mmHg=0.133 kPa)and sham groups ((13.5±2.3 ) mmHg), mean pulmonary artery pressure in shunt group ((27.4±2.4 ) mmHg) increased significantly (P<0.05). Compared with shunt group, mean pulmonary artery pressure in NFA 1 group ((21.2±2.0) mmHg) and NFA 2 group ((22.3±2.0) mmHg) decreased significantly (P<0.05). Pulmonary vascular structural remodeling including pulmonary artery stenosis presented in shunt group. Compared with normal ((114.3±1.2)%) and sham ((115.5±1.1)%) groups, arteriole contraction ratio to 10(-5) mol/L phenylephrine in shunt group ((132.6±1.4)%) increased significantly (P<0.05). Compared with shunt group, pulmonary vascular structural remodeling alleviated in NFA 1 and NFA 2 groups. Arteriole contraction ratio in NFA 1 group ((126.4±1.3)%) and NFA 2 group ((124.6±1.0)%) decreased significantly compared with shunt group (P<0.05). Patch clamp technique recorded typical CaCC currents. Compared with normal ((32.3±2.3 ) pA/pF) and sham groups ((35.3±1.2) pA/pF), the CaCC current density of PASMC in shunt group ((51.3±2.7) pA/pF) increased significantly (P<0.05). Compared with shunt group, the CaCC current density of PASMC in NFA 1 group ((40.2±1.5 ) pA/pF) and NFA 2 group ((42.7±2.2) pA/pF) decreased significantly (P<0.05). CONCLUSION: CaCC is involved in pulmonary arterial hypertension induced by high pulmonary blood flow through regulating membrane potential. NFA attenuate pulmonary vascular structural remodeling and pulmonary pressure through decreasing CaCC current density of PASMC membrane.

Genetic polymorphism of cytochrome P450 2C19 in healthy Malaysian subjects.

AIMS: Impaired S-mephenytoin 4'-hydroxylation is a well-described genetic polymorphism affecting drug metabolism in humans. Although ethnic differences in its distribution of polymorphism has been described, it is not known whether there is an ethnic heterogeneity of the structure and expression of the CYP2C19 enzyme in the Malaysian population. METHODS: Study subjects were 142 healthy, unrelated Malaysians aged 18-29 years. Baseline omeprazole and 2-h postingestion omeprazole and 5'-hydroxyomeprazole concentrations were measured for CYP2C19 phenotype determination. Identification of CYP2C19 genotypes was performed with the use of polymerase chain reaction. RESULTS: Phenotyping of CYP2C19 revealed that the prevalence of poor metabolizers (PMs) in the Malaysian population was 14.1%, whereas prevalence of PMs in genotyping was 12.6%. The PM genotypic prevalence rate was 5.6% in Malays, 19.1% in Chinese and 10.0% in Indian subjects. There were significant differences in PM genotypic prevalence rates among the three primary ethnic groups (P < or = 0.05). CONCLUSIONS: Phenotyping and genotyping revealed significant differences in the prevalence rates among the three ethnic groups in Malaysia, with Chinese recording highest prevalence.