ATP敏感性钾通道开放剂埃他卡林对大鼠低氧性肺动脉高压的影响

EFFECTS OF IPTKALIM, A NOVEL ATP-SENSITIVE POTASSIUM CHANNEL OPENER, ON HYPOXIA-INDUCED PULMONARY VASCULAR REMODELING IN RATS

目的 :探讨新型ATP敏感性钾通道开放剂 (KATPCO)埃他卡林 (iptkalim ,Ipt)对低氧性肺动脉高压 (HPH)大鼠肺血管重构的影响。方法 :将大鼠置于常压低氧舱内 (O2 1 0 %± 0 .5 % ) ,8h/d ,每周 6d ,4周后测定平均肺动脉压(mPAP)、RV/ (LV +S) ;用图象分析仪测量与呼吸性细支气管伴行的肺小动脉外径 (ED)、动脉中层壁厚 (MT)、动脉管壁中层面积 (MA)、动脉管腔面积 (VA)和血管总面积 (TAA)。结果 :慢性低氧组大鼠的mPAP和RV/ (LV +S)显著高于正常对照组 (P <0 .0 1 ) ;图象分析显示低氧组大鼠肺小动脉中层壁厚与动脉外径百分比 (MT % )、动脉壁中层面积与血管总面积百分比 (MA % )均显著高于对照组 (P <0 .0 1 ) ;慢性低氧组大鼠肺小动脉管腔面积 (VA)与血管总面积 (TAA)百分比显著低于正常组 (P <0 .0 1 )。Ipt 0 .75mg·kg- 1 ·d- 1 和 1 .50mg·kg- 1 ·d- 1 均可显著抑制低氧性肺血管壁重构 ,降低肺动脉压 ,减少右心室肥厚 ,1 .50mg·kg- 1 ·d- 1 则可逆转持续低氧所致的所有病理性变化。结论

Aim: To investigate whether pulmonary vascular remodeling in hypoxic pulmonary hypertensive rats could be prevented by treatment with a selective K ATP CO, iptkalim (Ipt). Methods: Rats were fed in hypoxic and normobaric environment (10%±0.5% O 2 ,8 h/day and 6 day/week) and divided into control group, hypoxia group(hypoxic rat treated with ig NS 5.0 ml·kg -1 ·d -1 ) , treated groupⅠ(hypoxic rat treated with ig Ipt 0.75 mg·kg -1 ·d -1 ), treated group Ⅱ(hypoxic rat treated with ig Ipt 1.5 mg·kg -1 ·d -1 ). After 4 wk, the mean pulmonary arterial pressure(mPAP) , right ventricle/left ventricle and septum\[RV/(LV+S)\] were measured, and the small pulmonary arterial morphologic changes were observed with morphometric analysis under microscopes in four groups. Results: The level of mPAP and RV/(LV+S) was significantly higher in the hypoxic group than those in control group ( P <0.01). Morphometric analysis revealed that the ratio of vascular medial wall thickness to external diameter (MT%) and the ratio of vascular medial cross sectional area to total arterial cross sectional area (MA%) were also significantly increased in the hypoxic group than those in control group ( P <0.01) and the ratio of vessel lumen cross sectional area to total arterial cross sectional area (VA%) was significantly lower in the hypoxic group than those in control group ( P <0.01). Ipt 0.75 mg·kg -1 ·d -1 or 1.5 mg·kg -1 ·d -1 decreased the level of mPAP(mmHg), RV/(LV+S), and inhibited the small pulmonary arterial remodeling significantly. Ipt 1.5 mg·kg -1 ·d -1 reversed all pathological indices. Conclusion: K ATP CO iptkalim can be a very promising candidate for the treatment of hypoxic pulmonary hypertension.wassignificantlyhigherinthehypoxicgroupthanthoseincontrolgroup(P<0.0 1 ).Morphometricanalysisrevealedthattheratioofvascularmedialwallthicknesstoe