Zhao Y J, Wang J, Rubin L J, Yuan X J
Department of Medicine, University of Maryland School of Medicine, Baltimore 21201, USA.
Am J Physiol. 1997 Feb;272(2 Pt 2):H904-12. doi: 10.1152/ajpheart.1997.272.2.H904.
Endogenous nitric oxide (NO) may contribute to the maintenance of normal pulmonary vasomotor tone, and inhaled NO is used to treat patients with pulmonary hypertension. Because pulmonary vascular tone is regulated by intracellular free Ca2+ concentration and membrane potential, which are controlled by the K+ channel activity in pulmonary artery (PA) smooth muscle cells, we sought to determine whether K+ channels are involved in NO-induced relaxation and, if so, which types of K+ channels are responsible. Authentic NO (approximately 0.3 microM) and sodium nitroprusside (SNP, 10 pM) both produced significant relaxation in isolated PA rings precontracted by increasing extracellular K+ concentration. Further elevation of the K+ concentration from 20 to 60 mM resulted in a significant increase in contraction but caused a marked decline in SNP- and NO-mediated PA relaxation. The dependence of SNP- and NO-induced relaxation on transmembrane K+ gradient suggests that K+ efflux through K+ channels is involved in these effects. Furthermore, 4-aminopyridine (4-AP, 5-10 mM), which blocks voltage-gated K+ channels (K(V)), and charybdotoxin (200 nM), which blocks Ca2+-activated K+ channels (K(Ca)), both significantly inhibited NO- and SNP-induced PA relaxation. The ATP-sensitive K+ channel blocker glibenclamide, however, had no effect on the relaxation response. The blocking of guanylate cyclase diminished, but did not abolish, the NO-induced relaxation, whereas 4-AP further decreased the NO-induced relaxant response in the presence of the guanylate cyclase inhibitor LY-83583. These data suggest that activation of both K(V) channels and K(Ca) channels by guanosine 3',5'-cyclic monophosphate-dependent and -independent pathways is a mechanism, at least in part, by which NO induces PA relaxation.
内源性一氧化氮（NO）可能有助于维持正常的肺血管舒缩张力，吸入NO用于治疗肺动脉高压患者。由于肺血管张力受细胞内游离Ca2+浓度和膜电位调节，而这两者又受肺动脉（PA）平滑肌细胞中钾通道活性的控制，我们试图确定钾通道是否参与NO诱导的舒张作用，如果是，哪些类型的钾通道起作用。纯NO（约0.3 microM）和硝普钠（SNP，10 pM）均可使通过增加细胞外钾浓度预收缩的离体PA环产生显著舒张。钾浓度从20 mM进一步升高至60 mM导致收缩显著增加，但使SNP和NO介导的PA舒张显著下降。SNP和NO诱导的舒张对跨膜钾梯度的依赖性表明，钾通过钾通道外流参与了这些作用。此外，阻断电压门控钾通道（K(V)）的4-氨基吡啶（4-AP，5-10 mM）和阻断钙激活钾通道（K(Ca)）的蝎毒素（200 nM）均显著抑制NO和SNP诱导的PA舒张。然而，ATP敏感性钾通道阻滞剂格列本脲对舒张反应无影响。鸟苷酸环化酶的阻断减弱但并未消除NO诱导的舒张，而在鸟苷酸环化酶抑制剂LY-83583存在的情况下，4-AP进一步降低了NO诱导的舒张反应。这些数据表明，鸟苷3',5'-环磷酸依赖和非依赖途径激活K(V)通道和K(Ca)通道是NO诱导PA舒张的一种机制，至少部分如此。
