Resta T C, Walker B R
Department of Physiology, University of New Mexico School of Medicine, Albuquerque 87131, USA.
Am J Physiol. 1996 Mar;270(3 Pt 2):H888-96. doi: 10.1152/ajpheart.1996.270.3.H888.
We have previously demonstrated that chronic hypoxia (CH) augments pulmonary arterial dilation to the endothelium-derived nitric oxide (EDNO)-dependent pulmonary vasodilator arginine vasopressin (AVP). The present study examined 1) whether this enhanced vasoreactivity is observed with other agents that act by stimulating constitutive NO synthase (cNOS), 2) whether CH increases arterial vascular smooth muscle sensitivity to NO, and 3) whether endogenous endothelin (ET) or an endothelium-derived hyperpolarizing factor (EDHF) contributes to this altered arterial reactivity following CH. We examined responses to the receptor-mediated EDNO-dependent dilators histamine and ET-1, the nonreceptor-mediated EDNO-dependent dilator ionomycin, and the NO donors 1, 3-propanediamine, N-4-[1-(3-aminopropyl)-2-hydroxy-2-nitrosohydrazino] butyl (spermine NONOate) and S-nitroso-N-acetylpenicillamine (SNAP) in U-46619-constricted, isolated perfused lungs from control and CH rats. Additional experiments examined responses to AVP in the presence of the ET-receptor antagonist PD-145065 or the K+ channel blockers glibenclamide or tetraethylammonium (TEA) in lungs from each group. Microvascular pressure was assessed by double occlusion, allowing calculation of segmental resistances. Total and arterial vasodilatory responses to histamine, ET-1, and ionomycin were augmented in lungs from CH vs. control animals. However, CH did not alter the vasodilation to spermine NONOate or SNAP. PD-145065, glibenclamide, and TEA had no effect on responses to AVP in either group. We conclude that increased activity of arterial cNOS may be responsible for the augmented pulmonary arterial dilation to EDNO-dependent vasodilators following CH.
我们先前已经证明，慢性低氧（CH）可增强肺动脉对内皮衍生的一氧化氮（EDNO）依赖性肺血管扩张剂精氨酸加压素（AVP）的扩张作用。本研究检测了：1）使用其他通过刺激组成型一氧化氮合酶（cNOS）起作用的药物时，是否也能观察到这种增强的血管反应性；2）CH是否会增加动脉血管平滑肌对NO的敏感性；3）内源性内皮素（ET）或内皮衍生的超极化因子（EDHF）是否参与了CH后这种改变的动脉反应性。我们检测了U-46619收缩的对照大鼠和CH大鼠的离体灌注肺对受体介导的EDNO依赖性扩张剂组胺和ET-1、非受体介导的EDNO依赖性扩张剂离子霉素以及NO供体1,3-丙二胺、N-4-[1-(3-氨基丙基)-2-羟基-2-亚硝基肼基]丁基（精胺硝普钠）和S-亚硝基-N-乙酰青霉胺（SNAP）的反应。另外的实验检测了每组肺组织在存在ET受体拮抗剂PD-145065或钾通道阻滞剂格列本脲或四乙铵（TEA）的情况下对AVP的反应。通过双重阻断评估微血管压力，从而计算节段阻力。与对照动物相比，CH大鼠肺组织对组胺、ET-1和离子霉素的总血管扩张反应和动脉血管扩张反应增强。然而，CH并未改变对精胺硝普钠或SNAP的血管扩张作用。PD-145065、格列本脲和TEA对两组中AVP的反应均无影响。我们得出结论，动脉cNOS活性增加可能是CH后肺动脉对EDNO依赖性血管扩张剂扩张作用增强的原因。
