15-羟廿碳四烯酸对缺氧性肺血管收缩电压门控性K^＋通道的作用机制

缺氧性肺血管收缩(HPV)是机体的一种保护功能，但其机制至今尚不完全清楚。15-羟廿碳四烯酸(15-Hydroxyeicosatetrienoic acid,15-HETE)是15-脂质氧化酶(15-LO)代谢花生四烯酸(AA)的产物，其对肺动脉平滑肌细胞(PSMVC)电压门控性K^ 通道(Kv)有抑制作用，使细胞去极化，细胞内钙离子浓度增加，进而导致细胞收缩，产生HPV，故15-HETE可能是形成HPV的始发介质。     

Allopurinol inhibits hypoxic pulmonary vasoconstriction. Role of toxic oxygen metabolites

The exact mechanism whereby hypoxic pulmonary vasoconstriction (HPV) is elicited is still unsettled. We have evaluated a possible role for toxic oxygen metabolites (TOM), employing a set-up of blood-perfused isolated rat lungs. HPV reflected as pulmonary arterial pressor responses, was evoked by alternately challenging the airways with a hypoxic- and a normoxic gas mixture, resulting in gradually increasing responses until a maximum was obtained. In a sequence of responses (mean +/- s.e. mean) increasing from 2.5 +/- 0.2 kPa to 3.2 +/- 0.1 kPa, administration to the perfusate of the inhibitor of xanthine oxidase (XO), allopurinol (AP) reduced the subsequent response to 2.5 +/- 0.2 kPa (P less than 0.001). By contrast, AP did not affect vasoconstriction induced by serotonin or bradykinin. In control experiments responses continued to increase after administration of hypoxanthine (substrate of XO). Neither pretreatment with daily injections of the antioxidant vitamin E for 3 days in advance, nor addition to the perfusate of the scavenger enzymes superoxide dismutase and catalase, or dimethylsulfoxide had any impact on HPV; the subsequent responses rose at the same rate and in the same way as before. Thus, the present study has shown that AP inhibition of XO depresses HPV. This could be due either to reduced production of TOM or to accumulation of purine metabolites. The absence of inhibitory effects of quenchers of TOM refutes a role for these metabolites in the elicitation of HPV. More likely, AP inhibits HPV by interfering with the purine metabolism.     

Mesenchymal stem cells attenuate hypoxic pulmonary vasoconstriction by a paracrine mechanism

BACKGROUND: Hypoxic pulmonary vasoconstriction (HPV) may be an adaptive mechanism to correct ventilation-perfusion mismatch in the face of hypoxia. In chronic hypoxia, prolonged vasoconstriction may result in pulmonary hypertension and cor pulmonale. It has been shown that during chronic hypoxia, mesenchymal stem cells (MSCs) may contribute to pulmonary vascular remodeling, anti-inflammation, and vascular stability. Also, MSCs have been shown to release growth factors when stressed by hypoxia. We hypothesized that MSCs reduce HPV by a paracrine mechanism. To test this, MSCs were stressed by hypoxia in tissue culture and the cell-free media was then used to treat the pulmonary arteries subjected to HPV. METHODS: Adult male (250-350 g) Sprague Dawley rat pulmonary arteries (n = 10/group) were isolated and suspended in physiological organ baths. Human MSCs were stressed with 60-min hypoxia and conditioned media was collected. Pulmonary artery rings were treated with vehicle or MSC-conditioned (cell-free) media prior to hypoxia. Force displacement was continuously recorded. Data (mean +/- SEM) were analyzed with two-way analysis of variance with post-hoc Bonferroni test. RESULTS: Pulmonary arteries exposed to MSC-conditioned media experienced an augmented vasodilatory phase as compared to vehicle. Maximum vasodilation was 53.58 +/- 6.42% versus 39.76 +/- 4.05% for vehicle (P < 0.001). In addition, delayed, phase II vasoconstriction was significantly attenuated as compared to vehicle. Maximum phase II vasoconstriction was 28.51 +/- 12.42 versus 86.29 +/- 15.99% for vehicle (P < 0.001). CONCLUSIONS: We conclude that acute hypoxia induces HPV and that MSC-conditioned media acutely attenuates this effect. Thus, in addition to a direct contribution to vessel remodeling in chronic hypoxia, MSCs may acutely protect and attenuate hypoxic pulmonary vasoreactivity through a paracrine mechanism.     

Interaction of verapamil and halogenated inhalation anesthetics on hypoxic pulmonary vasoconstriction

Calcium channel blockers and halogenated inhalation anesthetics reduce hypoxic pulmonary vasoconstriction (HPV) when administered separately to isolated rat lungs. This study was undertaken to investigate the effect of combining the calcium channel blocker verapamil with halothane or isoflurane. HPV was elicited in three groups of experiments. First, we studied the effect of halothane 1.3 MAC and varying concentrations of verapamil. Halothane reduced HPV as a mean by 34.7%, and a dose-dependent reduction was seen with verapamil. The depressant effect of the combination of halothane and verapamil was significantly greater than when the drugs were administered alone. We further investigated in separate groups the effects of varying concentrations of halothane and isoflurane, administered both separately and in combination with a constant dose of verapamil (1.02 nmol). Both anesthetics depressed HPV in a dose-dependent fashion. Verapamil reduced HPV as a mean by 34.2% and 39.3% in the halothane and isoflurane groups, respectively. The inhibition caused by combining verapamil with an anesthetic was significantly greater than when administered separately. We conclude that verapamil in combination with halothane or isoflurane has an additive dampening effect on HPV.     

Effect of diltiazem on hypoxic pulmonary vasoconstriction in dogs

We have examined the effect of diltiazem upon the pulmonary vascular response to the left lower lobe (LLL) hypoxia in dogs.Without diltiazem, the fraction of cardiac output perfusing the LLL (Q_LLL/Q_T) measured by the ultrasonic doppler rheometer in the hypoxic phase was 21.0 ± 11.7(%) of the ratio in the first normoxic phase. When diltiazem was given as a 0.48mg/kg intravenous bolus followed by an intravenous infusion of 0.48mg/kg/hr and 0.96mg/kg intravenous bolus followed by an intravenous infusion of 0.96mg/kg/hr, Q_LLL/Q_T in the hypoxic phase were 34.0 ± 14.0, 48.6 ± 16.1(%) of the ratio in the first normoxic phase respectively. Significant difference was observed at all diltiazem concentrations.With respect to Pa_{O 2}, significant difference was not observed at all diltiazem concentrations in the ratio of the hypoxic phase to the first control phase.So we concluded that diltiazem obviously attenuated hypoxic pulmonary vasoconstriction (HPV) response but did not decrease Pa_{O 2} because of keeping myocardial oxygen balance and better ventilation/perfusing relationship.(Okutomi T, Wakabayashi C, Ikeda K: Effect of diltiazem on hypoxic pulmonary vasoconstriction in dogs. J Anesth 3: 138–144, 1989)     

异丙酚对大鼠肺动脉压及缺氧性肺血管收缩反应的影响

目的:观察不同剂量异丙酚对肺动脉压及缺氧性肺血管收缩反应(HPV)的影响。方法:采用离体大鼠全血灌注肺模型。结果:空气 4％CO_2通气条件下肺动脉压为1.78±0.24kPa,分别给予异丙酚4mg/kg、6mg/kg、8mg/kg,MPAP分别下降至1.53±0.25kPa、1.40±0.23kPa、1.38±0.24kPa,与给药前相比MPAP明显降低,6mg/kg和8mg/kg异丙酚降压作用明显强于4mg/kg。吸入气为混合气(3％O_2 4％CO_2 93％N_2)情况下肺动脉压从1.60±0.23kPa上升至2.38±0.31kPa。分别给予异丙酚4mg/kg、6mg/kg、8mg/kg。MPAP分别降至2.01±O.35kPa、1.85±0.37kPa、1.83±O.41kPa,抑制缺氧性肺动脉升压反应分别为47％、67％、71％。且6mg/kg和8mg/kg与4mg/kg相比抑制程度有显著差异。结论:异丙酚可降低肺动脉压及抑制缺氧性肺血管收缩反应,且与剂量有关。     

川芎嗪对大鼠在体缺氧性肺血管收缩反应的影响

以大鼠在体（ｉｎ ｖｉｖｏ）全血恒流灌注模型观察川穹嗪对缺氧性肺血管收缩（ＨＰＶ）反应的影响。血液恒流灌入肺动脉的速度为１４ｍｌ／ｍｉｎ，平均肺动脉压（ＭＰＡＰ）为２．４４±０．４２ｋＰａ，吸入３％Ｏ２＋４％ＣＯ２＋９３％Ｎ２混合气后，ＭＰＡＰ明显升高至３．６９±０．５５ｈＰａ，产生ＨＰＶ反应。当注入川芎嗪４ｍｇ／ｋｇ和 ８ｍｇ／ｋｇ后， ＭＰＡＰ分别下降至 ２． ９０± ０． ３０ｋＰａ和 ２． ４８± ０． ３３ｋＰａ，抑制升压反应分别为 ６３％和９６％。结果表明，川芎嗪可明显抑制ＨＰＶ且与剂量有关。     

一氧化碳合成酶抑制剂对缺氧性肺血管收缩反应的影响

目的 观察内皮及内源性一氧化碳（CO）合成酶抑制剂（血红素氧化酶抑制剂ZnppIX)对大鼠缺氧性肺血管收缩反应的影响，探讨内源性CO在缺氧性肺血管收缩反应中的作用。方法 制备Wistar大鼠动脉环，观察内皮与缺氧性肺血管收缩反应的关系；并以一氧化氮合成酶抑制剂L－NAME为对照，观察ZnppIX对缺氧性肺血管收缩反应的影响。结果 缺氧可使去氧肾上腺素顶收缩的肺动脉环出现明显的收缩反应，去除内皮或血管环用L－NAME孵育后，缺氧性肺血管收缩反应受抑，而用ZnppIX及L－NAME共同孵育后，缺氧性肺血管收缩反应明显抑制或消除，与L－NAME组相比有显著性差异（P＜0．01）。L－NAME组的缺氧张力变化率与未孵育前相比也有显著性差异（P＜0．01）。结论 缺氧性肺血管收缩反应是内皮依赖性的，ZnppIX可抑制大鼠氧性肺血管收缩反应，内源性CO与NO一样参与了缺氧性血管收缩反应。     

The effects of endogenous sex hormones and acute hypoxia on vasoconstriction in isolated rat pulmonary artery rings

BACKGROUND: Studies have noted gender differences in various models but have not investigated whether hormone depletion will abolish these differences. Therefore, we measured isometric force displacement in normal males, castrated males, normal females, and ovarectomized females. MATERIALS AND METHODS: Adult male, adult female, castrated male, and ovarectomized female (250-350 g) Sprague Dawley rat pulmonary arteries (n = 7-8/group) were isolated and suspended in physiological organ baths. Force displacement was continuously recorded for 60 min of hypoxia. Data (mean +/- SEM) was analyzed with two-way analysis of variance with post-hoc Bonferroni test or Student's t-test. RESULTS: Maximum vasodilation of normal males was -79.47 +/- 3.34%, while normal adult females exhibited a maximum vasodilation of -88.70 +/- 6.21% (P = 0.8149). In addition, delayed, phase II vasoconstriction of male pulmonary arteries rings was 89.79 +/- 7.25%, while adult females demonstrated a maximum phase II vasoconstriction of 95.90 +/- 14.23% (P = 0.9342). Hormone depletion of males exhibited a maximum vasodilation of -70.45 +/- 5.08% for castrated males as compared to -79.47 +/- 3.34% for normal adult males (P = 0.3805). Castrated males exhibited a maximum phase II vasoconstriction of 86.20 +/- 15.76% compared to 89.79 +/- 7.25% exhibited by normal adult males (P = 0.9516). CONCLUSIONS: Hormone depletion in males and females did not alter pulmonary vasoreactivity in acute hypoxia.     

Marked decrease in arterial oxygen tension associated with continuous intravenous nifedipine administration

Intravenous nifedipine was administered to treat arterial hypertension in a 54-year-old woman presenting for removal of a meningioma. A marked decrease in arterial oxygen tension occurred during the nifedipine infusion. Inhibition of hypoxic pulmonary vasoconstriction by nifedipine is discussed.     

Role of potassium channels in isoflurane- and sevoflurane-induced attenuation of hypoxic pulmonary vasoconstriction in isolated perfused rabbit lungs

BACKGROUND: Although potassium channels are thought to be responsible for the initiation of hypoxic pulmonary vasoconstriction (HPV), their role in the HPV-inhibitory effect of volatile anesthetics is unclear. The current study tested if the HPV-inhibitory effect of isoflurane and sevoflurane can be affected by changing the potassium-channel opening status with specific potassium-channel inhibitors in isolated rabbit lungs. METHODS: Isolated rabbit lungs were divided into eight groups (n = 6 each in isoflurane groups and n = 8 in sevoflurane groups): those receiving no inhibitor treatment = control-isoflurane and control-sevoflurane groups; those treated with an adenosine triphosphate-sensitive potassium (K(ATP))-channel inhibitor, glibenclamide = glibenclamide-isoflurane and glibenclamide-sevoflurane groups; those treated with a high-conductance calcium-activated potassium (K(Ca))-channel inhibitor, iberiotoxin = iberiotoxin-isoflurane and iberiotoxin-sevoflurane groups; and those treated with a voltage-sensitive potassium (Kv)-channel inhibitor, 4-aminopyridine = 4-aminopyridine-isoflurane and 4-aminopyridine-sevoflurane groups. The effect of anesthetic on HPV was tested by exposure of the lungs to isoflurane at a concentration of 0, 0.5, 1, or 2 minimum alveolar concentration, or to sevoflurane at a concentration of 0, 0.5, 1, or 1.62 minimum alveolar concentration. The relation between anesthetic concentrations and the HPV response was analyzed by the Wagner equation. RESULTS: The inhibition of Kv channels by 4-aminopyridine and K(Ca) channels by iberiotoxin augmented the HPV response. The isoflurane-induced attenuation of HPV was attenuated by voltage-sensitive potassium-channel inhibition with 4-aminopyridine, potentiated by K(Ca)-channel inhibition with iberiotoxin, but not affected by K(ATP)-channel inhibition with glibenclamide. The sevoflurane-induced attenuation of HPV was not affected by any of the potassium-channel inhibitors. CONCLUSIONS: Isoflurane may modulate the HPV response partially through K(Ca) and Kv channels, but sevoflurane may attenuate the HPV response through other pathways rather than through the currently investigated potassium channels in isolated rabbit lungs.