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。     

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)     

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。     

Pulmonary blood flow reduction by prostaglandin F2α and pulmonary artery balloon manipulation during one-lung ventilation in dogs

The purpose of this experimental study was to compare two methods of pulmonary blood flow manipulation during one-lung ventilation (OLV), either reducing pulmonary blood flow to the non-ventilated lung by inflation of a pulmonary artery catheter balloon (PAB) or by infusion of prostaglandin F2 alpha (PGF2 alpha). Seven anaesthetized dogs were intubated with a Kottmeier endobronchial tube and ventilated with 66% O2. Systemic and pulmonary pressures and blood gases, cardiac output and airway pressure were measured, and the venous admixture (QSP/QT) was calculated. During two-lung ventilation (TLV) Pao2 was 43.6 +/- 1.9 kPa (mean +/- s.d.) and (QSP/QT) was 11 +/- 3%. OLV reduced Pao2 to 12.1 +/- 1.6 kPa (P less than or equal to 0.001) and increased QSP/QT to 40 +/- 4% (P less than or equal to 0.001). Mean pulmonary artery pressure and airway pressure increased. PAB inflation caused an increase in Pao2 to 19.9 +/- 2.9 kPa (P less than or equal to 0.02) and a decrease in QSP/QT to 27 +/- 6% (P less than or equal to 0.001). PGF2 alpha infusion (1.2 micrograms kg-1 min-1) into the pulmonary artery of the non-ventilated lung increased Pao2 to 22.4 +/- 3.3 kPa (P less than or equal to 0.001) and decreased QSP/QT to 25 +/- 4 (P less than or equal to 0.001). PGF2 alpha infusion resulted in a small increase in mean systemic and pulmonary artery pressures. During the infusion of 1.2 micrograms kg-1 min-1 of PGF2 alpha no signs of bronchoconstriction were observed. PAB inflation and PGF2 alpha infusion were equally effective in improving oxygenation and reducing venous admixture during OLV.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sevoflurane has no inhibitory effect on hypoxic pulmonary vasoconstriction (HPV) in dogs

There is no general agreement on the effect of inhalation anesthetics on hypoxic pulmonary vasoconstriction (HPV). We have examined the effect of sevoflurane upon the pulmonary vascular response to a left lower lobe (LLL) hypoxia in dogs by continuously measuring the fractional distribution to the LLL of total pulmonary blood flow (Q_LLL/Q_T) employing an ultrasonic transit time rheometer with flow probes attached to the LLL artery and the main pulmonary artery.During regional hypoxia without sevoflurane, blood flow distribution to the LLL as a mean was 48.2% of that determined under hyperoxic conditions. When sevoflurane was administered at concentrations of 2% and 4%, the LLL blood flow distributions during hypoxia were as a mean 40.2% and 47.0%, respectively, of the values obtained during the first hyperoxic periods. No change occurred in the pulmonary vascular resistance of the LLL(PVR_LLL) and the shunt ratio(Qs/Qt) between the concentrations used.Thus there was no significant effect of sevoflurane upon HPV whatever concentration used.(Okutomi T, Ikeda K: Sevoflurane has no inhibitory effect on hypoxic pulmonary vasoconstriction (HPV) in dogs. J Anesth 4: 123–130, 1990)     

通气侧肺吸入伊洛前列素对肺动脉压和缺氧性肺血管收缩的影响

目的 探讨雾化吸入伊洛前列素对大鼠单肺通气(one-lung ventilation,OLV)期间肺动脉压和缺氧性肺血管收缩(hypoxic pulmonary vasoconstriction,HPV)的影响。方法 雄性SD大鼠30只,随机分为A、B、C三组,每组10只。原位离体肺灌注模型建立后,调整气管导管深度致左侧肺OLV,FiO_2为100%,打开连接于呼吸回路的雾化器,A组吸入生理盐水,B组吸入伊洛前列素0.05μg·kg-1·min-1,C组吸入伊洛前列素0.1μg·kg~(-1)·min~(-1),记录灌注10min(T_1)、雾化吸入10min(T_2)和OLV 1h(T_3)的平均肺动脉压(MPAP)及左心房引流液氧分压(PaO_2)。通过测量T_1、T_2和T_3时的左心房引流液PaO_2计算氧合指数(oxygenation index,OI)。实验结束分别取双侧肺组织进行电镜检查。结果 与T_1时比较,T_2、T_3时三组MPAP明显升高(P0.05);T_2、T_3时B、C组MPAP明显低于A组(P0.05),且C组MPAP明显低于B组(P0.05)。与T_1时比较,T_2、T_3时三组OI明显降低(P0.05);T_2、T_3时C组OI明显高于B组(P0.05)。相对于B、C组通气侧,A组通气侧与A、B、C组非通气侧Ⅱ型肺泡上皮细胞核膜外突内陷,部分板层小体排空。结论 在大鼠原位肺灌注模型中,单肺通气期间雾化吸入伊洛前列素能明显降低平均肺动脉压,减少肺内分流并增加氧合。     

Cardiovascular and blood gas responses to inhaled anaesthetics in normoxic and hypoxic dogs

Changes in haemodynamics and blood gases were investigated before and after administration of 0.5, 1 and 1.5 MAC of halothane, enflurane and isoflurane in respectively 7, 7 and 9 dogs ventilated alternatively with a fraction of inspired O2 in N2 (FiO2) of 0.4 and with brief periods (10 min) of FiO2 of 0.1. Anaesthesia was induced with pentobarbital and the animals were paralysed with pancuronium. Acute hypoxic challenges with FiO2 of 0.1 consistently decreased arterial PO2 to 3.5-4.5 kPa and increased pulmonary vascular resistances by 60-100%. At identical inspired concentrations, as expressed in MAC units, all three inhaled anaesthetics induced a broadly comparable dose-related decrease in systemic blood pressures, due to a depression in cardiac performance as well as a reduction in systemic vascular resistances. Enflurane was the most potent myocardial depressor and isoflurane the most potent vasodilator, halothane being intermediate. Oxygen deprivation was associated with some enhancement of the cardiovascular depressant effects of the inhaled anaesthetics but, in spite of this, matching of O2 transport to tissue O2 demand appeared to be improved, probably in relation to a concomitant reduction in metabolic rate. Only isoflurane inhibited the hypoxic pulmonary pressor response, and this was associated with a slight deterioration in arterial oxygenation in both normoxic and hypoxic conditions.     

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。     

Pulmonary hemodynamic response to dopamine and dobutamine in hyperoxic and in hypoxic dogs

The pulmonary hemodynamic response to dopamine and to dobutamine was investigated in dogs ventilated with hyperoxia (fraction of inspired O2 concentration [FIO2], 0.4 balance nitrogen) and challenged with short periods of inspiratory hypoxia (FIO2 0.125 or 0.1 for 10 min). Dopamine at doses of 5, 10, and 20 micrograms X kg-1 X min-1 (n = 7 dogs) increased cardiac index (CI) and pulmonary artery pressure (PAP) without change in indexed pulmonary vascular resistance (PVRI) at both FIO2 0.4 and 0.125. Hypoxia-induced increases in PVRI were unaffected by dopamine. Dobutamine at doses of 5, 10, and 20 micrograms X kg-1 X min-1 (n = 7 dogs) increased CI, with an increase in PAP without change in PVRI at FIO2 0.4, and at FIO2 0.125 there was no change in PAP and a decrease in PVRI. Hypoxia-induced increases in PVRI were inhibited by dobutamine, partially at 5 and 10 micrograms X kg-1 X min-1, and completely at 20 micrograms X kg-1 X min-1. In two additional groups of seven dogs the effects of reducing FIO2 from 0.4 to 0.1 without and with dopamine or dobutamine either at 10 micrograms X kg-1 X min-1 (n = 7) or at 20 micrograms X kg-1 X min-1 (n = 7) were studied at an unchanged CI obtained by stepwise inflations of a balloon placed in the inferior vena cava. At constant flow both amines increased PVRI at FIO2 0.4 and did not significantly affect hypoxia-induced increases in PVRI.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hypoxic Pulmonary Vasoconstriction in Man: Effects of Hyperventilation

The pulmonary vasoconstriction response to hypoxia was studied in eight anaesthetized supine subjects. One lung was made hypoxic while the other was ventilated with 100% oxygen. This was achieved by separating the tidal gas-distribution to the lungs by means of a double-lumen tracheal catheter. The hypoxic pulmonary vasoconstriction (HPV) response was estimated from the blood flow diversion away from the hypoxic lung. Blood flow distribution between the lungs was calculated from the regional expired carbon dioxide production, assuming regional carbon dioxide production to be proportional to blood flow. The subjects were studied during six different conditions. Firstly, when ventilated with 100% oxygen to both lungs at a PaCO2 of about 6 kPa. Secondly, with 100% oxygen to the left lung and 5% oxygen in nitrogen to the right (test) lung. The ratio between carbon dioxide output from right and left lung was calculated. These measurements were repeated during two states of hyperventilation (PaCO2 of about 4.5 kPa and 3.5 kPa, respectively) with and without hypoxia (conditions 3-6). During normoventilation, blood flow distribution between the lungs was equal. During hypoxia, blood flow distribution to the hypoxic lung decreased by 35% of the pre-hypoxic value. Furthermore, a decrease in arterial oxygen tension from 51.5 +/- 4.5 to 11.5 +/- 2.1 kPa was observed. During excessive hyperventilation (PaCO2 3.2 +/- 0.2 kPa), blood flow distribution to the hypoxic right lung decreased by only 10% of its pre-hypoxic value. A further decrease in arterial oxygen tension to 8.5 +/- 1.8 kPa was observed. This decrease in PaO2 was possibly due to an increased venous admixture caused by an abolished HPV response. It is concluded that hyperventilation counteracts hypoxic pulmonary vasoconstriction in man.     

Methylprednisolone Reduces Vascular Resistance in Hypoxic and Atelectatic Lungs

The effect of pharmacological doses of methylprednisolone (MP) on the pulmonary vasoconstrictor response to hypoxia has been investigated in two groups of isolated rat lung preparations, one consisting of ventilated, and the other of atelectatic lungs. In both groups, MP reduced the vasoconstrictor response to hypoxia in a dose-dependent fashion. At a perfusate concentration of 3 mmol/l of MP, the response was reduced by about 80%. On the contrary, the vasoconstrictor response to injections of standardized doses of angiotensin II, used as an independent vasoconstrictor substance, were not significantly changed by MP, even when administered at a concentration which completely abolished the response to hypoxia. We suggest that MP inhibits the pulmonary vasoconstrictor response to hypoxia without influencing the general reactivity of the pulmonary vascular bed.     

肺动脉平滑肌细胞氧敏感钾通道与低氧性肺血管收缩

Lopez Barnc于1988年采用全细胞膜片钳技术发现了大鼠颈动脉体Ⅰ型细胞膜上对低氧敏感的钾（K^＋）通道,称为“氧敏感K^＋通道”（O2-sensitive K^＋ channels）。在肺动脉平滑肌细胞（PASMCs）巾亦存在此种离子通道。低氧时PASMCs的K^＋外向电流发生抑制,膜发生除极化,继而L^-型电压门控Ca^2＋通道开放,     

Multipoint pulmonary vascular pressure/flow relationships in hypoxic and in normoxic dogs: effects of nitrous oxide with and without cyclooxygenase inhibition

The authors investigated the effects of 70% nitrous oxide on overall mean pulmonary artery pressure (MPAP)/cardiac index (CI) relationships in 13 intact pentobarbital anesthetized dogs ventilated alternatively in normoxic (fraction of inspired O2, FIO2 0.3) and in hypoxic (FIO2 0.1) conditions. Five-point MPAP/CI plots were constructed by opening an arterio-venous femoral fistula or by stepwise inflations of a balloon in the inferior vena cava. These MPAP/CI plots were rectilinear in all experimental conditions. Over the entire range of CI studied, 1-5 l.min-1.m-2, hypoxia increased MPAP in seven dogs ("responders"), and did not affect MPAP in six other dogs ("nonresponders"). Hypoxic pulmonary vasoconstriction (HPV) was restored in "nonresponders" by administration of 1 g acetylsalicylic acid (ASA) intravenously. In "responders," nitrous oxide partially inhibited HPV. In "nonresponders" with a hypoxic pressor response restored by ASA, nitrous oxide enhanced both normoxic and hypoxic pulmonary vascular tone, and did not affect HPV. These results suggest that pulmonary vascular effects of nitrous oxide depend on preexisting pulmonary vascular tone, and may be modulated by cyclooxygenase products of arachidonic acid metabolism.     

Pulmonary artery pressure monitoring in persistent fetal circulation (PFC)

The use of the Swan-Ganz catheter to monitor pulmonary artery pressure in adults with cardiopulmonary failure has become commonplace. Our meager experience was with four neonates diagnosed as having persistent fetal circulation monitored by the use of this PA catheter. Tolazoline was infused directly into the pulmonary circulation via the catheter. Pulmonary artery pressure was temporarily reduced by tolazoline administration, with a marked increase in PaO2. More experience is required to define the role of the Swan-Ganz catheter in neonatal physiologic monitoring.     

Purification and characterization of rat testicular glutathione S-transferases： role in the synthesis of eicosanoids

Aim: Purification of glutathione S-transferases (GSTs) from rat testis; separation and identification of various subunits and their role in eicosanoid biosynthesis. Methods: Purification of rat testicular GSTs by affinity chromatography, employing S-hexylglutathione-linked epoxy-activated Sepharose 6B column and separation of individual subunits by reverse phase-high pressure liquid chromatography (RP-HPLC). Characterization of affinity purified GSTs by Sodium dodecyl sulfate-polyacrylamide gel electlophoresis (SDS-PAGE) and Western blot analysis. The role of testicular GSTs in eicosanoid biosynthesis was determined by incubating GSTs with 5,6-Leukotriene A4Me (LTA4Me) and prostaglandin H2(PGH2) and analyzing the products formed on HPLC/TLC. Results: The present study reveals that majority of rat testicular GSTs are of Yb size (60%) with molecular weight of 27kDa. The most predominant subunits, however, are GST Yn2(27%), followed by GST Yc(24%) and GST Ynl(20%). These testicular GSTs showed very high Leukotriene C4(LTC4) synthase activity with 5,6-Leukotriene A4Me(LTA4Me) as the substrate and prostaglandin D (PGD) synthase activity with prostaglandin H2(PGH2) as the substrate. Conclusion: Majority of rat testicular GSTs are Yb sized and are involved in the synthesis of eicosanoids like LTC4 and PGD2.(Asian J Androl 2000 Dec;2:277-282)     

Ventilatory effects of almitrine bismesilate in dogs breathing normoxic, hyperoxic and hypoxic mixtures

The ventilatory effects of 1 mg.kg-1 i.v. almitrine were studied in five dogs anaesthetized with halothane 2% under conditions of normoxia, hyperoxia and hypoxia. Ventilation (minute ventilation, respiratory frequency, tidal volume, duration of inspiration and expiration, ratio TI/Ttot and VT/TI), Pao2, Paco2, pHa, systemic arterial pressure and heart rate were measured in air before and following almitrine; in air, after inhalation of pure oxygen and after almitrine in hyperoxia; in air, during hypoxia with Fio2 progressively decreased from 0.21 to 0.12 and after almitrine in hypoxia (FIO2 = 0.12). Halothane decreased ventilatory response to hypoxia. Almitrine stimulated ventilation irrespective of the level of oxygenation and restored the ventilatory response to hypoxia. Hyperoxia did not suppress ventilatory action of almitrine whose action is probably partly central. Hypoxia and almitrine did not induce major systemic haemodynamic modification.     

Pulmonary artery diastolic and wedge pressure relationships in critically ill and injured patients

To study pulmonary artery wedge pressure (PAWP) and pulmonary artery diastolic pressure (PADP) relationships, we measured these simultaneously with cardiac outputs 1922 times in 128 patients who were critically ill or in an intensive care unit. In 356 (18.5%) of the readings, the PAWP exceeded the PADP, indicating that the PAWP reading might be erroneous. In 106 (5.5%) of these readings, the PAWP was 6.0 mm Hg or more higher than the PADP, indicating that the PAWP was almost certainly erroneous. In virtually all instances in which this discrepancy was recognized, changing the position of the catheter tip provided a PAWP value equal to or lower than the PADP. On the other extreme, in 49 (30%) of the patients, the PADP was 6.0 mm Hg or more higher than the PAWP. The pulmonary vascular resistance in these patients averaged (+/- SD) 257 +/- 145 dyne/s/cm-5 (normal, 80 to 160 dyne/s/cm-5). The mean pulmonary vascular resistance in the other 74 patients was significantly lower (158 +/- 72 dyne/s/cm-5). The mortality rate with the increased PADP-PAWP gradients was 59% (24/49). This was significantly higher than the mortality rate (34%, or 27/79) seen with lower PAWP-PADP gradients. Thus, the relationship between the PADP and PAWP should be examined closely in critically ill patients. A PAWP higher than the PADP indicates that the PAWP measurement may be erroneous. On the other hand, if the PADP exceeds the PAWP by 6.0 mm Hg or more, the patient has probably developed pulmonary hypertension and has a much poorer prognosis.     

低氧性肺动脉高压的肺血管重建机制研究进展

低氧性肺动脉高压(hypoxic pulmonary hypertension,HPH)与慢性缺氧有关,导致肺心病甚至死亡。低氧性肺血管收缩和肺血管重建(pulmonary vascular remodeling,PVR)通常认为是HPH的两个阶段,前者更强调早期血管收缩,而PVR才是造成血管舒张药无效的主要原因。既往认为PVR是炎症反应导致,但目前更强调多方面、多因子的共同结果。文章主要从细胞因子、氧化应激、细胞内外离子及细胞自噬和凋亡等在HPH进程中的作用出发,介绍目前对HPH治疗的研究进展,提出未来研究方向的猜想。作为一种不可逆的致死性疾病,肺动脉高压(pulmonary arterial hypertension,PAH)一直是当下肺移植相关研究的热点问题,但PAH类型多,且不同类型的PAH形成机制各不相同。文章综述了HPH的PVR形成机制及对应治疗方案。     

Increased leukotriene and prostaglandin release,and overactivity in the chronically ischemic bladder

PURPOSE: Chronic ischemia has been shown to alter bladder contractility. We studied the roles of cyclooxygenase (COX) and lipoxygenase products in ischemia induced bladder overactivity in the rabbit. MATERIALS AND METHODS: A total of 28 male New Zealand White rabbits were divided into 2 groups. In group 1 atherosclerotic occlusion of the iliac arteries was induced by balloon endothelial injury, followed by a short period of a high cholesterol diet. Group 2 received a regular diet alone. After 12 weeks blood flow measurements and cystometry were performed. Bladder tissues were processed for enzyme immunoassay of leukotrienes and prostaglandins (PGs), Western blotting of COX and lipoxygenase, isometric tension measurement and histology. RESULTS: Atherosclerotic occlusion of the iliac arteries significantly decreased bladder blood flow. Moderate ischemia caused bladder overactivity, while severe ischemia inhibited bladder contractions. Ischemia increased leukotriene B4, E4 and C4 release by 141%, 132% and 254%, and increased PG F2alpha and thromboxane A2 release by 95% and 93%, respectively, although it did not alter PG E2 release. Western blotting showed increased 5-lipoxygenase, COX-1 and COX-2 protein levels in ischemic bladder tissues. Moderate ischemia increased bladder smooth muscle contraction in response to carbachol and electrical field stimulation. Tissue treatment with the COX inhibitor indomethacin significantly increased control tissue contraction but had no effect on ischemic tissues. Treatment with the 5-lipoxygenase inhibitor REV5901 abolished this effect of indomethacin in control tissues. Treatment with REV5901 significantly decreased the contraction of ischemic tissues but had no significant effect on control tissues. The effect of indomethacin plus REV5901 was similar to the effect of REV5901 alone. Histology showed urothelial thickening and mild fibrosis in the moderately ischemic bladder. CONCLUSIONS: Chronic ischemia increased bladder 5-lipoxygenase, and COX-1 and COX-2 protein expression, and altered leukotriene and PG production. Treatment with COX and lipoxygenase inhibitors produced completely different effects in the ischemic bladder compared with the control bladder. Functional changes in the ischemic bladder were concurrent with structural changes in the urothelium. PGs modulate smooth muscle contractility in the healthy bladder. However, under ischemic conditions leukotrienes dominate bladder tone and appear to have a leading role in increased smooth muscle contraction and bladder overactivity.     

Alteration of urothelial-mediated tone in the ischemic bladder: role of eicosanoids

AIMS: Previously we showed that ischemia alters bladder smooth muscle contractility in the rabbit. This study investigates the role of urothelium and eicosanoid-release in ischemic bladder smooth muscle instability. MATERIALS AND METHODS: Male New Zealand white rabbits were divided into treated (n = 12) and age-matched control (n = 10) groups. The treated group underwent balloon endothelial injury of the iliac arteries, and then received 4 weeks of cholesterol diet, followed by 4 weeks of regular diet. The control group received a regular diet for 8 weeks. After 8 weeks, blood flow for both the iliac arteries and the bladder as well as bladder oxygen tension were recorded. In one-half of each ischemic and control bladder, the urothelium was removed. Bladder tissues were processed for organ bath and enzyme-immunoassay (EIA) of prostaglandins (PGs) and leukotrienes (LTs). RESULTS: A significant decrease in iliac arterial blood flow, bladder wall blood flow, and bladder oxygen tension was found in the treated group. Bladder ischemia increased the frequency and amplitude of baseline spontaneous smooth muscle contractility. Ischemic tissues with urothelium (Uro+) demonstrated significant increases in the contractile response to electrical field stimulation (EFS) and carbachol relative to control Uro+ tissues. Urothelial removal increased smooth muscle contraction in the control tissues but had no significant effect in the ischemic/hypoxic tissues. Contraction of control tissues without urothelium (Uro-) was similar to contraction of ischemic Uro+ tissues. Contractions of ischemic Uro+ and control Uro- tissues were unchanged after treatment with the cyclooxygenase (COX) inhibitor indomethacin, while they were significantly reduced by the 5-lipoxygenase (5-LO) inhibitor NDGA. EIA showed no change in PGs release from the ischemic urothelium, but significant increase in PGF(2-alpha) and thromboxane A(2) release from the ischemic suburothelial tissue. Ischemia increased the release of LTB(4), LTC(4), and LTE(4) from both urothelium and suburothelial tissue. CONCLUSIONS: Our studies suggest loss of urothelial-mediated tone and LTs-mediated smooth muscle instability in the chronically ischemic/hypoxic bladder.