慢性低氧所致肺动脉高压对大鼠肺血管平滑肌细胞及成纤维细胞中蛋白激酶CβI的膜转位和蛋白表达量的影响

目的通过观察慢性低氧所致肺动脉高压对大鼠肺血管平滑肌细胞及成纤维细胞中蛋白激酶CBI（PKCβI）的膜转位和蛋白表达量的影响,初步探讨PKCpI在慢性低氧诱导大鼠肺动脉高压的发生、发展过程中所起的作用。方法建立慢性常压低氧肺动脉高压大鼠模型,将雄性SD大鼠随机分为正常对照组、低氧1d、3d、7d、14d和21d组,应用蛋白免疫印迹和免疫组化技术检测肺动脉高压形成过程中大鼠肺血管平滑肌细胞及成纤维细胞中PKCβI的膜转位和蛋白表达水平。结果（1）RVSP和RV／（LV＋S）比值较正常对照组明显增加（P〈0．05）,低氧后3d、7d、14d和21d后大鼠肺血管明显增厚;（2）大鼠肺血管平滑肌细胞和成纤维细胞均有PKCβI的表达,且低氧14d后PKCβI的蛋白表达量较正常对照组相比降低（P〈0．05）。结论PKCβI蛋白表达量的下调可能参与了慢性低氧诱导的大鼠肺动脉高压肺血管重塑的发生、发展过程。     

Effect of chemokine receptor CXCR4 on hypoxia-induced pulmonary hypertension and vascular remodeling in rats

Background

CXCR4 is the receptor for chemokine CXCL12 and reportedly plays an important role in systemic vascular repair and remodeling, but the role of CXCR4 in development of pulmonary hypertension and vascular remodeling has not been fully understood.

Methods

In this study we investigated the role of CXCR4 in the development of pulmonary hypertension and vascular remodeling by using a CXCR4 inhibitor AMD3100 and by electroporation of CXCR4 shRNA into bone marrow cells and then transplantation of the bone marrow cells into rats.

Results

We found that the CXCR4 inhibitor significantly decreased chronic hypoxia-induced pulmonary hypertension and vascular remodeling in rats and, most importantly, we found that the rats that were transplanted with the bone marrow cells electroporated with CXCR4 shRNA had significantly lower mean pulmonary pressure (mPAP), ratio of right ventricular weight to left ventricular plus septal weight (RV/(LV+S)) and wall thickness of pulmonary artery induced by chronic hypoxia as compared with control rats.

Conclusions

The hypothesis that CXCR4 is critical in hypoxic pulmonary hypertension in rats has been demonstrated. The present study not only has shown an inhibitory effect caused by systemic inhibition of CXCR4 activity on pulmonary hypertension, but more importantly also has revealed that specific inhibition of the CXCR4 in bone marrow cells can reduce pulmonary hypertension and vascular remodeling via decreasing bone marrow derived cell recruitment to the lung in hypoxia. This study suggests a novel therapeutic approach for pulmonary hypertension by inhibiting bone marrow derived cell recruitment.     

Endogenous vasopressin does not mediate hypoxia-induced anapyrexia in rats

The present study was designed to test the hypothesis thatarginine vasopressin (AVP) mediates hypoxia-induced anapyrexia. Therectal temperature of awake, unrestrained rats was measured before andafter hypoxic hypoxia, AVP-blocker injection, or a combination of thetwo. Control animals received saline injections of the same volume.Basal body temperature was 36.52 ± 0.29°C. We observed asignificant (P < 0.05) reduction inbody temperature of 1.45 ± 0.33°C after hypoxia (7% inspiredO₂), whereas systemic andcentral injections of AVP V₁- andAVP V₂-receptor blockers caused nochange in body temperature. When intravenous injection of AVP blockerswas combined with hypoxia, we observed a reduction in body temperatureof 1.49 ± 0.41°C(V₁-receptor blocker) and of 1.30 ± 0.13°C (V₂-receptorblocker), similar to that obtained by application of hypoxia only.Similar results were observed when the blockers were injectedintracerebroventricularly. The data indicate that endogenous AVP doesnot mediate hypoxia-induced anapyrexia in rats.     

Effects of hypoxic pulmonary vasoconstriction on pulmonary gas exchange

Brimioulle, Serge, Philippe Lejeune, and Robert Naeije.Effects of hypoxic pulmonary vasoconstriction on pulmonary gasexchange. J. Appl. Physiol. 81(4):1535-1543, 1996.Several reports have suggested that hypoxicpulmonary vasoconstriction (HPV) might result in deterioration ofpulmonary gas exchange in severe hypoxia. We therefore investigated theeffects of HPV on gas exchange in normal and diseased lungs. Weincorporated a biphasic HPV stimulus-response curve observed in intactdogs (S. Brimioulle, P. Lejeune, J. L. Vachièry, M. Delcroix, R. Hallemans, and R. Naeije, J. Appl.Physiol. 77: 476-480, 1994) into a 50-compartment lung model (J. B. West, Respir.Physiol. 7: 88-110, 1969) to control the amount ofblood flow directed to each lung compartment according to the localhypoxic stimulus. The resulting model accurately reproduced the bloodgas modifications caused by HPV changes in dogs with acute lung injury.In single lung units, HPV had a moderate protective effect on alveolaroxygenation, which was maximal at near-normal alveolarPO₂ (75-80 Torr), mixed venousPO₂ (35 Torr), andPO₂ at which hemoglobin is 50%saturated (24 Torr). In simulated diseased lungs associated with40-60 Torr arterial PO₂,however, HPV increased arterial PO₂ by 15-20 Torr. We conclude that HPV can improve arterialoxygenation substantially in respiratory failure.

     

Role of vagal fibers in the hypoxia-induced increases in end-expiratory lung volume and diaphragmatic activity

Bonora, M., and M. Vizek. Role of vagalfibers in the hypoxia-induced increases in end-expiratory lung volumeand diaphragmatic activity. J. Appl.Physiol. 83(3): 700-706, 1997.The possible role of pulmonary C fibers in thehypoxia-induced concomitant increases in end-expiratory lung volume(EELV) and in the activity of the diaphragm at the end of expiration(DE) were evaluated bymeasuring the effects of hypoxia (10%O₂) on ventilation, EELV, andDE in eight chloralose-urethananesthetized rats. Recordings were made before and after blocking vagalC fibers and after bilateral vagotomy. C-fiber conduction was blockedby applying capsaicin perineurally to the cervical vagi. The efficiencyof C-fiber blockade was tested with intravenous capsaicin and itsselectivity by the Hering-Breuer reflex. Perineural capsaicin abolishedthe reflex apnea induced by intravenous capsaicin and transientlyreduced Hering-Breuer reflex. Perineural capsaicin affected neitherventilation, DE, and EELV in airnor the hypoxia-induced increases in these parameters. Vagotomy causedthe typical changes of breathing pattern in air, but the ventilatoryresponse to hypoxia was unchanged. Vagotomy performed during hypoxiaresulted in large decreases inDE and EELV. Hypoxia increasedDE and EELV in vagotomized rats but less than in intact rats. We conclude that the hypoxia-induced increases in EELV and diaphragmatic activity are probably not mediatedby vagal C fibers and that vagal afferents are involved but not fullyresponsible for this phenomenon.

     

Physiological and Genomic Consequences of Intermittent Hypoxia: Selected Contribution: Chemoreflex responses to CO2 before and after an 8-h exposure to hypoxia in humans

The ventilatorysensitivity to CO₂, in hyperoxia, is increased after an 8-hexposure to hypoxia. The purpose of the present study was to determinewhether this increase arises through an increase in peripheral orcentral chemosensitivity. Ten healthy volunteers each underwent 8-hexposures to 1) isocapnic hypoxia, with end-tidalPO₂ (PET_O2) = 55 Torr and end-tidal PCO₂(PET_CO2) = eucapnia; 2)poikilocapnic hypoxia, with PET_O2 = 55 Torr and PET_CO2 = uncontrolled;and 3) air-breathing control. The ventilatory response toCO₂ was measured before and after each exposure with theuse of a multifrequency binary sequence with two levels of PET_CO2: 1.5 and 10 Torr above the normalresting value. PET_O2 was held at 250 Torr.The peripheral (Gp) and the central (Gc) sensitivities were calculatedby fitting the ventilatory data to a two-compartment model. There wereincreases in combined Gp + Gc (26%, P < 0.05),Gp (33%, P < 0.01), and Gc (23%, P = not significant) after exposure to hypoxia. There were no significant differences between isocapnic and poikilocapnic hypoxia. We conclude that sustained hypoxia induces a significant increase inchemosensitivity to CO₂ within the peripheral chemoreflex.

     

PAF antagonists inhibit pulmonary vascular remodeling induced by hypobaric hypoxia in rats.

Chronic hypoxia causes pulmonary hypertension and pulmonary vascular remodeling in rats. Because platelet-activating factor (PAF) levels increase in lung lavage fluid and in plasma from chronically hypoxic rats, we examined the effect of two specific, structurally unrelated PAF antagonists, WEB 2170 and BN 50739, on hypoxia-induced pulmonary vascular remodeling. Treatment with either agent reduced hypoxia-induced pulmonary hypertension and right ventricular hypertrophy at 3 wk of hypoxic exposure (simulated altitude 5,100 m) but did not affect cobalt (CoCl2)-induced pulmonary hypertension. The PAF antagonists had no effect on the hematocrit of normoxic or chronically hypoxic rats or CoCl2-treated rats. Hypoxia-induced pulmonary hypertension was associated with an increase in the vessel wall thickness of the muscular arteries and reduction in the number of peripheral arterioles. In WEB 2170-treated rats, these changes were significantly less severe than those observed in untreated chronically hypoxic rats. PAF receptor blockade had no acute hemodynamic effects; i.e., it did not affect pulmonary arterial pressure or cardiac output nor did it affect the magnitude of acute hypoxic pulmonary vasoconstriction in awake normoxic or chronically hypoxic rats. Isolated lungs from chronically hypoxic rats showed a pressor response to the chemotactic tripeptide N-formyl-Met-Leu-Phe (fMLP) and an increase in the number of leukocytes lavaged from the pulmonary circulation. In vivo treatment with WEB 2170 significantly reduced the fMLP-induced pressor response compared with that observed in isolated lungs from untreated chronically hypoxic rats. These results suggest that PAF contributes to the development of chronic pulmonary hypertension induced by chronic hypoxia.(ABSTRACT TRUNCATED AT 250 WORDS)     

A Critical Role of the mTOR/eIF2α Pathway in Hypoxia-Induced Pulmonary Hypertension

Enhanced proliferation of pulmonary arterial vascular smooth muscle cells (PASMCs) is a key pathological component of vascular remodeling in hypoxia-induced pulmonary hypertension (HPH). Mammalian targeting of rapamycin (mTOR) signaling has been shown to play a role in protein translation and participate in the progression of pulmonary hypertension. Eukaryotic translation initiation factor-2α (eIF2α) is a key factor in regulation of cell growth and cell cycle, but its role in mTOR signaling and PASMCs proliferation remains unknown. Pulmonary hypertension (PH) rat model was established by hypoxia. Rapamycin was used to treat rats as an mTOR inhibitor. Proliferation of primarily cultured rat PASMCs was induced by hypoxia, rapamycin and siRNA of mTOR and eIF2α were used in loss-of-function studies. The expression and activation of eIF2α, mTOR and c-myc were analyzed. Results showed that mTOR/eIF2α signaling was significantly activated in pulmonary arteries from hypoxia exposed rats and PASMCs cultured under hypoxia condition. Treatment with mTOR inhibitor for 21 days attenuated vascular remodeling, suppressed mTOR and eIF2α activation, inhibited c-myc expression in HPH rats. In hypoxia-induced PASMCs, rapamycin and knockdown of mTOR and eIF2α by siRNA significantly abolished proliferation and increased c-myc expression. These results suggest a critical role of the mTOR/eIF2αpathway in hypoxic vascular remodeling and PASMCs proliferation of HPH.     

Role of inhibition of nitric oxide production in monocrotaline-induced pulmonary hypertension

Mathew, Rajamma, Elizabeth S. Gloster, T. Sundararajan, Carl I. Thompson, Guillermo A. Zeballos, andMichael H. Gewitz. Role of inhibition of nitric oxide productionin monocrotaline-induced pulmonary hypertension. J. Appl. Physiol. 82(5): 1493-1498, 1997.Monocrotaline (MCT)-induced pulmonary hypertension (PH) isassociated with impaired endothelium-dependent nitric oxide(NO)-mediated relaxation. To examine the role of NO in PH,Sprague-Dawley rats were given a single subcutaneous injection ofnormal saline [control (C)], 80 mg/kg MCT, or the same doseof MCT and a continuous subcutaneous infusion of 2 mg · kg¹ · day¹of molsidomine, a NO prodrug (MCT+MD). Two weeks later, plasma NO₃ levels, pulmonary arterialpressure (Ppa), ratio of right-to-left ventricular weights (RV/LV) toassess right ventricular hypertrophy, and pulmonary histology wereevaluated. The plasma NO₃ level inthe MCT group was reduced to 9.2 ± 1.5 µM(n = 12) vs. C level of 17.7 ± 1.8 µM (n = 8; P < 0.02). In the MCT+MD group,plasma NO₃ level was 12.3 ± 2.0 µM (n = 8). Ppa and RV/LV in theMCT group were increased compared with C [Ppa, 34 ± 3.4 mmHg(n = 6) vs. 19 ± 0.8 mmHg(n = 8) and 0.41 ± 0.01 (n = 9) vs. 0.25 ± 0.008 (n = 8), respectively;P < 0.001]. In the MCT+MDgroup, Ppa and RV/LV were not different when compared with C [19 ± 0.5 mmHg (n = 5) and 0.27 ± 0.01 (n = 9), respectively;P < 0.001 vs. MCT]. Medial wall thickness of lung vessels in the MCT group was increased comparedwith C [31 ± 1.5% (n = 9)vs. 13 ± 0.66% (n = 9);P < 0.001], and MDpartially prevented MCT-induced pulmonary vascular remodeling [22 ± 1.2% (n = 11);P < 0.001 vs. MCT and C].These results indicate that a defect in the availability of bioactive NO may play an important role in the pathogenesis of MCT-induced PH.

     

Generation of oxidative stress contributes to the development of pulmonary hypertension induced by hypoxia.

Chronic hypoxia causes pulmonary hypertension and right ventricular hypertrophy associated with pulmonary vascular remodeling. Because hypoxia might promote generation of oxidative stress in vivo, we hypothesized that oxidative stress may play a role in the hypoxia-induced cardiopulmonary changes and examined the effect of treatment with the antioxidant N-acetylcysteine (NAC) in rats. NAC reduced hypoxia-induced cardiopulmonary alterations at 3 wk of hypoxia. Lung phosphatidylcholine hydroperoxide (PCOOH) increased at days 1 and 7 of the hypoxic exposure, and NAC attenuated the increase in lung PCOOH. Lung xanthine oxidase (XO) activity was elevated from day 1 through day 21, especially during the initial 3 days of the hypoxic exposure. The XO inhibitor allopurinol significantly inhibited the hypoxia-induced increase in lung PCOOH and pulmonary hypertension, and allopurinol treatment only for the initial 3 days also reduced the hypoxia-induced right ventricular hypertrophy and pulmonary vascular thickening. These results suggest that oxidative stress produced by activated XO in the induction phase of hypoxic exposure contributes to the development of chronic hypoxic pulmonary hypertension.     

Apneic threshold for CO2 in the anesthetized rat: fundamental properties under steady-state conditions

Experiments were performed to measure the apneicthreshold for CO₂ and itsfundamental properties in anesthetized rats under steady-stateconditions. Breathing was detected from diaphragmatic electromyogramactivity. Mechanical hyperventilation resulted in apnea once arterialPCO₂(Pa_CO2) had fallen farenough. Apnea was not a reflex response to lung inflationbecause it did not occur immediately, was not prevented by vagotomy,and was reversed by raising Pa_CO2without changing mechanical hyperventilation. The apneic threshold wasmeasured by hyperventilating rats mechanically withO₂ until apnea had occurred andthen raising Pa_CO2 at constant hyperventilation until breathing reappeared. The meanPa_CO2 level of the apneic threshold in42 rats was 32.8 ± 0.4 Torr. The level of thethreshold did not depend on the volume at which the lungs wereinflated. The level of the threshold, under steady-state conditions,was the same when approached from hypocapnia as from eupnea. The levelof the threshold could be raised by 9 Torr by chronic elevation of theeupneic Pa_CO2 level by 18 Torr.

     

Vascular remodeling and ET-1 expression in rat strains with different responses to chronic hypoxia

Chronic hypoxia leads to a greater degree of pulmonary hypertension in the Wistar-Kyoto (WKY) rat than in the Fischer 344 (F-344) rat. We questioned whether this difference is associated with baseline differences in pulmonary artery anatomy, a greater degree of hypoxia-induced pulmonary vascular remodeling in the WKY rat, and/or differences in expression of endothelin (ET)-1. Male F-344 and WKY rats were maintained in normoxia or normobaric hypoxia for 21 days. Morphometry revealed that baseline pulmonary artery anatomy was similar in the two strains. However, during chronic hypoxia, the WKY rats developed a greater degree of muscularization of small pulmonary arteries. Baseline plasma and lung immunoreactive ET-1 levels were similar in the WKY and F-344 rats and increased significantly during hypoxia in the WKY rats. Northern analysis demonstrated increased lung preproET-1 mRNA during hypoxia in both strains, with a greater increase in WKY rats. Immunostaining demonstrated increased ET-1 in bronchial epithelium and peripheral pulmonary arteries during hypoxia, although to a greater degree in the WKY rats. We conclude that the WKY strain demonstrates increased susceptibility to hypoxia-induced pulmonary vascular remodeling compared with the F-344 strain and that increased lung and circulating ET-1 levels during hypoxia may partly explain this difference.     

Dopamine, sensory discharge, and stimulus interaction with CO2 and O2 in cat carotid body

It is hypothesized that carotid bodychemosensory activity is coupled to neurosecretion. The purpose of thisstudy was to examine whether there was a correspondence between carotidbody tissue dopamine (DA) levels and neuronal discharge (ND) measured from the carotid sinus nerve of perfused cat carotid bodies and tocharacterize interaction betweenCO₂ andO₂ in these responses. ND andtissue DA were measured after changing from normoxic, normocapnic control bicarbonate buffer (PO₂>120 Torr, PCO₂ 25-30 Torr, pH ~ 7.4) to normoxic hypercapnia(PCO₂ 55-57 Torr, pH7.1-7.2) or to hypoxic solutions(PO₂ 30-35 Torr) withnormocapnia (PCO₂ 25-30 Torr, pH ~ 7.4) or hypocapnia (PCO₂10-15 Torr, pH 7.6-7.8). Similar temporal changes for ND and tissue DA were found for all of the stimuli, although there was a much different proportional relationship fornormoxic hypercapnia. Both ND and DA increased above baseline valuesduring flow interruption and normocapnic hypoxia, and both decreasedbelow baseline values during hypoxic hypocapnia. In contrast, normoxichypercapnia caused an initial increase in ND, from a baseline of 175 ± 12 (SE) to a peak of 593 ± 20 impulses/s within 4.6 ± 0.9 s, followed by adaptation, whereas ND declined to 423 ± 20 impulses/s after 1 min. Tissue DA initially increased from a baselineof 17.9 ± 1.2 µM to a peak of 23.2 ± 1.2 µM within 3.0 ± 0.7 s, then declined to 2.6 ± 1.0 µM. The substantialdecrease in tissue DA during normoxic hypercapnia was not consistentwith the parallel changes in DA with ND that were observed for hypoxic stimuli.

     

Adiponectin ameliorates hypoxia-induced pulmonary arterial remodeling

We have demonstrated that adiponectin has anti-atherosclerotic properties. We also reported hypoadiponectinemia and nocturnal reduction in circulating adiponectin concentrations in patients of severe obstructive sleep apnea-hypopnea syndrome (OSAS). OSAS is often complicated with pulmonary hypertension. In this study, we investigated the effect of adiponectin on chronic hypoxia-induced pulmonary arterial remodeling in mice. Exposure of mice to 3-weeks sustained hypoxia (10% O₂) resulted in significant accumulation of adiponectin in pulmonary arteries. The percentage media wall thickness (%MT), representing pulmonary arterial remodeling, under hypoxic condition, was greater in adiponectin-knockout mice than wild-type mice. Overexpression of adiponectin significantly decreased hypoxia-induced pulmonary arterial wall thickening and right ventricular hypertrophy. These findings demonstrate for the first time that overexpression of adiponectin suppresses the development of hypoxic-induced pulmonary remodeling, and that adiponectin may combat a new strategy for pulmonary vascular changes that underlie pulmonary hypertension in OSAS.     

Depressed ventilatory response to hypoxia in hypothermic newborn piglets: role of glutamate

To evaluatewhether changes in extracellular glutamate (Glu) levels in the centralnervous system could explain the depressed hypoxic ventilatory responsein hypothermic neonates, 12 anesthetized, paralyzed, and mechanicallyventilated piglets <7 days old were studied. The Glu levels in thenucleus tractus solitarius obtained by microdialysis, minute phrenicoutput (MPO), O₂ consumption, arterial blood pressure, heart rate, and arterial blood gases weremeasured in room air and during 15 min of isocapnic hypoxia (inspiredO₂ fraction = 0.10) at braintemperatures of 39.0 ± 0.5°C [normothermia (NT)]and 35.0 ± 0.5°C [hypothermia (HT)]. During NT, MPO increased significantly during hypoxia and remained above baseline. However, during HT, there was a marked decrease in MPOduring hypoxia (NT vs. HT, P < 0.03). Glu levels increased significantly in hypoxia during NT;however, this increase was eliminated during HT(P < 0.02). A significant linearcorrelation was observed between the changes in MPO and Glu levelsduring hypoxia (r = 0.61, P < 0.0001). Changes in pH, arterialPO₂, O₂ consumption, arterial bloodpressure, and heart rate during hypoxia were not different between theNT and HT groups. These results suggest that the depressed ventilatoryresponse to hypoxia observed during HT is centrally mediated and inpart related to a decrease in Glu concentration in the nucleus tractussolitarius.

     

Lactate efflux from exercising human skeletal muscle: role of intracellular PO2

It remainscontroversial whether lactate formation during progressive dynamicexercise from submaximal to maximal effort is due to muscle hypoxia. Tostudy this question, we used direct measures of arterial and femoralvenous lactate concentration, a thermodilution blood flow technique,phosphorus magnetic resonance spectroscopy (MRS), and myoglobin (Mb)saturation measured by ¹H nuclearMRS in six trained subjects performing single-leg quadriceps exercise.We calculated net lactate efflux from the muscle and intracellularPO₂ with subjects breathing room airand 12% O₂. Data were obtained at50, 75, 90, and 100% of quadriceps maximalO₂ consumption at each fraction ofinspired O₂. Mb saturation wassignificantly lower in hypoxia than in normoxia [40 ± 3 vs. 49 ± 3% (SE)] throughout incremental exercise to maximalwork rate. With the assumption of aPO₂ at which 50% of Mb-binding sitesare bound with O₂ of 3.2 Torr,Mb-associated PO₂ averaged 3.1 ± 0.3 and 2.3 ± 0.2 Torr in normoxia and hypoxia, respectively. Netblood lactate efflux was unrelated to intracellular PO₂ across the range of incrementalexercise to maximum (r = 0.03 and 0.07 in normoxia and hypoxia, respectively) but linearly related toO₂ consumption(r = 0.97 and 0.99 in normoxia andhypoxia, respectively) with a greater slope in 12%O₂. Net lactate efflux was alsolinearly related to intracellular pH(r = 0.94 and 0.98 in normoxia andhypoxia, respectively). These data suggest that with increasing workrate, at a given fraction of inspiredO₂, lactate efflux is unrelated tomuscle cytoplasmic PO₂, yet theefflux is higher in hypoxia. Catecholamine values from comparablestudies are included and indicate that lactate efflux in hypoxia may bedue to systemic rather than intracellular hypoxia.

     

Hypoxic pulmonary hypertension is prevented in rats with common bile duct ligation.

Biliary cirrhosis in the rat triggers intrapulmonary vasodilatation and gas-exchange abnormalities that characterize the hepatopulmonary syndrome. This vasodilatation correlates with increased levels of pulmonary microcirculatory endothelial NO synthase (eNOS) and hepatic and plasma endothelin-1 (ET-1). Importantly, during cirrhosis, the pulmonary vascular responses to acute hypoxia are blunted. The purpose of this work was to examine the pulmonary vascular responses and adaptations to the combination of liver cirrhosis and chronic hypoxia (CH). In addition to hemodynamic measurements, we investigated whether pulmonary expression changes of eNOS, ET-1 and its receptors (endothelin A and B), or heme oxygenase 1 in experimental cirrhosis affect the development of hypoxic pulmonary hypertension. We induced cirrhosis in male Sprague-Dawley rats using common bile duct ligation (CBDL) and exposed them to CH (inspired PO2 approximately 76 Torr) or maintained them in Denver (Den, inspired PO2 approximately 122 Torr) for 3 wk. Our data show 1) CBDL-CH rats had a persistent blunted hypoxic pulmonary vasoconstriction similar to CBDL-Den; 2) the development of hypoxic pulmonary hypertension was completely prevented in the CBDL-CH rats, as indicated by normal pulmonary arterial pressure and lack of right ventricular hypertrophy and pulmonary arteriole remodeling; and 3) selective increases in expression of ET-1, pulmonary endothelin B receptor, eNOS, and heme oxygenase 1 are potential mechanisms of protection against hypoxic pulmonary hypertension in the CBDL-CH rats. These data demonstrate that unique and undefined hepatic-pulmonary interactions occur during liver cirrhosis and chronic hypoxia. Understanding these interactions may provide important information for the prevention and treatment of pulmonary hypertension.     

Alterations in structure of elastic laminae of rat pulmonary arteries in hypoxic hypertension

Liu, S. Q. Alterations in structure of elastic laminaeof rat pulmonary arteries in hypoxic hypertension. J. Appl. Physiol. 81(5): 2147-2155, 1996.The effectof hypoxic hypertension on the remodeling process of the elasticlaminae of the rat hilar pulmonary arteries (PAs) was studied byelectron microscopy. Rats were exposed to hypoxia (10%O₂) for periods of 0.5, 2, 6, 12, 48, 96, 144, and 240 h. Changes in the structure of the PA elastic laminae were examined and analyzed with respect to changes in the PAwall tensile stress. The PA blood pressure increased rapidly within thefirst several hours of hypoxia and reached a stable level within 2 days, whereas the PA wall tensile stress increased initially due toelevated blood pressure and then decreased after 48 h due to vesselwall thickening and returned to the control level after 4 days. Inassociation with these changes, the elastic laminae, which appearedhomogeneous in normal control rats, changed into structures composed ofrandomly oriented filaments and edematous contents with an increase inthe volume during the early period of hypoxia and regained theirhomogeneous appearance and normal volume after 4 days. The changes inthe elastic laminae were correlated with changes in the tensile stress.These changes were associated with a transient decrease in thestiffness of the PAs. In hypoxic rats given nifedipine, no change wasfound in the blood pressure, the tensile stress, or the structure ofthe elastic laminae of the PAs despite continuous exposure to hypoxia.These results suggested that altered tensile stress in the PA wallplayed a critical role in the initiation and regulation of structuralchanges in the elastic laminae and that these changes might contribute to alterations in the mechanical properties of the PA in hypoxic hypertension.

     

Human ventilatory response to acute hyperoxia during and after 8h of both isocapnic and poikilocapnic hypoxia

Tansley, J. G., C. Clar, M. E. F. Pedersen, and P. A. Robbins. Human ventilatory response to acute hyperoxia during andafter 8 h of both isocapnic and poikilocapnic hypoxia.J. Appl. Physiol. 82(2): 513-519, 1997.During 8 h of either isocapnic or poikilocapnic hypoxia,there may be a rise in ventilation(E) thatcannot be rapidly reversed with a return to higherPO₂ (L. S. G. E. Howard and P. A. Robbins. J. Appl. Physiol. 78:1098-1107, 1995). To investigate this further, threeprotocols were compared: 1) 8-hisocapnic hypoxia [end-tidalPCO₂(PET_CO2 ) held atprestudy value, end-tidal PO₂(PET_O2) = 55 Torr],followed by 8-h isocapnic euoxia(PET_O2 = 100 Torr);2) 8-h poikilocapnic hypoxia followed by 8-h poikilocapnic euoxia; and3) 16-h air-breathing control.Before and at intervals throughout each protocol, theE response to eucapnichyperoxia (PET_CO2 held1-2 Torr above prestudy value,PET_O2 = 300 Torr) wasdetermined. There was a significant rise in hyperoxic E over 8 hduring both forms of hypoxia (P < 0.05, analysis of variance) that persisted during the subsequent 8-heuoxic period (P < 0.05, analysis ofvariance). These results support the notion that an 8-h period ofhypoxia increases subsequenthyperoxic E, even if acid-base changes have been minimized through maintenance ofisocapnia during the hypoxic period.