Intermittent hypoxia causes mandibular growth retardation and macroglossia in growing rats.

INTRODUCTION: In this study, we aimed to examine the role of intermittent hypoxia (IH) in dentofacial morphologic changes in growing rats. METHODS: Seven-week-old male rats were exposed to IH at 20 cycles per hour (nadir of 4% oxygen to peak of 21% oxygen) for 8 hours per day for 6 weeks. Control rats were exposed to normoxia (N). Maxillofacial growth was compared between the 2 groups by linear measurements on cephalometric radiographs. To examine the dental arch morphology, study models and microcomputed tomography images of the jaws were taken. Additionally, tongue size was measured. RESULTS: The gonial angle and the ramus of the mandible were smaller in the IH group than in the N group, whereas the body weights were not different between the 2 groups. Morphometric analysis of the dentition showed a significantly wider mandibular dentition and narrower maxillary dentition in the IH than in the N group. The relative width (+4.2 %) and length (tongue apex to vallate papillae, +3.5 %) of the tongue to the mandible were significantly greater in the IH group than in the N group. CONCLUSIONS: IH induced dentofacial morphologic discrepancies in growing rats.

Chronic intermittent hypoxia accelerates coronary microcirculatory dysfunction in insulin-resistant Goto-Kakizaki rats.

Chronic intermittent hypoxia (IH) induces oxidative stress and inflammation, which impair vascular endothelial function. Long-term insulin resistance also leads to endothelial dysfunction. We determined, in vivo, whether the effects of chronic IH and insulin resistance on endothelial function augment each other. Male 12-wk-old Goto-Kakizaki (GK) and Wistar control rats were subjected to normoxia or chronic IH (90-s N2, 5% O2 at nadir, 90-s air, 20 cycles/h, 8 h/day) for 4 wk. Coronary endothelial function was assessed using microangiography with synchrotron radiation. Imaging was performed at baseline, during infusion of acetylcholine (ACh, 5 µg·kg(-1)·min(-1)) and then sodium nitroprusside (SNP, 5 µg·kg(-1)·min(-1)), after blockade of both nitric oxide (NO) synthase (NOS) with N(ω)-nitro-l-arginine methyl ester (l-NAME, 50 mg/kg) and cyclooxygenase (COX, meclofenamate, 3 mg/kg), and during subsequent ACh. In GK rats, coronary vasodilatation in response to ACh and SNP was blunted compared with Wistar rats, and responses to ACh were abolished after blockade. In Wistar rats, IH blunted the ability of ACh or SNP to increase the number of visible vessels. In GK rats exposed to IH, neither ACh nor SNP were able to increase visible vessel number or caliber, and blockade resulted in marked vasoconstriction. Our findings indicate that IH augments the deleterious effects of insulin resistance on coronary endothelial function. They appear to increase the dependence of the coronary microcirculation on NO and/or vasodilator prostanoids, and greatly blunt the residual vasodilation in response to ACh after blockade of NOS/COX, presumably mediated by endothelium-derived hyperpolarizing factors.

An unusual autopsy case of lethal hypothermia exacerbated by body lice-induced severe anemia.

Pediculus humanus humanus (known as body lice) are commonly found in the folds of clothes, and can cause skin disorders when they feed on human blood, resulting in an itching sensation. Body lice are known as vectors of infectious diseases, including typhus, recurrent fever, and trench fever. An infestation with blood-sucking body lice induces severe cutaneous pruritus, and this skin disorder is known as "vagabond's disease." A body lice infestation is sometimes complicated with iron deficiency anemia. In the present case, a man in his late 70s died of lethal hypothermia in the outdoors during the winter season. The case history and autopsy findings revealed that the cause of the lethal hypothermia was iron deficiency anemia, which was associated with a prolonged infestation of blood-sucking body lice. Also, he had vagabond's disease because the skin on his body was abnormal and highly pigmented. This is an unusual autopsy case since the body lice contributed to the cause of the death.

Pulmonary arterial hypertension in rats due to age-related arginase activation in intermittent hypoxia.

Pulmonary arterial hypertension (PAH) is prevalent in patients with obstructive sleep apnea syndrome (OSAS). Aging induces arginase activation and reduces nitric oxide (NO) production in the arteries. Intermittent hypoxia (IH), conferred by cycles of brief hypoxia and normoxia, contributes to OSAS pathogenesis. Here, we studied the role of arginase and aging in the pathogenesis of PAH in adult (9-mo-old) and young (2-mo-old) male Sprague-Dawley rats subjected to IH or normoxia for 4 weeks and analyzed them with a pressure-volume catheter inserted into the right ventricle (RV) and by pulsed Doppler echocardiography. Western blot analysis was conducted on arginase, NO synthase isoforms, and nitrotyrosine. IH induced PAH, as shown by increased RV systolic pressure and RV hypertrophy, in adult rats but not in young rats. IH increased expression levels of arginase I and II proteins in the adult rats. IH also increased arginase I expression in the pulmonary artery endothelium and arginase II in the pulmonary artery adventitia. Furthermore, IH reduced pulmonary levels of nitrate and nitrite but increased nitrotyrosine levels in adult rats. An arginase inhibitor (N(ω)-hydroxy-nor-1-arginine) prevented IH-induced PAH and normalized nitrite and nitrate levels in adult rats. IH induced arginase up-regulation and PAH in adult rats, but not in young rats, through reduced NO production. Our findings suggest that arginase inhibition prevents or reverses PAH.

MDMA induces cardiac contractile dysfunction through autophagy upregulation and lysosome destabilization in rats.

The underlying mechanisms of cardiotoxicity of 3,4-methylenedioxymethylamphetamine (MDMA, "ecstasy") abuse are unclear. Autophagy exerts either adaptive or maladaptive effects on cardiac function in various pathological settings, but nothing is known on the role of autophagy in the MDMA cardiotoxicity. Here, we investigated the mechanism through which autophagy may be involved in MDMA-induced cardiac contractile dysfunction. Rats were injected intraperitoneally with MDMA (20mg/kg) or saline. Left ventricular (LV) echocardiography and LV pressure measurement demonstrated reduction of LV systolic contractility 24h after MDMA administration. Western blot analysis showed a time-dependent increase in the levels of microtubule-associated protein light chain 3-II (LC3-II) and cathepsin-D after MDMA administration. Electron microscopy showed the presence of autophagic vacuoles in cardiomyocytes. MDMA upregulated phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) at Thr172, mammalian target of rapamycin (mTOR) at Thr2446, Raptor at Ser792, and Unc51-like kinase (ULK1) at Ser555, suggesting activation of autophagy through the AMPK-mTOR pathway. The effects of autophagic inhibitors 3-methyladenine (3-MA) and chloroquine (CQ) on LC3-II levels indicated that MDMA enhanced autophagosome formation, but attenuated autophagosome clearance. MDMA also induced release of cathepsins into cytosol, and western blotting and electron microscopy showed cardiac troponin I (cTnI) degradation and myofibril damage, respectively. 3-MA, CQ, and a lysosomal inhibitor, E64c, inhibited cTnI proteolysis and improved contractile dysfunction after MDMA administration. In conclusion, MDMA causes lysosome destabilization following activation of the autophagy-lysosomal pathway, through which released lysosomal proteases damage myofibrils and induce LV systolic dysfunction in rat heart.

An unusual autopsy case of cytokine storm-derived influenza-associated encephalopathy without typical histopathological findings: autopsy case report.

Cytokine storm-derived influenza-associated encephalopathy is a severe complication, affecting not only the brain but also multiple systemic organs including the heart and lungs. Hundreds of Japanese children are afflicted by influenza-associated encephalopathy every year. Influenza-associated encephalopathy can be diagnosed by pathological changes, such as advanced brain edema and disruption of astrocytic projections, which is known as clasmatodendrosis. In the present case, despite the absence of significant histopathological findings in the brain, the diagnosis of influenza-associated encephalopathy was made on the basis of autopsy findings such as brain swelling, pathological findings including diffuse alveolar damage, and increase in the concentrations of interleukin-6 in both the serum and cerebrospinal fluid. In this case, the interval from high fever to death was approximately 7 hours and may have been too short for histopathological features to develop. This is an unusual autopsy case of cytokine storm-derived influenza-associated encephalopathy without typical histopathological findings.

Intermittent-hypoxia induced autophagy attenuates contractile dysfunction and myocardial injury in rat heart.

Sleep apnea syndrome (SAS) is considered to be associated with heart failure (HF). It is known that autophagy is induced in various heart diseases thereby promotes survival, but its excess may be maladaptive. Intermittent hypoxia (IH) plays pivotal role in the pathogenesis of SAS. We aimed to clarify the relationships among IH, autophagy, and HF. Rats underwent IH at a rate of 20cycles/h (nadir of 4% O2 to peak of 21% O2 with 0% CO2) or normal air breathing (control) for 8h/d for 3weeks. IH increased the cardiac LC3II/LC3I ratio. The IH induced upregulation of LC3II was attenuated by the administration of an inhibitor of autophagosome formation 3-methyladenine (3-MA), but enhanced by an inhibitor of autophagosome-lysosome fusion chloroquine (CQ), showing enhanced autophagic flux in IH hearts. Electron microscopy confirmed an increase in autophagosomes and lysosomes in IH. With 3-MA or CQ, IH induced progressive deterioration of fractional shortening (FS) on echocardiography over 3weeks, although IH, 3-MA, or CQ alone had no effects. With CQ, IH for 4weeks increased serum troponin T levels, reflecting necrosis. Western blotting analyses showed dephosphorylation of Akt and mammalian target of rapamycin (mTOR) at Akt (Ser2448, 2481) sites, suggesting the activation of autophagy via Akt inactivation. Conclusions. IH-mediated autophagy maintains contractile function, whereas when autophagy is inhibited, IH induces systolic dysfunction due to myocyte necrosis. General significance. This study highlighted the potential implications of autophagy in cardio-protection in early SAS patients without comorbidity, reproduced in normal rats by 3~4weeks of IH.

Pulmonary vascular tone is dependent on the central modulation of sympathetic nerve activity following chronic intermittent hypoxia.

Chronic intermittent hypoxia (IH) provokes a centrally mediated increase in sympathetic nerve activity (SNA). Although this sympathetic hyperexcitation has been linked to systemic hypertension, its effect on the pulmonary vasculature is unclear. This study aimed to assess IH-mediated sympathetic excitation in modulating pulmonary vasculature tone, particularly acute hypoxia vasoconstrictor response (HPV), and the central ß-adrenergic signaling pathway for facilitating the increase in SNA. Sprague-Dawley rats were exposed to IH (cycle of 4% O2 for 90 s/air for 90 s) for 8 h/day for 6 weeks. Subsequently, rats were anesthetized and either pulmonary SNA was recorded (electrophysiology), or the pulmonary vasculature was visualized using microangiography. Pulmonary sympathetic and vascular responses to acute hypoxia were assessed before and after central ß1-adrenergic receptor blockade (Metoprolol, 200 nmol i.c.v.). Chronic IH increased baseline SNA (110% increase), and exacerbated the sympathetic response to acute hypoxia. Moreover, the magnitude of HPV in IH rats was blunted compared to control rats (e.g., 10 and 20% vasoconstriction, respectively). In only the IH rats, ß1-receptor blockade with metoprolol attenuated the hypoxia-induced increase in pSNA and exacerbated the magnitude of acute HPV, so that both sympathetic and HPV responses were similar to that of control rats. Interestingly, the expression of ß1-receptors within the brainstem was similar between both control and IH rats. These results suggest that the centrally mediated increase in SNA following IH acts to blunt the local vasoconstrictor effect of acute hypoxia, which reflects an inherent difference between vasodilator and vasoconstrictor actions of SNA in pulmonary and systemic circulations.

Amniotic fluid embolism induces uterine anaphylaxis and atony following cervical laceration.

Amniotic fluid embolism (AFE) is a rare, high-risk obstetric complication primarily found in the lungs and potentially related to anaphylaxis. Tryptase release from the mast cell reflects anaphylaxis. Case report and findings: A female, aged over 40 years, presented with uterine atony and lethal hemorrhage after induced vaginal labor. Cervical laceration was accompanied by severe hemorrhage. Stromal edema and myometrial swelling were consistent with uterine atony. Alcian blue staining and zinc coproporphyrin immunostaining disclosed AFE, which was more prominent in the uterus than in the lungs. Tryptase immunostaining was diffuse and prominent around the activated mast cells (halos) in the uterus, including the cervix. Similar distribution of findings on the AFE markers, tryptase halos, complement receptor C5aR, and atony in the uterus suggested the causality of AFE to anaphylaxis, complement activation and atony. It is probable that disseminated intravascular coagulation (DIC), induced by AFE, uterine atony and cervical laceration, caused the lethal hemorrhage. It is likely that AFE, in association with cervical laceration, induces uterine anaphylaxis, complement activation, atony, DIC and lethal hemorrhage.

Lethal pulmonary air embolism caused by the removal of a double-lumen hemodialysis catheter.

Pulmonary air embolisms due to the removal of a central venous catheter are rare, but catheter removal is known to be a high risk factor for air embolism. In particular, the removal of a large catheter, such as a double-lumen hemodialysis catheter, can allow a large amount of air to enter into the bloodstream, which often results in sudden death. So, during catheter removal, special care should be taken to prevent air from entering blood vessels, for example, to ensure that the patient's head is tilted downward, that they have inhaled and are holding their breath, and that a covering gauze and inert ointment have been applied to the exit site. We report a lethal case of pulmonary air embolism caused by the removal of a double-lumen catheter from the right internal jugular vein of a patient who was sitting up and had not been instructed to hold their breath.

Immunoradiation Therapy for End-Stage Undifferentiated Cervical Cancer That Restored Sensitivity to Chemotherapy and Resulted in the Disappearance of the Cancer.

Among cervical cancers, small cell undifferentiated carcinoma is rare. Because of its rapid progression, the prognosis is extremely poor. During the course of cisplatin-based chemotherapy for stage Ⅳ small cell undifferentiated carcinoma of the cervix, the patient developed drug resistance, and standard treatment was no longer feasible. Therefore, immunoradiotherapy was administered to activate anticancer immunity. Surprisingly, the cancer drug sensitivity was restored, and cisplatin was again successful, and the cancer disappeared. In addition, the activation of cancer-specific immunity maintained the disappearance of the cancer. It should be noted that immunoradiotherapy not only increases anti-cancer immunity but may also contribute to overcoming cancer drug resistance.

Late-Stage Ovarian Cancer With Systemic Multiple Metastases Shows Marked Shrinkage Using a Combination of Wilms' Tumor Antigen 1 (WT1) Dendritic Cell Vaccine, Natural Killer (NK) Cell Therapy, and Nivolumab.

A patient with bilateral ovarian cancer, peritoneal dissemination, and multiple liver and lung metastases was found with a sudden accumulation of ascites six months after delivery. Chemotherapy was started, but the prognosis was judged to be poor, so immuno-cell therapy was combined with chemotherapy. After multiple cycles of Wilms' tumor antigen 1 (WT1) dendritic cell vaccine therapy and highly activated natural killer (NK) cell therapy, the patient showed a disappearance of ascites and a remarkable reduction of multiple cancers in the whole body. Furthermore, there were no side effects other than reactive fever caused by the administration of immune cells, and no damage to the patient's body was observed. This case suggests that not only the combined effects of chemotherapy and immunotherapy but also the combined use of various types of immuno-cell therapy may provide beneficial clinical effects in patients with extremely poor prognoses and few options for standard treatment.

WT1 Dendritic Cell Vaccine Therapy Improves Immune Profile and Prolongs Progression-Free Survival in End-Stage Lung Cancer.

WT1-pulsed dendritic cell (WT1-DC) therapy was performed for end-stage squamous cell lung cancer that rapidly worsened soon after completion of carboplatin and paclitaxel. A rapid improvement in immune profile was observed with the initiation of WT1-DC. Docetaxel and ramucirumab were initiated as second-line agents during WT1-DC. The improvement of the immune profile status continued, and at the same time, the cancer showed a predominant shrinkage. Progression-free survival was over 577 days, and the patient was able to lead a normal daily life with a performance status of 1. These findings suggest that WT1-DC improves the immune profile, and this may contribute to the long-lasting and sustained effect of chemotherapy.

Delayed-Type Hypersensitivity: An Excellent Indicator of Anti-tumor Immunity With Wilms' Tumor 1 (WT1) Dendritic Cell Vaccine Therapy.

INTRODUCTION: It is a well-known fact that anti-tumor immunity is a crucial long-term survival factor in cancer. Wilms' tumor 1 (WT1) dendritic cell vaccine therapy (WT1-DC) is an immuno-cell therapy that has been implemented against various cancers as a tumor-specific immunotherapy targeting the common cancer antigen WT1. METHODS: Seven doses of WT1-DC vaccine were administered to six patients, three of whom had stage IV lung cancer with metastases and the other three had stage IV pancreatic cancer with metastases, all of whom were receiving chemotherapy and had similar physical conditions. Their immune response was assessed using delayed-type hypersensitivity (DTH) and immune profile status (IPS) such as blood neutrophil percentage, lymphocyte percentage, and neutrophil-to-lymphocyte (N/L) ratio. RESULTS: In lung cancer, DTH increased with repeated DC administration, and IPS improved with it, whereas in pancreatic cancer, DTH did not increase, and IPS worsened from the fifth inoculation. Fever in the 37° range was observed after DC administration in lung cancer, but not in pancreatic cancer. CONCLUSION: These results suggest that DTH and IPS are correlated in dynamics and that DTH is a good indicator of the state of anti-tumor immunity. Since IPS is a prognostic factor in advanced cancer, the magnitude of DTH due to WT1-DC inoculation is a useful indicator to estimate the patient's prognosis. Although DTH is an extremely simple test, its clinical significance has not been fully investigated. The present study demonstrates the importance of DTH in cancer treatment with WT1-DC.

Radioimmunotherapy With WT1 Dendritic Cell Vaccine for End-Stage Lung Adenocarcinoma Markedly Shrinks Tumors.

In advanced lung adenocarcinoma with metastases, the current standard of care does not in principle include aggressive cancer treatment with surgery and radiotherapy. Therefore, when chemotherapy cannot be continued, the patient is generally switched to palliative care. Our patient with stage IV lung adenocarcinoma in his 60s was receiving chemotherapy, which had to be discontinued due to severe side effects. As standard treatment was no longer indicated, he underwent radioimmunotherapy combined with WT1 dendritic cell vaccine therapy. As a result, the massive lung cancer shrank significantly and blood tests showed an improved immune profile. The growth of the lung cancer was suppressed, and the patient is completely symptom-free. After completing radioimmunotherapy, the patient continues to live a life similar to that of a healthy person. This case suggests that radioimmunotherapy can be useful as an active treatment in patients who are not eligible for standard treatment.

Albanol A from the root bark of Morus alba L. induces apoptotic cell death in HL60 human leukemia cell line.

Albanol A (1), isolated from the root bark extract of Morus alba (mulberry), was evaluated for the cytotoxic and apoptosis-inducing activities in human leukemia (HL60) cells, and for the inhibitory activity in human DNA topoisomerases (Topo) I and II. This compound showed potent cytotoxic activity (IC(50) 1.7 microM) on the cells, and potent inhibitory activity on topoisomerase II (IC(50) 22.8 microM). In addition, albanol A induced early apoptosis which was detected by observing the membrane phospholipid exposure in flow cytometry. Western blot analysis showed that albanol A markedly reduced the levels of procaspases-3, 8, and 9, while being increased the levels of cleaved caspases-3, 8, and 9. The Bax/Bcl-2 ratio was significantly increased by albanol A treatment. Furthermore, albanol A induced caspase-2 activation. These results suggested that albanol A induces apoptotic cell death in HL60 via both the cell death receptor pathway by stimulation of death receptor, and the mitochondrial pathway by Topo II inhibition through caspase-2 activation. Therefore, albanol A may be a promising lead compound for developing an effective drug for treatment of leukemia.

Intermittent hypoxia induces disturbances in craniofacial growth and defects in craniofacial morphology.

OBJECTIVES: To investigate intermittent hypoxia (IH) induced changes in craniofacial morphology and bone mineral density (BMD) in the mandible of growing rats. DESIGN: Seven-week-old male Sprague-Dawley rats were exposed to IH for 4 days or 3 weeks. Sham-operated rats simultaneously breathed room air. Lateral and transverse cephalometric radiographs of the craniofacial region were obtained, and the linear distances between cephalometric landmarks were statistically analyzed. BMD and bone microstructure of the mandible were evaluated using micro-computed tomography (micro-CT). RESULTS: Cephalometric analyses demonstrated that exposure to IH only in the two groups for 3 weeks decreased the size of the mandibular and viscerocranial bones, but not that of the neurocranial bones, in early adolescent rats. These findings are consistent with upper airway narrowing and obstructive sleep apnea (OSA). Micro-CT showed that IH increased the BMD in the cancellous bone of the mandibular condyle and the inter-radicular alveolar bone in the mandibular first molar (M1) region. CONCLUSIONS: This study is the first to identify growth retardation of the craniofacial bones in an animal model of sleep apnea. Notably, 3 weeks of IH can induce multiple changes in the bones around the upper airway in pubertal rats, which can enhance upper airway narrowing and the development of OSA. The reproducibility of these results supports the validity and usefulness of this model. These findings also emphasize the critical importance of morphometric evaluation of patients with OSA.

Intermittent Hypoxia Influences Alveolar Bone Proper Microstructure via Hypoxia-Inducible Factor and VEGF Expression in Periodontal Ligaments of Growing Rats.

Intermittent hypoxia (IH) recapitulates morphological changes in the maxillofacial bones in children with obstructive sleep apnea (OSA). Recently, we found that IH increased bone mineral density (BMD) in the inter-radicular alveolar bone (reflecting enhanced osteogenesis) in the mandibular first molar (M1) region in the growing rats, but the underlying mechanism remains unknown. In this study, we focused on the hypoxia-inducible factor (HIF) pathway to assess the effect of IH by testing the null hypothesis of no significant differences in the mRNA-expression levels of relevant factors associated with the HIF pathway, between control rats and growing rats with IH. To test the null hypothesis, we investigated how IH enhances mandibular osteogenesis in the alveolar bone proper with respect to HIF-1α and vascular endothelial growth factor (VEGF) in periodontal ligament (PDL) tissues. Seven-week-old male Sprague-Dawley rats were exposed to IH for 3 weeks. The microstructure and BMD in the alveolar bone proper of the distal root of the mandibular M1 were evaluated using micro-computed tomography (micro-CT). Expression of HIF-1α and VEGF mRNA in PDL tissues were measured, whereas osteogenesis was evaluated by measuring mRNA levels for alkaline phosphatase (ALP) and bone morphogenetic protein-2 (BMP-2). The null hypothesis was rejected: we found an increase in the expression of all of these markers after IH exposure. The results provided the first indication that IH enhanced osteogenesis of the mandibular M1 region in association with PDL angiogenesis during growth via HIF-1α in an animal model.

Pulmonary Macrophages Attenuate Hypoxic Pulmonary Vasoconstriction via ß3AR/iNOS Pathway in Rats Exposed to Chronic Intermittent Hypoxia.

Chronic intermittent hypoxia (IH) induces activation of the sympathoadrenal system, which plays a pivotal role in attenuating hypoxic pulmonary vasoconstriction (HPV) via central ß1-adrenergic receptors (AR) (brain) and peripheral ß2AR (pulmonary arteries). Prolonged hypercatecholemia has been shown to upregulate ß3AR. However, the relationship between IH and ß3AR in the modification of HPV is unknown. It has been observed that chronic stimulation of ß3AR upregulates inducible nitric oxide synthase (iNOS) in cardiomyocytes and that IH exposure causes expression of iNOS in RAW264.7 macrophages. iNOS has been shown to have the ability to dilate pulmonary vessels. Hence, we hypothesized that chronic IH activates ß3AR/iNOS signaling in pulmonary macrophages, leading to the promotion of NO secretion and attenuated HPV. Sprague-Dawley rats were exposed to IH (3-min periods of 4-21% O2) for 8 h/d for 6 weeks. The urinary catecholamine concentrations of IH rats were high compared with those of controls, indicating activation of the sympathoadrenal system following chronic IH. Interestingly, chronic IH induced the migration of circulating monocytes into the lungs and the predominant increase in the number of pro-inflammatory pulmonary macrophages. In these macrophages, both ß3AR and iNOS were upregulated and stimulation of the ß3AR/iNOS pathway in vitro caused them to promote NO secretion. Furthermore, in vivo synchrotron radiation microangiography showed that HPV was significantly attenuated in IH rats and the attenuated HPV was fully restored by blockade of ß3AR/iNOS pathway or depletion of pulmonary macrophages. These results suggest that circulating monocyte-derived pulmonary macrophages attenuate HPV via activation of ß3AR/iNOS signaling in chronic IH.

ß2-Adrenergic receptor-dependent attenuation of hypoxic pulmonary vasoconstriction prevents progression of pulmonary arterial hypertension in intermittent hypoxic rats.

In sleep apnea syndrome (SAS), intermittent hypoxia (IH) induces repeated episodes of hypoxic pulmonary vasoconstriction (HPV) during sleep, which presumably contribute to pulmonary arterial hypertension (PAH). However, the prevalence of PAH was low and severity is mostly mild in SAS patients, and mild or no right ventricular hypertrophy (RVH) was reported in IH-exposed animals. The question then arises as to why PAH is not a universal finding in SAS if repeated hypoxia of sufficient duration causes cycling HPV. In the present study, rats underwent IH at a rate of 3 min cycles of 4-21% O2 for 8 h/d for 6 w. Assessment of diameter changes in small pulmonary arteries in response to acute hypoxia and drugs were performed using synchrotron radiation microangiography on anesthetized rats. In IH-rats, neither PAH nor RVH was observed and HPV was strongly reversed. Nadolol (a hydrophilic ß(1, 2)-blocker) augmented the attenuated HPV to almost the same level as that in N-rats, but atenolol (a hydrophilic ß1-blocker) had no effect on the HPV in IH. These ß-blockers had almost no effect on the HPV in N-rats. Chronic administration of nadolol during 6 weeks of IH exposure induced PAH and RVH in IH-rats, but did not in N-rats. Meanwhile, atenolol had no effect on morphometric and hemodynamic changes in N and IH-rats. Protein expression of the ß1-adrenergic receptor (AR) was down-regulated while that of ß2AR was preserved in pulmonary arteries of IH-rats. Phosphorylation of p85 (chief component of phosphoinositide 3-kinase (PI3K)), protein kinase B (Akt), and endothelial nitric oxide synthase (eNOS) were abrogated by chronic administration of nadolol in the lung tissue of IH-rats. We conclude that IH-derived activation of ß2AR in the pulmonary arteries attenuates the HPV, thereby preventing progression of IH-induced PAH. This protective effect may depend on the ß2AR-Gi mediated PI3K/Akt/eNOS signaling pathway.