piperidines and Hypoxia

Middle East Respiratory Syndrome (MERS) is a novel respiratory illness firstly reported in Saudi Arabia in 2012. It is caused by a new corona virus, called MERS corona virus (MERS-CoV). Most people who have MERS-CoV infection developed severe acute respiratory illness.. This work is done to determine the clinical characteristics and the outcome of intensive care unit (ICU) admitted patients with confirmed MERS-CoV infection.. This study included 32 laboratory confirmed MERS corona virus infected patients who were admitted into ICU. It included 20 (62.50%) males and 12 (37.50%) females. The mean age was 43.99 ± 13.03 years. Diagnosis was done by real-time reverse transcription polymerase chain reaction (rRT-PCR) test for corona virus on throat swab, sputum, tracheal aspirate, or bronchoalveolar lavage specimens. Clinical characteristics, co-morbidities and outcome were reported for all subjects.. Most MERS corona patients present with fever, cough, dyspnea, sore throat, runny nose and sputum. The presence of abdominal symptoms may indicate bad prognosis. Prolonged duration of symptoms before patients' hospitalization, prolonged duration of mechanical ventilation and hospital stay, bilateral radiological pulmonary infiltrates, and hypoxemic respiratory failure were found to be strong predictors of mortality in such patients. Also, old age, current smoking, smoking severity, presence of associated co-morbidities like obesity, diabetes mellitus, chronic heart diseases, COPD, malignancy, renal failure, renal transplantation and liver cirrhosis are associated with a poor outcome of ICU admitted MERS corona virus infected patients.. Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (. SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.. A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.. HFNC did not significantly modify work of breathing in healthy subjects. However, a significant reduction in the minute volume was achieved, capillary [Formula: see text] remaining constant, which suggests a reduction in dead-space ventilation with flows > 20 L/min. (ClinicalTrials.gov registration NCT02495675).. 3 组患者手术时间、术中显性失血量及术后 1 周血红蛋白下降量比较差异均无统计学意义（. 对于肥胖和超重的膝关节单间室骨关节炎患者，采用 UKA 术后可获满意短中期疗效，远期疗效尚需进一步随访观察。.. Decreased muscle strength was identified at both time points in patients with hEDS/HSD. The evolution of most muscle strength parameters over time did not significantly differ between groups. Future studies should focus on the effectiveness of different types of muscle training strategies in hEDS/HSD patients.. These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.. This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies.. NCT04138212, date of registration: October 24, 2019.. Results of current investigation indicated that milk type and post fermentation cooling patterns had a pronounced effect on antioxidant characteristics, fatty acid profile, lipid oxidation and textural characteristics of yoghurt. Buffalo milk based yoghurt had more fat, protein, higher antioxidant capacity and vitamin content. Antioxidant and sensory characteristics of T. If milk is exposed to excessive amounts of light, Vitamins B. The two concentration of ZnO nanoparticles in the ambient air produced two different outcomes. The lower concentration resulted in significant increases in Zn content of the liver while the higher concentration significantly increased Zn in the lungs (p < 0.05). Additionally, at the lower concentration, Zn content was found to be lower in brain tissue (p < 0.05). Using TEM/EDX we detected ZnO nanoparticles inside the cells in the lungs, kidney and liver. Inhaling ZnO NP at the higher concentration increased the levels of mRNA of the following genes in the lungs: Mt2 (2.56 fold), Slc30a1 (1.52 fold) and Slc30a5 (2.34 fold). At the lower ZnO nanoparticle concentration, only Slc30a7 mRNA levels in the lungs were up (1.74 fold). Thus the two air concentrations of ZnO nanoparticles produced distinct effects on the expression of the Zn-homeostasis related genes.. Until adverse health effects of ZnO nanoparticles deposited in organs such as lungs are further investigated and/or ruled out, the exposure to ZnO nanoparticles in aerosols should be avoided or minimised.

Topics: A549 Cells; Acetylmuramyl-Alanyl-Isoglutamine; Acinetobacter baumannii; Acute Lung Injury; Adaptor Proteins, Signal Transducing; Adenine; Adenocarcinoma; Adipogenesis; Administration, Cutaneous; Administration, Ophthalmic; Adolescent; Adsorption; Adult; Aeromonas hydrophila; Aerosols; Aged; Aged, 80 and over; Aging; Agriculture; Air Pollutants; Air Pollution; Airway Remodeling; Alanine Transaminase; Albuminuria; Aldehyde Dehydrogenase 1 Family; Algorithms; AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; Alzheimer Disease; Amino Acid Sequence; Ammonia; Ammonium Compounds; Anaerobiosis; Anesthetics, Dissociative; Anesthetics, Inhalation; Animals; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Humanized; Antifungal Agents; Antigens, Bacterial; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antimetabolites, Antineoplastic; Antineoplastic Agents; 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Intravenous remifentanil may be the preferred analgesic when regional techniques are contraindicated.. To perform a systematic review on the use of remifentanil for analgesia in labor.. We searched MEDLINE (January 1995-August 2007) for studies on obstetric analgesia with remifentanil.. We found 32 references representing the use of remifentanil in 257 women in labor. In most cases, patients reported relief of pain and a high level of satisfaction, with no severe side effects in mothers or neonates. When compared with meperidine and nitrous oxide in clinical trials, remifentanil provided better analgesia with fewer adverse effects.. Analgesia with intravenous remifentanil is more effective and safer than other alternatives to regional analgesic techniques in obstetrics. Nevertheless, the optimum system for infusing the drug must b e established and further studies of maternal and fetal safety should be carried out.

Topics: Analgesia, Epidural; Analgesia, Obstetrical; Analgesia, Patient-Controlled; Analgesics; Analgesics, Opioid; Apgar Score; Clinical Trials as Topic; Female; Fetus; Humans; Hypoxia; Infant, Newborn; Infusions, Intravenous; Meperidine; Nitrous Oxide; Oxygen Inhalation Therapy; Patient Acceptance of Health Care; Piperidines; Pregnancy; Prospective Studies; Remifentanil

Topics: Anesthetics, Intravenous; Carbon Dioxide; Drug Interactions; Humans; Hypoxia; Piperidines; Propofol; Remifentanil; Respiratory Mechanics

The pulmonary endothelium modulates vascular tone by the release of endothelium-derived constricting (EDCF) and relaxing (EDRF) factors, among them endothelin-1, nitric oxide, prostacyclin, and putative endothelium-derived hyperpolarizing factors. Abnormalities in EDCF and EDRF generation have been demonstrated in a number of cardiopulmonary disease states, such as primary and secondary pulmonary hypertension, chronic obstructive lung disease, cardiopulmonary bypass, and congestive heart failure. An imbalance between EDCF and EDRF, termed "pulmonary endothelial dysfunction," may contribute to the alteration in vascular tone characteristic of pulmonary disease. The following review summarizes the present knowledge of the role of EDCF and EDRF in such processes with major focus on pulmonary endothelial dysfunction in hypoxia-induced pulmonary hypertension.

Topics: Animals; Antihypertensive Agents; Atrasentan; Bosentan; Controlled Clinical Trials as Topic; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Endothelium, Vascular; Epoprostenol; Heart Failure; Humans; Hypertension, Pulmonary; Hypoxia; Lung Diseases, Obstructive; Nitric Oxide; Oligopeptides; Peptides, Cyclic; Piperidines; Pulmonary Circulation; Pyrrolidines; Receptors, Endothelin; RNA, Messenger; Sulfonamides; Time Factors; Vasoconstriction; Vasodilation

Serotonin causes contraction of the vascular smooth muscle cells in most blood vessels studied in vitro. This contraction is mainly due to activation of S2-serotonergic receptors. The monoamine can cause relaxation through activation of serotonergic receptors, different from the S2-serotonergic receptor and located on endothelial cells, or through an inhibitory effect on adrenergic neurotransmission. In certain blood vessels, the contractile effects can be markedly enhanced by hypoxia or moderate cooling. At low concentrations serotonin amplifies the vasoconstrictor responses to other vasoactive substances. Ultimately the effect of serotonin on vascular constriction is defined by the balance between these different actions. In the intact organism under normal conditions serotonin may play a modulatory role but exacerbation of the contractile effects because of hypersensitivity of the smooth muscle cells, local physical or humoral factors or loss of the relaxatory ability may lead to abnormal tissue responses. Thus, serotonin-induced vasoconstrictor responses may play a role in the etiology of vasospasm and peripheral vascular diseases, in particular at sites of endothelial lesions. Both the vasoconstrictor and the platelet aggregating effects of serotonin combined with its accelerated turnover may be important in the induction and maintenance of the augmented peripheral vascular resistance in arterial hypertension.

Topics: Animals; Blood Platelets; Calcium; Cold Temperature; Electric Stimulation; Hypoxia; Ketanserin; Lidoflazine; Methiothepin; Methysergide; Microcirculation; Models, Biological; Muscle Contraction; Muscle, Smooth, Vascular; Piperidines; Receptors, Serotonin; Regional Blood Flow; Serotonin; Serotonin Antagonists; Vasoconstriction; Vasodilation

The use of monitored anaesthesia care (MAC) is necessary and ubiquitous for fiberoptic bronchoscopy. Anaesthetic management of patients with severe tracheal stenosis has always been a challenge. The efficacy and safety of the MAC with sufentanil target controlled infusion (TCI) and remifentanil TCI in patients with severe tracheal stenosis are still unknown.. This study is a prospective, investigator-initiated, two-arm, randomised control trial to compare the efficacy and safety of sufentanil TCI with remifentanil TCI in patients with severe tracheal stenosis undergoing fiberoptic bronchoscopy. 270 patients will be randomly assigned to the sufentanil TCI group or remifentanil TCI group, with a 1:1 ratio in two groups. The primary outcome is the incidence of hypoxaemia (an oxygen saturation of <90%). The secondary outcome investigates the severity of hypoxaemia, cough severity, haemodynamic variables, sedation scores and satisfaction scores.. The study has been approved by the Medical Ethics Committee of Shanghai Pulmonary Hospital (approval No. K19-122). The results will be submitted for publication in peer-reviewed journals.. ChiCTR2100043380.

Topics: Anesthesia; Bronchoscopy; China; Humans; Hypoxia; Piperidines; Prospective Studies; Randomized Controlled Trials as Topic; Remifentanil; Sufentanil; Tracheal Stenosis

Middle East Respiratory Syndrome (MERS) is a novel respiratory illness firstly reported in Saudi Arabia in 2012. It is caused by a new corona virus, called MERS corona virus (MERS-CoV). Most people who have MERS-CoV infection developed severe acute respiratory illness.. This work is done to determine the clinical characteristics and the outcome of intensive care unit (ICU) admitted patients with confirmed MERS-CoV infection.. This study included 32 laboratory confirmed MERS corona virus infected patients who were admitted into ICU. It included 20 (62.50%) males and 12 (37.50%) females. The mean age was 43.99 ± 13.03 years. Diagnosis was done by real-time reverse transcription polymerase chain reaction (rRT-PCR) test for corona virus on throat swab, sputum, tracheal aspirate, or bronchoalveolar lavage specimens. Clinical characteristics, co-morbidities and outcome were reported for all subjects.. Most MERS corona patients present with fever, cough, dyspnea, sore throat, runny nose and sputum. The presence of abdominal symptoms may indicate bad prognosis. Prolonged duration of symptoms before patients' hospitalization, prolonged duration of mechanical ventilation and hospital stay, bilateral radiological pulmonary infiltrates, and hypoxemic respiratory failure were found to be strong predictors of mortality in such patients. Also, old age, current smoking, smoking severity, presence of associated co-morbidities like obesity, diabetes mellitus, chronic heart diseases, COPD, malignancy, renal failure, renal transplantation and liver cirrhosis are associated with a poor outcome of ICU admitted MERS corona virus infected patients.. Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (. SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.. A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.. HFNC did not significantly modify work of breathing in healthy subjects. However, a significant reduction in the minute volume was achieved, capillary [Formula: see text] remaining constant, which suggests a reduction in dead-space ventilation with flows > 20 L/min. (ClinicalTrials.gov registration NCT02495675).. 3 组患者手术时间、术中显性失血量及术后 1 周血红蛋白下降量比较差异均无统计学意义（. 对于肥胖和超重的膝关节单间室骨关节炎患者，采用 UKA 术后可获满意短中期疗效，远期疗效尚需进一步随访观察。.. Decreased muscle strength was identified at both time points in patients with hEDS/HSD. The evolution of most muscle strength parameters over time did not significantly differ between groups. Future studies should focus on the effectiveness of different types of muscle training strategies in hEDS/HSD patients.. These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.. This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies.. NCT04138212, date of registration: October 24, 2019.. Results of current investigation indicated that milk type and post fermentation cooling patterns had a pronounced effect on antioxidant characteristics, fatty acid profile, lipid oxidation and textural characteristics of yoghurt. Buffalo milk based yoghurt had more fat, protein, higher antioxidant capacity and vitamin content. Antioxidant and sensory characteristics of T. If milk is exposed to excessive amounts of light, Vitamins B. The two concentration of ZnO nanoparticles in the ambient air produced two different outcomes. The lower concentration resulted in significant increases in Zn content of the liver while the higher concentration significantly increased Zn in the lungs (p < 0.05). Additionally, at the lower concentration, Zn content was found to be lower in brain tissue (p < 0.05). Using TEM/EDX we detected ZnO nanoparticles inside the cells in the lungs, kidney and liver. Inhaling ZnO NP at the higher concentration increased the levels of mRNA of the following genes in the lungs: Mt2 (2.56 fold), Slc30a1 (1.52 fold) and Slc30a5 (2.34 fold). At the lower ZnO nanoparticle concentration, only Slc30a7 mRNA levels in the lungs were up (1.74 fold). Thus the two air concentrations of ZnO nanoparticles produced distinct effects on the expression of the Zn-homeostasis related genes.. Until adverse health effects of ZnO nanoparticles deposited in organs such as lungs are further investigated and/or ruled out, the exposure to ZnO nanoparticles in aerosols should be avoided or minimised.

Topics: A549 Cells; Acetylmuramyl-Alanyl-Isoglutamine; Acinetobacter baumannii; Acute Lung Injury; Adaptor Proteins, Signal Transducing; Adenine; Adenocarcinoma; Adipogenesis; Administration, Cutaneous; Administration, Ophthalmic; Adolescent; Adsorption; Adult; Aeromonas hydrophila; Aerosols; Aged; Aged, 80 and over; Aging; Agriculture; Air Pollutants; Air Pollution; Airway Remodeling; Alanine Transaminase; Albuminuria; Aldehyde Dehydrogenase 1 Family; Algorithms; AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; Alzheimer Disease; Amino Acid Sequence; Ammonia; Ammonium Compounds; Anaerobiosis; Anesthetics, Dissociative; Anesthetics, Inhalation; Animals; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Humanized; Antifungal Agents; Antigens, Bacterial; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antimetabolites, Antineoplastic; Antineoplastic Agents; 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Extracorporeal Shock Wave Lithotripsy is usually performed in day surgery setting, consequently people who undergo to this procedure need a safe and fast recovery. Conscious sedation with remifentanil can relieve from pain and keep patients in touch with anaesthesiologists. Few publications tell about infusion rates administered to perform this procedure7. The aim of this study is to assess which is the most appropriate infusion rate.. Patients were randomly assigned to two groups. Two different infusion rates were compared: 0,05 mcg/kg/min, GROUP A (N.=114), vs. 0.1 µg/kg/min, GROUP B (N.=114). Patients' vital signs, additional analgesic requests, PONV (postoperative nausea and vomiting) and other side effects were registered. The deepness of sedation and patient's satisfaction were evaluated referring to Obsever's Assessment of Alertness and Sedation scale (O/ASS) and using a Likert's scale respectively. Pain intensity was assessed with a 11-points VAS (visual analogue scale). Differences between groups were analyzed using Student t test for independent variables. The χ2 test was used to analyze categorical variables.. The study enrolled 228 patients and assigned them to two groups (N.=114). No significant differences were found regarding Likert's scale values (P=0.20), additional analgesic request (P=0.30) and mean VAS values (P>0.05) between the two groups. The difference between the two groups about PONV, hypotension, oxygen desaturation and respiratory depression was statistically significant (P<0.05), as a matter of fact in group A these side effects occurred less frequently. The fifth degree of O/ASS was estimated in about 1.61±0.19 min and 2.987±0.20 min in group A and in group B respectively (P<0.05).. According with previous results remifentanil at the infusion rate of 0.05 µg/kg/min provides an effective analgesia, causing a lower incidence of side effect than 0.1 µg/kg/min, granting a fast and safe recovery.

Topics: Analgesia; Anesthesia, Intravenous; Anesthetics, Intravenous; Conscious Sedation; Dose-Response Relationship, Drug; Double-Blind Method; Female; Hemodynamics; Humans; Hypotension; Hypoxia; Incidence; Infusions, Intravenous; Lithotripsy; Male; Middle Aged; Pain, Postoperative; Patient Satisfaction; Piperidines; Postoperative Complications; Postoperative Nausea and Vomiting; Remifentanil; Urolithiasis

Sedation or anaesthesia is recommended for all patients undergoing bronchoscopy unless absolute contraindications exist. However, the widely used combination of propofol and opiates for moderate sedation (MS) in bronchoscopy results in a high incidence of hypoxaemia and a relatively high cough score during the procedure. In this study, we evaluated the efficacy and safety of target-controlled infusion (TCI) of propofol and remifentanil, together with the use of high frequency jet ventilation (HFJV), to achieve general anesthesia (GA) in diagnostic fibre-optic bronchoscopy.. A total of 92 consecutive patients scheduled for flexible bronchoscopy were randomly assigned to receive either MS using TCI-delivered propofol and remifentanil (n = 46), or GA using TCI-delivered propofol and remifentanil with HFJV (n = 46). The following were compared between the MS and GA groups: incidence of hypoxaemia, cough score, haemodynamic parameters, partial pressure of carbon dioxide in arterial blood, duration of bronchoscopy and patient satisfaction score.. The average and minimum oxygen saturation values in the MS group were lower than those in the GA group. The MS group showed a higher incidence of hypoxaemia. There was no significant difference in the partial pressure of carbon dioxide between the two groups. Cough score and duration of the bronchoscopy were markedly lower in the GA group, and patient satisfaction score was higher in the GA group.. GA, achieved via TCI-delivered propofol and remifentanil with HFJV, provides better conditions for diagnostic bronchoscopy - it decreases the occurrence of hypoxaemia, shortens the duration of bronchoscopy and increases patient satisfaction.

Topics: Adult; Aged; Anesthesia, General; Bronchoscopy; Carbon Dioxide; Conscious Sedation; Female; Fiber Optic Technology; Hemodynamics; High-Frequency Jet Ventilation; Humans; Hypnotics and Sedatives; Hypoxia; Male; Middle Aged; Oxygen; Patient Satisfaction; Piperidines; Propofol; Remifentanil; Young Adult

Obstructive sleep apnea (OSA) is characterized by recurrent nocturnal hypoxia and sleep disruption. Sleep fragmentation caused hyperalgesia in volunteers, while nocturnal hypoxemia enhanced morphine analgesic potency in children with OSA. This evidence directly relates to surgical OSA patients who are at risk for airway compromise due to postoperative use of opioids. Using accepted experimental pain models, we characterized pain processing and opioid analgesia in male volunteers recruited based on their risk for OSA.. After approval from the Intitutional Review Board and informed consent, we assessed heat and cold pain thresholds and tolerances in volunteers after overnight polysomnography (PSG). Three pro-inflammatory and 3 hypoxia markers were determined in the serum. Pain tests were performed at baseline, placebo, and two effect site concentrations of remifentanil (1 and 2 µg/ml), an μ-opioid agonist. Linear mixed effects regression models were employed to evaluate the association of 3 PSG descriptors [wake after sleep onset, number of sleep stage shifts, and lowest oxyhemoglobin saturation (SaO(2)) during sleep] and all serum markers with pain thresholds and tolerances at baseline, as well as their changes under remifentanil.. Forty-three volunteers (12 normal and 31 with a PSG-based diagnosis of OSA) were included in the analysis. The lower nadir SaO(2) and higher insulin growth factor binding protein-1 (IGFBP-1) were associated with higher analgesic sensitivity to remifentanil (SaO(2), P = 0.0440; IGFBP-1, P = 0.0013). Other pro-inflammatory mediators like interleukin-1β and tumor necrosis factor-α (TNF-α) were associated with an enhanced sensitivity to the opioid analgesic effect (IL-1β, P = 0.0218; TNF-α, P = 0.0276).. Nocturnal hypoxemia in subjects at high risk for OSA was associated with an increased potency of opioid analgesia. A serum hypoxia marker (IGFBP-1) was associated with hypoalgesia and increased potency to opioid analgesia; other pro-inflammatory mediators also predicted an enhanced opioid potency.. Clinicaltrials.gov NCT00672737.

Topics: Adult; Analgesics, Opioid; Biomarkers; Humans; Hypoxia; Inflammation Mediators; Male; Middle Aged; Pain; Pain Threshold; Piperidines; Remifentanil; Sleep; Sleep Apnea, Obstructive; Young Adult

The safety profiles and efficacies of remifentanil and dexmedetomidine (a sedative-analgesic without respiratory depression) for sedation during flexible bronchoscopy were investigated.. Seventy-two patients undergoing elective flexible bronchoscopy were randomly assigned to a propofol-remifentanil group (Group PR, n=36) or a propofol-dexmedetomidine group (Group PD, n=36). The primary outcome was the incidence of oxygen desaturation. Haemodynamic variables, adverse events, need of oral cavity suction, cough scores, satisfaction scores of patients and bronchoscopists, levels of sedation, and recovery times were also compared.. The incidence of oxygen desaturation was significantly lower in the PD group than in the PR group (P=0.01). There were no significant differences between groups in terms of level of sedation, oxygen saturation, mean arterial pressure, heart rate over time, cough scores, or patient satisfaction scores (P>0.05). However, cough scores and bronchoscopist satisfaction scores (P<0.01) were lower in the PD group. In addition, topical anaesthesia (P<0.01) was required more frequently and recovery time (P=0.00) was significantly longer in the PD group. However, oral suction (P=0.03) was required less frequently in the PD group.. Dexmedetomidine was associated with fewer incidents of oxygen desaturation and a reduced need for oral cavity suction than remifentanil during flexible bronchoscopy. However, dexmedetomidine was associated with a longer recovery time and poorer bronchoscopist satisfaction score.

Topics: Adult; Aged; Analgesics, Non-Narcotic; Anesthesia Recovery Period; Blood Pressure; Bronchoscopy; Conscious Sedation; Cough; Dexmedetomidine; Double-Blind Method; Female; Heart Rate; Humans; Hypnotics and Sedatives; Hypoxia; Male; Middle Aged; Oxygen; Partial Pressure; Patient Satisfaction; Piperidines; Propofol; Remifentanil; Young Adult

To evaluate the efficiency and safety of intravenous (i.v.) remifentanil and propofol for gastroscopy in healthy adults.. Randomized, double-blinded study.. Endoscopy Center, West China Hospital, Sichuan University (Chengdu, People's Republic of China).. 199 adult ASA physical status I and II patients.. Patients were randomly allocated to either the fentanyl group (n = 99) or the remifentanil group (n = 100). Patients received either fentanyl 0.5 microg/kg or remifentanil 0.5 microg/kg, followed by a bolus injection of one mg/kg of propofol. The subsequent doses of propofol were 0.5 mg/kg when the patient was conscious or body movement appeared.. Noninvasive blood pressure, heart rate, arterial pulse oxygen saturation, and respiratory rate were recorded before gastroscopy and at two-minute intervals until the end of the gastroscopy procedure. Patients were asked to evaluate their level of cognition using the Digit-Symbol Substitution Test score before gastroscopy and at 10 minutes after discontinuation of the drug injection.. Recovery time was significantly shorter in the remifentanil group than in the fentanyl group (P < 0.05). Postoperative Digit-Symbol Substitution Test scores were significantly higher in the remifentanil group than in the fentanyl group (P < 0.01). Total dosage of propofol given in the remifentanil group was significantly less than it was in the fentanyl group (P < 0.01). Frequency of apnea was significantly higher in the remifentanil group (P < 0.05). There were no significant differences in frequency of hypoxemia, bag ventilation, or body movement between the two groups (P > 0.05).. Intravenous remifentanil and propofol were more efficient for gastroscopy than i.v. fentanyl and propofol.

Topics: Adult; Anesthesia Recovery Period; Anesthetics, Combined; Anesthetics, Intravenous; Apnea; Cognition; Dose-Response Relationship, Drug; Double-Blind Method; Fentanyl; Gastroscopy; Humans; Hypoxia; Piperidines; Propofol; Remifentanil; Respiration, Artificial

Target-controlled infusions (TCIs) of remifentanil and fentanyl in conscious sedation regimes for extra-corporeal shock-wave lithotripsy have not been reported. We estimated the effect site concentrations of remifentanil and fentanyl needed to obtain adequate analgesia in 50% of patients (EC50) and compared both drugs in terms of intra- and post-procedure complications.. Forty-four adult patients were randomly distributed into two groups: Group R received remifentanil and Group F received fentanyl TCI with initial effect site concentrations of 1.5 and 2 ng mL(-1), respectively. Pain was assessed using a 10-point verbal analogue scale and <3 was considered adequate analgesia. Increments or decrements of 0.5 ng mL(-1) were then introduced for subsequent patients according to Dixon's up and down method. During the rest of the procedure, TCI was adjusted to maintain verbal analogue scale <3.. Remifentanil and fentanyl EC50 were 2.8 ng mL(-1) (95% confidence interval (CI): 1.8-3.7 ng mL(-1)) and 2.9 ng mL(-1) (95% CI: 1.7-4.1 ng mL(-1)), respectively (n.s.). At EC50, the probability of having a respiratory rate <10 was 4% (95% CI: 0-57%) for remifentanil and 56% (95% CI: 13-92%) for fentanyl. Hypoxaemia, vomiting and sedation were more frequent in Group F during and after the procedure (P < 0.05).. A similar EC50 but more respiratory depression, sedation and PONV were found with fentanyl TCI than with remifentanil TCI.

Topics: Adolescent; Adult; Analgesics, Opioid; Conscious Sedation; Drug Delivery Systems; Female; Fentanyl; Humans; Hypoxia; Infusions, Intravenous; Lithotripsy; Male; Middle Aged; Pain; Pain Measurement; Piperidines; Remifentanil; Respiratory Function Tests; Vomiting

Sameridine is a new compound with both local anesthetic and opioid properties (partial micro -opioid receptor agonist). It was intended for intrathecal administration to provide anesthesia for surgery and extended postoperative analgesia. In this double-blinded pharmacodynamic study with a two-parallel-group design, we investigated, during a 24-h period, the effects of intrathecal sameridine and bupivacaine on ventilation at rest and at ventilatory challenges during hypercarbia and hypoxia. Twenty-four healthy volunteers received either 25 mg of sameridine or 15 mg of bupivacaine intrathecally. Ventilation was measured by pneumotachography and in-line capnography. Sedation was rated by a visual analog scale. Segmental spread and development of motor and sensory block were similar in both groups. There was a decrease in tidal volume 2.5 to 6 h after injection in the bupivacaine group. This was seen only at 4 h in the sameridine group. There were no other major ventilatory differences between sameridine and bupivacaine during resting ventilation. Hypercarbic (tidal volume, mean inspiratory flow) and hypoxic (mean inspiratory flow) ventilatory responses were slightly decreased in the sameridine group, but not in the bupivacaine group. We conclude that intrathecal administration of sameridine or bupivacaine in healthy volunteers produces similar, minor effects on ventilatory responses over a 24-h observation period.

Topics: Adult; Algorithms; Anesthetics, Local; Bupivacaine; Carbon Dioxide; Conscious Sedation; Double-Blind Method; Electrocardiography; Female; Humans; Hypoxia; Injections, Spinal; Male; Monitoring, Intraoperative; Motor Neurons; Nerve Block; Neurons, Afferent; Piperidines; Receptors, Opioid, mu; Respiratory Mechanics

To assess the efficacy and safety of remifentanil for analgesia and sedation during subarachnoidea anesthesia, and to compare remifentanil with propofol.. Ninety ASA I-III patients undergoing orthopedic or traumatologic surgery under subarachnoid anesthesia were enrolled for prospective study and randomly assigned to two treatment groups. The propofol group (n = 45) received a single dose of 0.5 mg/kg followed by infusion at 3 mg/kg/h. The remifentanil group (n = 45) received a single dose of 0.5 microgram/kg followed by infusion at 0.1 microgram/kg/min. We evaluated quality of sedation, pain intensity during nerve blockade, hemodynamic and respiratory parameters and time until recovery.. The remifentanil group experienced less moderate-to-intense pain (13%) than did the propofol group (63%) (p < 0.01). Sedation was adequate in both groups and was easy to control by adjusting the rate of infusion. Times until recovery of consciousness and respiratory frequency after withdrawal of infusion until recovery of baseline levels were 7.87 +/- 3.54 min and 5.22 +/- 2.49 min, respectively, in the remifentanil group and 8.72 +/- 4.59 min and 5.36 +/- 2.49 min, respectively, in the propofol group, respectively. Patients in the remifentanil group experienced a significantly greater decrease in SpO2 than did those in the propofol group (20% and 4%, respectively; p < 0.05). Mean blood pressure was higher for patients treated with remifentanil. The incidence of vomiting was also higher in the remifentanil group than in the propofol group (9% vs 0%).. Remifentanil is more effective in reducing pain related to nerve blockade and level of sedation is lower; however remifentanil is associated with a higher incidence of respiratory depression and vomiting.

Topics: Adolescent; Adult; Aged; Anesthesia, Spinal; Anesthetics, General; Female; Humans; Hypnotics and Sedatives; Hypoxia; Male; Middle Aged; Orthopedic Procedures; Pain, Postoperative; Piperidines; Propofol; Prospective Studies; Remifentanil; Respiration Disorders; Safety; Vomiting

Topics: Amides; Aminopyrine; Analgesics; Clinical Trials as Topic; Drug Evaluation; Fumarates; Humans; Hypoxia; Piperidines; Placebos; Propionates; Pyridines

Over-expressions of epidermal growth factor receptor and vascular endothelial growth factor receptor were frequently associated with the metastasis of solid tumors. Vandetanib, a dual tyrosine kinase inhibitor of epidermal growth factor receptor and vascular endothelial growth factor receptor, was broadly effective in treating a variety of human solid tumors. The compelling evidence that hypoxia is involved in tumor resistance to cancer therapy. Hypoxia-inducible factor (HIF-1α), a major transcription factor in response to hypoxia, has been considered as a promising specific target for cancer therapy. We reported a stronger vandetanib derivative, compound 39, which was more potently decreased viability of A549, HT-29, MCF-7, HepG2, and HeLa cells than its parent compound vandetanib. Remarkable hypoxia-selectivity was observed in A549 cells (IC

Topics: Apoptosis; Cell Hypoxia; Cell Line, Tumor; Cell Proliferation; ErbB Receptors; HeLa Cells; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Neoplasms; Piperidines; Quinazolines; Receptors, Vascular Endothelial Growth Factor; Vascular Endothelial Growth Factor A

We aimed to investigate the hypothesis that sigma receptor ligands, haloperidol and ifenprodil, attenuate hypoxia-induced striatal dopamine release in vitro and determine the possible mechanisms.. Extracellular concentrations of dopamine were measured using acute brain slices method under hypoxic, aglycemic and ischemic conditions. Sigma receptor ligands haloperidol and ifenprodil attenuate striatal dopamine release induced by hypoxia in contrast to aglycemia and ischemia. To determine the possible contribution of glutamatergic system on this effect, we compared the effect of NMDA receptor antagonist MK-801 and haloperidol in hypoxia induced by Na-K-ATPaz enzyme inhibitor ouabain. Also, we compared the effect of dopamine uptake blocker nomifensine and haloperidol to determine the role of dopamine transporter on this effect.. Haloperidol and nomifensine almost completely abolish ouabain-induced dopamine release unlike MK-801. Different effects of sigma ligands and glutamate receptor antagonists on the hypoxia and ouabain induced dopamine release show that glutamate receptor blockade is partial involved in inhibitory effect of sigma ligand on dopamine release under hypoxic conditions. Similar effect of dopamine uptake blocker nomifensine and sigma receptor ligand haloperidol on ouabain induced dopamine release supports the possibility that inhibition of reverse dopamine transport by sigma ligands might be involved in their protective effect.. Data in this study suggest that sigma ligands may be a new therapeutic intervention for the management of hypoxic conditions.

Topics: Animals; Corpus Striatum; Dizocilpine Maleate; Dopamine; Dopamine Antagonists; Dopamine Plasma Membrane Transport Proteins; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Haloperidol; Hypoxia; Ligands; Nomifensine; Ouabain; Piperidines; Rats; Receptors, N-Methyl-D-Aspartate; Receptors, sigma

JZL184 is a selective inhibitor of monoacylglycerol lipase (MAGL) that has neuroprotective effect. However, the role of JZL184 in cerebral ischemia/reperfusion (I/R) injury and the exact mechanism have not been fully understood. This study was designed to elucidate the role of JZL184 in cerebral I/R injury induced by oxygen-glucose deprivation/reoxygenation (OGD/R) in hippocampal neurons. Hippocampal neurons were pretreated with various concentrations of JZL184 for 2 h, followed by OGD for 3 h and reoxygen for 24 h. Our results showed that JZL184 improved cell viability in hippocampal neurons in response to OGD/R. JZL184 treatment significantly inhibited the production of reactive oxygen species (ROS) and malondialdehyde (MDA), as well as increased superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities in OGD/R-induced hippocampal neurons. The increased TNF-α, IL-1β, and IL-6 productions in OGD/R-induced hippocampal neurons were decreased after treatment with JZL184. Moreover, the OGD/R-caused intense TUNEL staining in hippocampal neurons was attenuated by JZL184. JZL184 treatment prevented OGD/R-caused increases in bax and cleaved caspase-3 expression and a decrease in bcl-2 expression. Furthermore, JZL184 treatment significantly promoted the activation of Nrf2/ARE signaling pathway in OGD/R-induced hippocampal neurons. Additionally, silencing of Nrf2 reversed the protective effect of JZL184 on hippocampal neurons under OGD/R condition. Taken together, these findings suggested that JZL184 exerted protective effect against OGD/R-induced injury in hippocampal neurons via activating Nrf2/ARE signaling pathway, which provided

Topics: Animals; Benzodioxoles; Brain Ischemia; Cell Survival; Glucose; Hippocampus; Humans; Hypoglycemia; Hypoglycemic Agents; Hypoxia; Models, Animal; Monoacylglycerol Lipases; Neurons; Neuroprotective Agents; Piperidines; Rats; Rats, Sprague-Dawley; Reperfusion Injury

Halofuginone is a febrifugine derivative originally isolated from Chinese traditional herb Chang Shan that exhibits anti-hypertrophic, anti-fibrotic and anti-proliferative effects. We sought to investigate whether halofuginone induced pulmonary vasodilation and attenuates chronic hypoxia-induced pulmonary hypertension (HPH).. Patch-clamp experiments were conducted to examine the activity of voltage-dependent Ca. Halofuginone increased voltage-gated K

Topics: Animals; Calcium; Hypertension, Pulmonary; Hypoxia; Mice; Myocytes, Smooth Muscle; Pharmaceutical Preparations; Phosphatidylinositol 3-Kinases; Piperidines; Pulmonary Artery; Quinazolinones

Vandetanib-eluting radiopaque beads (VERB) have been developed for use in transarterial chemoembolization of liver tumours, with the goal of combining embolization with local delivery of antiangiogenic therapy. The objective of this study was to investigate how embolization-induced hypoxia may affect antitumoural activity of vandetanib, an inhibitor of vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR), in the context of hepatocellular carcinoma (HCC) treatment. We studied the effect of vandetanib on proliferation, cell cycle and apoptosis of HCC cells, in hypoxic conditions, as well as the direct effects of the beads on 3D HCC spheroids. Vandetanib suppressed proliferation and induced apoptosis of HCC cells in vitro and was equipotent in hypoxic and normoxic conditions. High degrees of apoptosis were observed among cell lines in which vandetanib suppressed ERK1/2 phosphorylation and upregulated the proapoptotic protein Bim, but this did not appear essential for vandetanib-induced cell death in all cell lines. Vandetanib also suppressed the hypoxia-induced secretion of VEGF from HCC cells and inhibited proliferation of endothelial cells. Incubation of tumour spheroids with VERB led to sustained growth inhibition equivalent to the effect of free drug. We conclude that vandetanib has both antiangiogenic and direct anticancer activity against HCC cells even in hypoxic conditions, warranting the further evaluation of VERB as novel anticancer agents.

Topics: Apoptosis; Carcinoma, Hepatocellular; Cell Cycle; Cell Line, Tumor; Chemoembolization, Therapeutic; Drug Liberation; Human Umbilical Vein Endothelial Cells; Humans; Hypoxia; Liver Neoplasms; MAP Kinase Signaling System; Neovascularization, Pathologic; Piperidines; Quinazolines; Vascular Endothelial Growth Factors

This study investigated the effect of rimonabant, a cannabinoid receptor type 1 antagonist, on calcium/calmodulin- dependent protein kinase II and cannabinoid receptor type 1 in chronic intermittent hypoxia.. Healthy male rats were divided into control group, intermittent hypoxia group for 4 or 6 weeks, hypoxic intervention group that received rimonabant (1 mg/kg/d) before exposure to hypoxia for 4 or 6 weeks (n = 10/group). Morphological changes and expressions of the two indexes in the cerebral hippocampus cells were determined by haematoxylin-eosin staining and immunohistochemistry, respectively.. In the intermittent hypoxia group at 4 weeks, the hippocampal cells were damaged with sparse cytoplasm and unclear boundaries, which are even worse at 6 weeks. In contrast, the hippocampal cells of the hypoxic intervention group were neatly arranged at 4 weeks. At 6 weeks, cells were larger with scarce cytoplasm and nuclear changes indicative of cell death. Calcium/calmodulin-dependent protein kinase II and cannabinoid receptor type 1 expression in the cerebral hippocampus was elevated in the intermittent hypoxia group at 4 weeks with even greater at 6 weeks. Cannabinoid receptor type 1 expression was reduced in the hypoxic intervention group compared to the intermittent hypoxia group. Correlation analysis revealed significant positive correlation of them in the intermittent hypoxia group.. Chronic intermittent hypoxia induced structural damage in the hippocampus and increased cannabinoid receptor type 1 and calcium/calmodulin-dependent protein kinase II expression, which may mediate cognitive impairment associated with chronic intermittent hypoxia. Rimonabant had a protective effect against chronic intermittent hypoxia.

Topics: Animals; Brain Injuries; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cannabinoid Receptor Antagonists; Chronic Disease; Disease Models, Animal; Gene Expression Regulation; Hippocampus; Hypoxia; Male; Piperidines; Pyrazoles; Rats; Receptor, Cannabinoid, CB1; Rimonabant

A 63-year-old woman with pulmonary adenocarcinoma (stage IIIB) that was positive for an epidermal growth factor receptor (EGFR) mutation and an anaplastic lymphoma kinase (ALK) rearrangement was treated with erlotinib as the first-line treatment, resulting in a stable disease. Due to skin rashes, fatigue and anorexia, erlotinib was suspended on erlotinib day 44. Alectinib was administered as the second-line treatment, exhibiting a partial response. On alectinib day 56, drug-induced lung injury forced suspension of alectinib, which was cured with corticosteroid therapy. ALK-tyrosine kinase inhibitors may be more effective for patients positive for both EGFR mutation and ALK rearrangement than other agents.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Adrenal Cortex Hormones; Anaplastic Lymphoma Kinase; Carbazoles; Cough; ErbB Receptors; Erlotinib Hydrochloride; Female; Fever; Humans; Hypoxia; Lung Neoplasms; Middle Aged; Mutation; Piperidines; Receptor Protein-Tyrosine Kinases; Treatment Outcome

Recent studies have demonstrated that the expression of sphingosine kinase 1, the enzyme that catalyses formation of the bioactive lipid, sphingosine 1-phosphate, is increased in lungs from patients with pulmonary arterial hypertension. In addition, Sk1(-/-) mice are protected from hypoxic-induced pulmonary arterial hypertension. Therefore, we assessed the effect of the sphingosine kinase 1 selective inhibitor, PF-543 and a sphingosine kinase 1/ceramide synthase inhibitor, RB-005 on pulmonary and cardiac remodelling in a mouse hypoxic model of pulmonary arterial hypertension. Administration of the potent sphingosine kinase 1 inhibitor, PF-543 in a mouse hypoxic model of pulmonary hypertension had no effect on vascular remodelling but reduced right ventricular hypertrophy. The latter was associated with a significant reduction in cardiomyocyte death. The protection involves a reduction in the expression of p53 (that promotes cardiomyocyte death) and an increase in the expression of anti-oxidant nuclear factor (erythroid-derived 2)-like 2 (Nrf-2). In contrast, RB-005 lacked effects on right ventricular hypertrophy, suggesting that sphingosine kinase 1 inhibition might be nullified by concurrent inhibition of ceramide synthase. Therefore, our findings with PF-543 suggest an important role for sphingosine kinase 1 in the development of hypertrophy in pulmonary arterial hypertension.

Topics: Animals; Biomarkers; Body Weight; Cells, Cultured; Disease Models, Animal; Enzyme Inhibitors; Female; Heart Ventricles; HEK293 Cells; Humans; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Methanol; Mice, Inbred C57BL; Models, Biological; Myocytes, Smooth Muscle; Phosphotransferases (Alcohol Group Acceptor); Piperidines; Pressure; Pulmonary Artery; Pyrrolidines; Signal Transduction; Sulfones; Ventricular Remodeling

Hypoxia and inflammation have been identified as the hallmarks of colitis, intertwined with metabolism. Here, we report that halofuginone (HF), an antiparasitic drug, attenuates dextran sulfate sodium (DSS)-induced colitis in mice, as represented by attenuating the disease activity index, inhibiting colonic shortening, ameliorating colonic lesions and histological signs of damage, reducing colonic myeloperoxidase activity, and suppressing the production of pro-inflammatory cytokines in colon tissue. Intriguingly, the hypoxia-inducible factor 1alpha (HIF-1α) and tumor necrosis factor alpha were also suppressed by HF treatment in colon tissues, exhibiting a tissue-specific effect. To further reveal the metabolic signatures upon HF treatment, mass spectrometry-based metabolomic analysis of the small molecular metabolites in liver, spleen and colon tissues was performed. As a result, we found that HF treatment counteracted the levels of acylcarnitines, including palmitoyl-l-carnitine, isobutyrylcarnitine, vaccenylcarnitine, and myristoylcarnitine, in colon tissues with DSS induction, but no significant change in the levels of acylcarnitines was observed in liver or spleen tissues. The metabolic signatures may indicate that incomplete fatty acid oxidation (FAO) in the colon could be restored upon HF treatment as the tissue-specific metabolic characterization. Taken together, our findings uncovered that the HF potentiated anti-inflammatory effect in DSS-induced colitis in mice and its underlying mechanisms could be associated with the inhibition of HIF-1α and reduced levels of acylcarnitines, suggesting that both the inhibition of HIF-1α and the counteraction of incomplete FAO might be useful in the prevention and treatment of inflammatory bowel disease.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Biomarkers; Body Weight; Colitis; Cytokines; Dextran Sulfate; Disease Models, Animal; Energy Metabolism; Enzyme Activation; Fatty Acids; Gene Expression; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation Mediators; Liver; Male; Metabolic Networks and Pathways; Mice; Models, Biological; Oxidation-Reduction; Peroxidase; Phenotype; Piperidines; Quinazolinones; RNA, Messenger; Spleen

Ascorbic acid bound to KMUP-1 and sildenafil were examined for their antioxidant effects on vascular endothelium growth factor (VEGF) and endothelium nitric oxide synthase (eNOS) in hypoxic pulmonary artery (PA). Inhaled KMUP-1 and oral sildenafil released NO from eNOS. The effect of buffered l-ascorbic acid, alone and bound to KMUP-1 or sildenafil, for treating pulmonary arterial hypertension (PAH) is unclear. In this study, the antioxidant capacity of ascorbic acid increased the beneficial effects of KMUP-1 on PAH. KMUP-1A and sildenafil-A (5 mg/kg/d) were administered to hypoxic PAH rats. Pulmonary artery blood pressure, and VEGF, Rho kinase II (ROCK II), eNOS, soluble guanylate cyclase (sGC-α), and protein kinase G expression in lung tissues were measured to link PAH and right ventricular hypertrophy. Hypoxic rats had higher pulmonary artery blood pressure, greater PA medial wall thickness and cardiac weight, and a higher right ventricle/left ventricle + septum [RV/(LV+S)] ratio than normoxic rats. Oral KMUP-1A or sildenafil-A for 21 days in hypoxia prevented the rarefaction of eNOS in immunohistochemistry (IHC), reduced the IHC of VEGF in PAs, restored eNOS/protein kinase G/phosphodiesterase 5A; unaffected sGC-α and inactivated ROCK II expression were also found in lung tissues. In normoxic PA, KMUP-1A/Y27632 (10μM) increased eNOS and reduced ROCK II. ROCK II/reactive oxidative species was increased and eNOS was reduced after long-term hypoxia for 21 days. KMUP-1A or Y27632 blunted ROCK II in short-term hypoxic PA at 24 hours. l-Ascorbic acid + l-sodium ascorbate (40, 80μM) buffer alone directly inhibited the IHC of VEGF in hypoxic PA. Finally, KMUP-1A or sildenafil-A reduced PAH and associated right ventricular hypertrophy.

Topics: Amides; Animals; Ascorbic Acid; Endothelium, Vascular; Hypertension, Pulmonary; Hypoxia; Male; Nitric Oxide Synthase Type III; Piperidines; Pulmonary Artery; Pyridines; Rats; Sildenafil Citrate; Vascular Endothelial Growth Factors; Xanthines

Whole cell based screens to identify hits against Mycobacterium tuberculosis (Mtb), carried out under replicating and non-replicating (NRP) conditions, resulted in the identification of multiple, novel but structurally related spiropiperidines with potent antitubercular properties. These compounds could be further classified into three classes namely 3-(3-aryl-1,2,4-oxadiazol-5-yl)-1'-alkylspiro[indene-1,4'-piperidine] (abbr. spiroindenes), 4-(3-aryl-1,2,4-oxadiazol-5-yl)-1'-alkylspiro[chromene-2,4'-piperidine] (abbr. spirochromenes) and 1'-benzylspiro[indole-1,4'-piperidin]-2(1H)-one (abbr. spiroindolones). Spiroindenes showed ⩾ 4 log10 kill (at 2-12 μM) on replicating Mtb, but were moderately active under non replicating conditions. Whole genome sequencing efforts of spiroindene resistant mutants resulted in the identification of I292L mutation in MmpL3 (Mycobacterial membrane protein Large), required for the assembly of mycolic acid into the cell wall core of Mtb. MIC modulation studies demonstrated that the mutants were cross-resistant to spirochromenes but not to spiroindolones. This Letter describes lead identification efforts to improve potency while reducing the lipophilicity and hERG liabilities of spiroindenes. Additionally, as deduced from the SAR studies, we provide insights regarding the new chemical opportunities that the spiroindolones can offer to the TB drug discovery initiatives.

Topics: Animals; Antitubercular Agents; Bacteria; Drug Resistance, Bacterial; Genome, Bacterial; High-Throughput Screening Assays; Hypoxia; Lipids; Matrix Metalloproteinase 13; Mice; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Piperidines; Spiro Compounds; Structure-Activity Relationship

Obstructive sleep apnea (OSA) and its main feature, chronic intermit-tent hypoxia (IH) during sleep, is closely associated with insulin resistance (IR) and diabetes. Rimonabant can regulate glucose metabolism and improve IR. The present study aimed to assess the effect of IH and rimonabant on glucose metabolism and insulin sensitivity, and to explore the possible mechanisms.. Thirty-two rats were randomly assigned into 4 groups: Control group, subjected to intermittent air only; IH group, subjected to IH only; IH+NS group, subjected to IH and treated with normal saline; and IH+Rim group, subjected to IH and treated with 10 mg/kg/day of rimonabant. All rats were killed after 28 days of exposure. Then, the blood and skeletal muscle were collected. We measured fasting blood glucose levels, fasting blood insulin levels, and the expression of glucose transporter 4 (GLUT4) in both mRNA and protein levels in skeletal muscle.. IH can slow weight gain, increase serum insulin level, and reduce insulin sensitivity in rats. The expressions of GLUT4 mRNA, total GLUT4, and plasma membrane protein of GLUT4 (PM GLUT4) in skeletal muscle were decreased. Rimonabant treatment was demonstrated to improve weight gain and insulin sensitivity of the rats induced by IH. Rimonabant significantly upregulated the expression of GLUT4 mRNA, PM GLUT4, and total GLUT4 in skeletal muscle.. The present study demonstrates that IH can cause IR and reduced expression of GLUT4 in both mRNA and protein levels in skeletal muscle of rats. Rimonabant treatment can improve IH - induced IR, and the upregulation of GLUT4 expression may be involved in this process.

Topics: Animals; Blood Glucose; Cannabinoid Receptor Antagonists; Gene Expression Regulation; Glucose; Glucose Transporter Type 4; Hypoxia; Immunohistochemistry; Insulin Resistance; Male; Muscle, Skeletal; Piperidines; Pyrazoles; Random Allocation; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Rimonabant; Sleep Apnea, Obstructive

Cannabis is one of the most commonly used recreational drugs at ages highly correlated with potential pregnancy. Endocannabinoid signalling regulates important stages of neuronal development. When cannabinoid receptors, which are widely distributed through the nervous system, are activated by exogenous cannabinoids, breathing in adult rats is depressed. Here, we show that, in newborn mice, endocannabinoids, through the activation of cannabinoid receptor type 1 (CB1 R), participate in the modulation of respiration and its control. Blocking CB1 Rs at birth suppressed the brake exerted by endocannabinoids on ventilation in basal and in hypoxic conditions. The number of apnoeas and their duration were also minimized by activation of CB1 Rs in normoxic and in hypoxic conditions. However, prenatal cannabis intoxication, caused by a daily injection of WIN55,212-2, in pregnant mice durably modified respiration of the offspring, as shown by hyperventilation in basal conditions, an altered chemoreflex in response to hypoxia, and longer apnoeas. When CB1 Rs were blocked in WIN55,212-2 treated newborns, persistent hyperventilation was still observed, which could partly be explained by a perturbation of the central respiratory network. In fact, in vitro medullary preparations from WIN55,212-2 treated pups, free of peripheral or of supramedullary structures, showed an altered fictive breathing frequency. In conclusion, the endocannabinoid pathway at birth seems to modulate breathing and protect the newborn against apnoeas. However, when exposed prenatally to an excess of cannabinoid, the breathing neuronal network in development seems to be modified, probably rendering the newborn more vulnerable in the face of an unstable environment.

Topics: Animals; Animals, Newborn; Apnea; Benzoxazines; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Female; Hypoxia; Immunohistochemistry; Medulla Oblongata; Mice, Inbred C57BL; Morpholines; Naphthalenes; Periodicity; Piperidines; Plethysmography; Pregnancy; Prenatal Exposure Delayed Effects; Pyrazoles; Receptor, Cannabinoid, CB1; Respiration; Tyrosine 3-Monooxygenase

Chronic intermittent hypoxia-hypercapnia (CIHH) exposure leads to learnning and memory deficits in rats. Overactivation of N-methyl-D-aspartate receptors(NMDARs) can lead to the death of neurons through a process termed excitotoxicity, which is involved in CIHH-induced cognitive deficits. Excessively activated NR2B (GluN2B)-containing NMDARs was reported as the main cause of excitotoxicity. The ERK1/2 (extracellular signal-regulated kinase 1/2) signaling cascade acts as a key component in NMDARs-dependent neuronal plasticity and survival. Ca2+/calmodulin-dependent protein kinase II (CaMKII), synapse-associated protein 102 (SAP102) and Ras GTPase-activating protein (SynGAP) have been shown to be involved in the regulation of NMDAR-ERK signalling cascade. Recent studies revealed statins (the HMG-CoA reductase inhibitor) have effect on the expression of NMDARs. The present study intends to explore the potential effect of lovastatin on CIHH-induced cognitive deficits and the NR2B-ERK signaling pathway.. Eighty male Sprague Dawley rats were randomly divided into five groups. Except for those in the control group, the rats were exposed to chronic intermittent hypoxia-hypercapnia (CIHH) (9 ∼ 11%O2, 5.5 ∼ 6.5%CO2) for 4 weeks. After lovastatin administration, the rats performed better in the Morris water maze test. Electron microscopy showed alleviated hippocampal neuronal synaptic damage. Further observation suggested that either lovastatin or ifenprodil (a selective NR2B antagonist) administration similarly downregulated NR2B subunit expression leading to a suppression of CaMKII/SAP102/SynGAP signaling cascade, which in turn enhanced the phosphorylation of ERK1/2. The phosphorylated ERK1/2 induced signaling cascade involving cAMP-response element-binding protein (CREB) phosphorylation and brain-derived neurotrophic factor (BDNF) activation, which is responsible for neuroprotection.. These findings suggest that the ameliorative cognitive deficits caused by lovastatin are due to the downregulation of excessive NR2B expression accompanied by increased expression of ERK signaling cascade. The effect of NR2B in upregulating pERK1/2 maybe due, at least in part, to inactivation of CaMKII/SAP102/SynGAP signaling cascade.

Topics: Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Chronic Disease; Disease Models, Animal; Excitatory Amino Acid Antagonists; Gene Expression Regulation; GTPase-Activating Proteins; Hippocampus; Hypercapnia; Hypoxia; Learning Disabilities; Lovastatin; Male; MAP Kinase Signaling System; Maze Learning; Membrane Microdomains; Memory Disorders; Neuropeptides; Nootropic Agents; Piperidines; Pulmonary Disease, Chronic Obstructive; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Signal Transduction; Spatial Learning; Synaptosomes

The aim was to investigate whether intravenous infusion of remifentanil would depress phrenic long term facilitation (pLTF) evoked by acute intermittent hypoxia (AIH) in adult, male, urethane anaesthetized Sprague-Dawley rats, bilaterally vagotomized, paralyzed and mechanically ventilated. The experimental group received a remifentanil infusion (0.5 μg/kg/min i.v., n=12), whereas the control group (n=6) received saline. Rats were exposed to AIH protocol. Phrenic nerve amplitude (PNA), burst frequency (f) and breathing rhythm parameters (Ti, Te, Ttot) were analyzed during 5 hypoxias and at 15, 30, and 60 minutes after the final hypoxia, and compared to baseline values. At the end of the experiment, the infusion of remifentanil was stopped and phrenic nerve activity was compared to baseline values prior to remifentanil infusion. In the control group, peak phrenic nerve activity (pPNA) significantly increased at 60 min (T60, increase by 138.8±28.3%, p=0.006) after the last hypoxic episode compared to baseline values, i.e. pLTF was induced. In remifentanil treated rats, there were no significant changes in peak phrenic nerve activity at T60 compared to baseline values (decrease by 5.3±16.5%, p>0.05), i.e. pLTF was abolished. Fifteen minutes following cessation of remifentanil infusion, pPNA increased by 93.2±40.2% (p<0.05) and remained increased compared to pre-remifentanil-infusion values for more than 30 minutes, i.e. pLTF could be observed after cessation of the remifentanil infusion. In conclusion, the short acting μ-opioid receptor agonist, remifentanil, reversibly abolished phrenic long term facilitation in urethane anesthetized rats.

Topics: Analgesics, Opioid; Animals; Hypnotics and Sedatives; Hypoxia; Long-Term Potentiation; Male; Phrenic Nerve; Piperidines; Rats; Rats, Sprague-Dawley; Remifentanil

Endocannabinoids are among the most intensively studied lipid mediators of cardiovascular functions. In the present study the effects of decreased and increased activity of the endocannabinoid system (achieved by cannabinoid-1 (CB1) receptor blockade and inhibition of cannabinoid reuptake, respectively) on the systemic and cerebral circulation were analyzed under steady-state physiological conditions and during hypoxia and hypercapnia (H/H).. In anesthetized spontaneously ventilating rats the CB1-receptor antagonist/inverse agonist AM-251 (10 mg/kg, i.v.) failed to influence blood pressure (BP), cerebrocortical blood flow (CoBF, measured by laser-Doppler flowmetry) or arterial blood gas levels. In contrast, the putative cannabinoid reuptake inhibitor AM-404 (10 mg/kg, i.v.) induced triphasic responses, some of which could be blocked by AM-251. Hypertension during phase I was resistant to AM-251, whereas the concomitant CoBF-increase was attenuated. In contrast, hypotension during phase III was sensitive to AM-251, whereas the concomitant CoBF-decrease was not. Therefore, CoBF autoregulation appeared to shift towards higher BP levels after CB1-blockade. During phase II H/H developed due to respiratory depression, which could be inhibited by AM-251. Interestingly, however, the concomitant rise in CoBF remained unchanged after AM-251, indicating that CB1-blockade potentially enhanced the reactivity of the CoBF to H/H. In accordance with this hypothesis, AM-251 induced a significant enhancement of the CoBF responses during controlled stepwise H/H.. Under resting physiological conditions CB1-receptor mediated mechanisms appear to have limited influence on systemic or cerebral circulation. Enhancement of endocannabinoid levels, however, induces transient CB1-independent hypertension and sustained CB1-mediated hypotension. Furthermore, enhanced endocannabinoid activity results in respiratory depression in a CB1-dependent manner. Finally, our data indicate for the first time the involvement of the endocannabinoid system and CB1-receptors in the regulation of the cerebral circulation during H/H and also raise the possibility of their contribution to the autoregulation of CoBF.

Topics: Animals; Arachidonic Acids; Arterial Pressure; Cerebrovascular Circulation; Endocannabinoids; Heart Rate; Hemodynamics; Hypercapnia; Hypertension; Hypoxia; Laser-Doppler Flowmetry; Male; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1

Hyperglycemia attenuates cardioprotection by remifentanil-preconditioning in ischemia-reperfusion in vivo in diabetic rats. However, the effects of hyperglycemia in cultured ventricular myocytes remains unknown. Therefore, we examined the in vitro effects of hyperglycemia on hypoxia-reoxygenation (H/R) and cardioprotection from remifentanil-preconditioning in isolated neonatal rat ventricular myocytes (NRVMs), including effects on apoptotic signaling pathways and Ca(2+) homeostasis.. NRVMs were cultured in medium with 5.5 mM (normoglycemia) or 25.5 mM glucose for one day. Then, NRVMs in H/R groups were exposed to 1 h of hypoxia and 5 h of reoxygenation with or without remifentanil-preconditioning at 1 μM. Cell viability, apoptosis, and Ca(2+) homeostasis were assessed by MTT assay, caspase-3 assay, confocal microscopy and immunoblots.. In normoglycemia, remifentanil-preconditioning improved the viability of cardiomyocytes (P < 0.01) and prevented the increase of caspase-3 activity and Ca(2+) overload after H/R injury (P < 0.05). In addition, decrease in Akt, ERK1/2, and Bcl-2, and the increase in Bax by H/R was attenuated by remifentanil-preconditioning (P < 0.05). However, in hyperglycemia, the viability was partially impaired after H/R but not improved by remifentanil-preconditioning. Apoptotic activity, Ca(2+) concentration, and apoptotic kinases except Akt were not affected by either H/R or remifentanil-preconditioning under hyperglycemia. Akt phosphorylation was decreased by H/R but not restored by remifentanil preconditioning.. Remifentanil preconditioning under normoglycemia renders NRVMs resistant to H/R injury by reducing apoptosis and intracellular Ca(2+) concentrations. The mechanism appears to be modulation of apoptotic signaling. However, hyperglycemia mitigates H/R injury in NRVMs, and may reduce the protective effect of remifentanil-preconditioning that may be associated with the Akt pathways.

Topics: Analgesics, Opioid; Animals; Animals, Newborn; Apoptosis; Calcium; Cell Survival; Cells, Cultured; Extracellular Signal-Regulated MAP Kinases; Hyperglycemia; Hypoxia; Ischemic Preconditioning, Myocardial; Myocytes, Cardiac; Piperidines; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Remifentanil

Pre-B-cell colony-enhancing factor (PBEF) is known as a rate-limiting enzyme that converts nicotinamide (NAM) to NMN in the salvage pathway of mammalian NAD⁺ biosynthesis. Previously we found PBEF is exclusively expressed in neurons in the mouse brain; heterozygous PBEF knockout (Pbef⁺/⁻) mice have larger ischemic lesion than wild type mice in photothrombosis-induced ischemia. For the mechanistic study of neuronal protective role of PBEF, we used in vitro oxygen-glucose deprivation (OGD) and glutamate excitotoxicity models of primary cultured neurons in current study. Our results showed that the treatments of neurons with NAM and NAD⁺, the substrate and downstream product of PBEF, respectively, significantly reduced neuronal death after OGD and glutamate excitotoxicity, while treatment of neurons treated with FK866, a PBEF inhibitor, increased neuronal death after OGD. Furthermore, over-expression of human PBEF reduced glutamate excitotoxicity, while over-expression of human PBEF mutants (i.e. H247A and H247E) without enzymatic activity had no effect on neuronal death. We further tested the effect of PBEF on mitochondrial function and biogenesis. Our results show that addition of NAD⁺ and NAM increased mitochondrial biogenesis in neurons after OGD. Over-expression of PBEF in neurons reduced mitochondrial membrane potential depolarization following glutamate stimulation, while over-expression of H247A and H247E did not affect mitochondrial membrane potential depolarization. We conclude that PBEF has a neuroprotective effect in ischemia through its enzymatic activity for NAD⁺ production that can ameliorate mitochondrial dysfunction.

Topics: Acrylamides; Animals; Brain; Cell Death; Cells, Cultured; DNA, Mitochondrial; Embryo, Mammalian; Female; Glucose; Glutamic Acid; Hypoxia; Membrane Potential, Mitochondrial; Mice; Mice, Inbred C57BL; Mitochondria; Mutation; NAD; Neurons; Neuroprotective Agents; Niacinamide; Nicotinamide Phosphoribosyltransferase; Piperidines; Pregnancy

We have previously shown that inhibition of transforming growth factor-β (TGF-β) signaling attenuates hypoxia-induced inhibition of alveolar development and abnormal pulmonary vascular remodeling in the newborn mice and that endothelin-A receptor (ETAR) antagonists prevent and reverse the vascular remodeling. The current study tested the hypothesis that inhibition of TGF-β signaling attenuates endothelin-1 (ET-1) expression and thereby reduces effects of hypoxia on the newborn lung. C57BL/6 mice were exposed from birth to 2 wk of age to either air or hypoxia (12% O(2)) while being given either BQ610 (ETAR antagonist), BQ788 (ETBR antagonist), 1D11 (TGF-β neutralizing antibody), or vehicle. Lung function and development and TGF-β and ET-1 synthesis were assessed. Hypoxia inhibited alveolar development, decreased lung compliance, and increased lung resistance. These effects were associated with increased TGF-β synthesis and signaling and increased ET-1 synthesis. BQ610 (but not BQ788) improved lung function, without altering alveolar development or increased TGF-β signaling in hypoxia-exposed animals. Inhibition of TGF-β signaling reduced ET-1 in vivo, which was confirmed in vitro in mouse pulmonary endothelial, fibroblast, and epithelial cells. ETAR blockade improves function but not development of the hypoxic newborn lung. Reduction of ET-1 via inhibition of TGF-β signaling indicates that TGF-β is upstream of ET-1 during hypoxia-induced signaling in the newborn lung.

Topics: Animals; Animals, Newborn; Cells, Cultured; Endothelial Cells; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Gene Expression; Hypoxia; Lung; Mice; Mice, Inbred C57BL; Oligopeptides; Piperidines; Receptor, Endothelin A; Receptor, Endothelin B; Signal Transduction; Transforming Growth Factor beta

Patients with chronic obstructive pulmonary disease (COPD) are at an increased risk for the development of lung cancer, the mechanisms for which are incompletely understood. We hypothesized that the hypoxic pulmonary microenvironment present in COPD would augment lung carcinogenesis. Mice were subjected to chemical carcinogenesis protocols and placed in either hypoxia or normoxia. Mice exposed to chronic hypoxia developed tumors with increased volume compared with normoxic controls. Both lungs and tumors from hypoxic mice showed a preferential stabilization of HIF-2α and increased expression of VEGF-A, FGF2, and their receptors as well as other survival, proliferation, and angiogenic signaling pathways regulated by HIF-2α. We showed that tumors arising in hypoxic animals have increased sensitivity to VEGFR-2/EGFR inhibition, as chemoprevention with vandetanib showed markedly increased activity in hypoxic mice. These studies showed that lung tumors arising in a hypoxic microenvironment express increased growth, angiogenic, and survival signaling that could contribute to the increased lung cancer risk in COPD. Furthermore, the differential sensitivity of tumors arising in hypoxia to VEGFR-2/EGFR inhibition suggests that the altered signaling present in tumors arising in hypoxic lung might be therapeutically exploited in patients with underlying COPD.

Topics: Animals; Antioxidants; Basic Helix-Loop-Helix Transcription Factors; Biomarkers, Tumor; Blotting, Western; Butylated Hydroxytoluene; Carcinogens; Cell Proliferation; Cytokines; Epithelial-Mesenchymal Transition; ErbB Receptors; Female; Hypoxia; Immunoenzyme Techniques; Lung Neoplasms; Methylcholanthrene; Mice; Neovascularization, Pathologic; Piperidines; Proto-Oncogene Proteins c-myc; Pulmonary Alveoli; Quinazolines; Sleep Apnea Syndromes; Urethane; Vascular Endothelial Growth Factor Receptor-2

Hypoxic pulmonary vasoconstriction (HPV) is an essential mechanism of the lung that matches blood perfusion to alveolar ventilation to optimize gas exchange. Recently we have demonstrated that acute but not sustained HPV is critically dependent on the classical transient receptor potential 6 (TRPC6) channel. However, the mechanism of TRPC6 activation during acute HPV remains elusive. We hypothesize that a diacylglycerol (DAG)-dependent activation of TRPC6 regulates acute HPV.. We investigated the effect of the DAG analog 1-oleoyl-2-acetyl-sn-glycerol (OAG) on normoxic vascular tone in isolated perfused and ventilated mouse lungs from TRPC6-deficient and wild-type mice. Moreover, the effects of OAG, the DAG kinase inhibitor R59949 and the phospholipase C inhibitor U73122 on the strength of HPV were investigated compared to those on non-hypoxia-induced vasoconstriction elicited by the thromboxane mimeticum U46619.. OAG increased normoxic vascular tone in lungs from wild-type mice, but not in lungs from TRPC6-deficient mice. Under conditions of repetitive hypoxic ventilation, OAG as well as R59949 dose-dependently attenuated the strength of acute HPV whereas U46619-induced vasoconstrictions were not reduced. Like OAG, R59949 mimicked HPV, since it induced a dose-dependent vasoconstriction during normoxic ventilation. In contrast, U73122, a blocker of DAG synthesis, inhibited acute HPV whereas U73343, the inactive form of U73122, had no effect on HPV.. These findings support the conclusion that the TRPC6-dependency of acute HPV is induced via DAG.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Diacylglycerol Kinase; Diglycerides; Dose-Response Relationship, Drug; Enzyme Inhibitors; Estrenes; Hypoxia; In Vitro Techniques; Lung; Mice; Mice, Inbred C57BL; Mice, Knockout; Perfusion; Piperidines; Pulmonary Circulation; Pyrrolidinones; Quinazolinones; Signal Transduction; Time Factors; TRPC Cation Channels; TRPC6 Cation Channel; Type C Phospholipases; Vasoconstriction; Vasoconstrictor Agents

Our recent studies have indicated that acetylcholine (ACh) protects cardiomyocytes from prolonged hypoxia through activation of the PI3K/Akt/HIF-1alpha/VEGF pathway and that cardiomyocyte-derived VEGF promotes angiogenesis in a paracrine fashion. These results suggest that a cholinergic system plays a role in modulating angiogenesis. Therefore, we assessed the hypothesis that the cholinergic modulator donepezil, an acetylcholinesterase inhibitor utilized in Alzheimer's disease, exhibits beneficial effects, especially on the acceleration of angiogenesis. We evaluated the effects of donepezil on angiogenic properties in vitro and in vivo, using an ischemic hindlimb model of alpha7 nicotinic receptor-deleted mice (alpha7 KO) and wild-type mice (WT). Donepezil activated angiogenic signals, i.e., HIF-1alpha and VEGF expression, and accelerated tube formation in human umbilical vein endothelial cells (HUVECs). ACh and nicotine upregulated signal transduction with acceleration of tube formation, suggesting that donepezil promotes a common angiogenesis pathway. Moreover, donepezil-treated WT exhibited rich capillaries with enhanced VEGF and PCNA endothelial expression, recovery from impaired tissue perfusion, prevention of ischemia-induced muscular atrophy with sustained surface skin temperature in the limb, and inhibition of apoptosis independent of the alpha7 receptor. Donepezil exerted comparably more effects in alpha7 KO in terms of angiogenesis, tissue perfusion, biochemical markers, and surface skin temperature. Donepezil concomitantly elevated VEGF expression in intracardiac endothelial cells of WT and alpha7 KO and further increased choline acetyltransferase (ChAT) protein expression, which is critical for ACh synthesis in endothelial cells. The present study concludes that donepezil can act as a therapeutic tool to accelerate angiogenesis in cardiovascular disease patients.

Topics: Acetylcholine; Alzheimer Disease; Animals; Caspase 3; Caspase 7; Cholinesterase Inhibitors; Donepezil; Endothelial Cells; Hindlimb; Humans; Hypoxia; Indans; Indocyanine Green; Ischemia; Mice; Mice, Knockout; Microscopy, Fluorescence; Neovascularization, Pathologic; Piperidines; Vascular Endothelial Growth Factor A

Topics: Airway Obstruction; Anesthetics, Intravenous; Bradycardia; Cardiotonic Agents; Cholangiopancreatography, Endoscopic Retrograde; Choledocholithiasis; Decerebrate State; Flumazenil; GABA Agonists; Humans; Hypnotics and Sedatives; Hypoxia; Intraoperative Complications; Intubation, Intratracheal; Male; Midazolam; Middle Aged; Naloxone; Piperidines; Propofol; Remifentanil; Sleep Apnea, Obstructive

Topics: Anesthesia; Anesthetics, Combined; Anesthetics, Intravenous; Bronchoscopy; Child, Preschool; Foreign Bodies; Humans; Hypoxia; Piperidines; Propofol; Remifentanil; Respiratory Mechanics; Risk Factors; Treatment Outcome

Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear protein that once activated by genotoxic agents, modulates its own activity and that of several other nuclear proteins. The absence or pharmacological inhibition of this protein has been proven to be beneficial in the treatment of different diseases involving a hypoxic situation. We previously reported that PARP-1 modulates the hypoxia-inducible factor-1 (HIF-1) response in vitro, but this effect has not yet been demonstrated in vivo. The brain is especially susceptible to hypoxic injury, and the present study demonstrates that PARP-1 plays a major role in the post-hypoxic response of HIF-1alpha in the cerebral cortex. Immediate post-hypoxic HIF-1alpha accumulation was higher in the presence of PARP-1, and this differential response was mediated by nitric oxide and to a lesser extent, reactive oxygen species. PARP-1 was also found to induce a more rapid but less sustained HIF-1 transcriptional activity by up-regulating the factor inhibiting HIF. The implication of PARP-1 in these results was further demonstrated by pharmacologically inhibiting PARP in wild-type mice. In conclusion, our data suggest that PARP-1 has an important regulatory role in the in vivo response of brain HIF-1 to hypoxia/reoxygenation.

Topics: Analysis of Variance; Animals; Antipyrine; Brain; Disease Models, Animal; Edaravone; Enzyme Inhibitors; Excitatory Amino Acid Transporter 2; Free Radical Scavengers; Gene Expression Regulation; Hypoxia; Hypoxia-Inducible Factor 1; Isoquinolines; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide; Oxidative Stress; Oxygen; Piperidines; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; RNA, Messenger; Thiobarbituric Acid Reactive Substances

We have reported that eucapnic intermittent hypoxia (E-IH) causes systemic hypertension, elevates plasma endothelin 1 (ET-1) levels, and augments vascular reactivity to ET-1 and that a nonspecific ET-1 receptor antagonist acutely lowers blood pressure in E-IH-exposed rats. However, the effect of chronic ET-1 receptor inhibition has not been evaluated, and the ET receptor subtype mediating the vascular effects has not been established. We hypothesized that E-IH causes systemic hypertension through the increased ET-1 activation of vascular ET type A (ET(A)) receptors. We found that mean arterial pressure (MAP) increased after 14 days of 7 h/day E-IH exposure (109 +/- 2 to 137 +/- 4 mmHg; P < 0.005) but did not change in sham-exposed rats. The ET(A) receptor antagonist BQ-123 (10 to 1,000 nmol/kg iv) acutely decreased MAP dose dependently in conscious E-IH but not sham rats, and continuous infusion of BQ-123 (100 nmol.kg(-1).day(-1) sc for 14 days) prevented E-IH-induced increases in MAP. ET-1-induced constriction was augmented in small mesenteric arteries from rats exposed 14 days to E-IH compared with those from sham rats. Constriction was blocked by the ET(A) receptor antagonist BQ-123 (10 microM) but not by the ET type B (ET(B)) receptor antagonist BQ-788 (100 microM). ET(A) receptor mRNA content was greater in renal medulla and coronary arteries from E-IH rats. ET(B) receptor mRNA was not different in any tissues examined, whereas ET-1 mRNA was increased in the heart and in the renal medulla. Thus augmented ET-1-dependent vasoconstriction via vascular ET(A) receptors appears to elevate blood pressure in E-IH-exposed rats.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Coronary Vessels; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Hypertension; Hypoxia; Infusions, Parenteral; Male; Mesenteric Arteries; Oligopeptides; Peptides, Cyclic; Piperidines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Renal Artery; Time Factors; Vasoconstriction

Histamine has been proposed to be an excitatory transmitter between the carotid body (CB) chemoreceptor (glomus) cells and petrosal ganglion (PG) neurons. The histamine biosynthetic pathway, its storage and release, as well as the presence of histamine H1, H2 and H3 receptors have been found in the CB. However, there is only indirect evidence showing the presence of histamine in glomus cells, or weather its application produces chemosensory excitation. Thus, we studied the histamine immunocytochemical localization in the cat CB, and the effects of histamine, and H1, H2 and H3 receptor blockers on carotid sinus nerve (CSN) discharge, using CB and PG preparations in vitro. We found histamine immunoreactivity in dense-cored vesicles of glomus cells. Histamine induced dose-dependent increases in CSN discharge in the CB, but not in the PG. The H1-antagonist pyrilamine reduced the CB responses induced by histamine, the H2-antagonists cimetidine and ranitidine had no effect, while the H3-antagonist thioperamide enhanced histamine-induced responses. Present data suggests that histamine plays an excitatory modulatory role in the generation of cat CB chemosensory activity.

Topics: Acetylcholine; Action Potentials; Animals; Carotid Body; Cats; Chemoreceptor Cells; Dose-Response Relationship, Drug; Histamine; Histamine Agonists; Histamine H1 Antagonists; Histamine H3 Antagonists; Hypoxia; In Vitro Techniques; Male; Microscopy, Immunoelectron; Nicotine; Nicotinic Agonists; Piperidines; Pyrilamine; Tyrosine 3-Monooxygenase

Prolonged exposure to decreased oxygen tension causes contraction and proliferation of pulmonary arterial smooth muscle cells (PASMCs) and pulmonary hypertension. Hypoxia-induced inhibition of voltage-gated K(+) (K(v)) channels may contribute to the development of pulmonary hypertension by increasing intracellular calcium concentration ([Ca(2+)](i)). The peptide endothelin-1 (ET-1) has been implicated in the development of pulmonary hypertension and acutely decreases K(v) channel activity. ET-1 also activates several transcription factors, although whether ET-1 alters K(V) channel expression is unclear. The hypoxic induction of ET-1 is regulated by the transcription factor hypoxia-inducible factor-1 (HIF-1), which we demonstrated to regulate hypoxia-induced decreases in K(V) channel activity. In this study, we tested the hypothesis that HIF-1-dependent increases in ET-1 lead to decreased K(v) channel expression and subsequent elevation in [Ca(2+)](i). Resting [Ca(2+)](i) and K(v) channel expression were measured in cells exposed to control (18% O(2), 5% CO(2)) and hypoxic (4% O(2), 5% CO(2)) conditions. Hypoxia caused a decrease in expression of K(v)1.5 and K(v)2.1 and a significant increase in resting [Ca(2+)](i). The increase in [Ca(2+)](i) was reduced by nifedipine, an inhibitor of voltage-dependent calcium channels, and removal of extracellular calcium. Treatment with BQ-123, an ET-1 receptor inhibitor, prevented the hypoxia-induced decrease in K(v) channel expression and blunted the hypoxia-induced increase in [Ca(2+)](i) in PASMCs, whereas ET-1 mimicked the effects of hypoxia. Both hypoxia and overexpression of HIF-1 under normoxic conditions increased ET-1 expression. These results suggest that the inhibition of K(v) channel expression and rise in [Ca(2+)](i) during chronic hypoxia may be the result of HIF-1-dependent induction of ET-1.

Topics: Animals; Calcium Signaling; Endothelin-1; Gene Expression Regulation; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Kv1.5 Potassium Channel; Male; Mice; Models, Biological; Myocytes, Smooth Muscle; Oligopeptides; Peptides, Cyclic; Perfusion; Piperidines; Pulmonary Artery; Rats; Rats, Wistar; Shab Potassium Channels

Myointimal hyperplasia (MIH) cells are related to permanent upregulated proliferation as tumor-like cells. The aim of this study is to assess whether treatment of cells after hypoxia by Iroxanadine heat-shock protein (HSP-coinducer) predicts recovery through cell proliferation.. Vascular smooth muscle cells (VSMC) and brain capillary endothelial cells (HBEC) were isolated from human origin and MIH-cells from early carotid restenosis after surgery. Cell proliferation was quantified by bromuridine (BrdU) incorporation after hypoxia/reoxygenation. HSP72 and cyclin-dependent kinase (CDKN1A) mRNA expression was assessed by reverse transcription-polymerase chain reaction (PCR) and cell cycle distribution by flow cytometry (FACS) analysis.. After hypoxia/reoxygenation, the proliferation of MIH-cells increased, whereas endothelial cells decreased (MIH: 0.266+/-0.016 versus 0.336+/-0.024; P<0.05; HBEC: 1.249+/-0.10 versus 0.878+/-0.11; P<0.05). Whereas augmented proliferation of MIH-cells was reduced (40% to 45%) by HSP-coinducer, diminished HBEC proliferation increased (46.2%). Stress-activated-protein-kinase (SAPK)p38-dependent cell cycle redistribution was generated by an increase in HSP72 and CDKN1A mRNA levels in MIH-cells.. The 2 key players of early restenosis (MIH, EC) were oppositely regulated and correspondingly after treatment by HSP-coinducer reverse recovered. Drug candidate may have therapeutic potential in (re)restenosis.

Topics: Aged; Brain; Capillaries; Cell Proliferation; Cells, Cultured; Endothelial Cells; Heat-Shock Proteins; Humans; Hyperplasia; Hypoxia; Middle Aged; Oxazines; Piperidines; Tunica Intima

We report in the present study the role of endothelin (ET-1) and ET-1 receptors in the sustained hypoxia-induced systemic hypertension.. Wistar rats were randomly assigned to live continuously in hypobaric hypoxia (CH rats) or normoxia (N rats). At the end of hypoxic stress exposure (5 weeks at 450 mm Hg), measurements of mean systemic arterial pressure were done. The effects of ET-1 in the presence or not of the endothelium and/or of specific ET-A inhibitors (BQ-123) or ET-B inhibitors (BQ-788), have been investigated in an isolated model of rat thoracic aorta. Finally, plasmatic ET-1 concentrations have been determined by assay procedure.. Following five weeks of chronic hypoxic stress, CH rats presented a significant increase of mean systemic arterial pressure (N: 129.1+/-6.8 mm Hg vs CH: 152.5+/-3.4 mm Hg; P<0.05). Despite of this hypoxia-induced hypertension, ET-1 plasmatic concentration was not different between N and CH rats. Finally, CH rats presented a reduce response to ET-1 when compared to N rats. This phenomenon seems to be associated to the ET-A vascular smooth muscle cell receptors, since difference between N and CH rats was still present in endothelium denuded aortic rings in the presence or not of the specific ET-B inhibitors (BQ-788). In addition, in the presence of the specific ET-A inhibitor (BQ-123) response to ET-1 was abolished in N and CH rats to the same extent (N:-98%; CH:-99%).. This work clearly suggests that, following long term exposure to hypoxia, ET-1 and ET-1 receptors are not involved in the persistence of systemic hypertension in a rat model, and that chronic exposure to severe hypoxic stress was associated with a downregulation of the ET-A receptors response to ET-1.

Topics: Animals; Aorta, Thoracic; Endothelin-1; Hypertension; Hypoxia; In Vitro Techniques; Male; Muscle, Smooth, Vascular; Oligopeptides; Peptides, Cyclic; Piperidines; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Vasoconstriction

The regulatory effect of substance P on respiration is mediated via neurokinin (NK) receptors. While previous studies suggest that NK-1 receptors are involved, little is known about the role NK-2 receptors in ventilatory responses to hypoxia. Ventilatory responses to acute hypoxia (8% O2 in N2) were measured by indirect plethysmography in unanaesthetized, unrestrained NK-1 receptor gene deficient (NK-1-/-) and wild-type mice. In additional experiments mice were treated with an NK-2 receptor antagonist prior to hypoxic challenge. Resting ventilatory parameters were not different between groups. NK-1-/- mice displayed significantly greater shortening of expiratory time and higher increase of breathing frequency during hypoxia than wild-type mice. Treatment with the NK-2 receptor antagonist SR 48968 (1 mg/kg) resulted in a further shortening of inspiratory and expiratory time in NK-1-/- but not wild-type mice. These results demonstrate that both NK-1 and NK-2 receptors are involved in the modification of ventilation in response to acute hypoxia.

Topics: Animals; Benzamides; Female; Hypoxia; Male; Mice; Mice, Knockout; Piperidines; Plethysmography; Receptors, Neurokinin-1; Receptors, Neurokinin-2; Respiration

The objective of this study was to investigate the protective effect of U50,488H, a selective kappa-opioid receptor agonist, in the ischemia/reperfusion (I/R) rat and to delineate the underlying mechanism. Rat heart I/R injury was induced by occluding the left anterior descending coronary artery for 45 min and restoring perfusion for 120 min. U50,488H or vehicle was intravenously injected before ischemia. Electrocardiogram, heart rate (HR), arterial blood pressure (ABP), left ventricular pressure (LVP), systolic function (+dp/dtmax), and diastolic function (-dp/dtmax) were monitored in the course of the experiment. Myocardial infarction size was evaluated. Plasma concentrations of cardiac troponin T (cTnT), creatine kinase (CK), and lactate dehydrogenase (LDH) were measured. Single rat ventricular myocyte was obtained by enzymatic dissociation method. The potassium currents (IK) of isolated ventricular myocytes were recorded with the whole-cell configuration of the patch-clamp technique. Compared with the sham control group, no significant change was found in HR, while ABP, LVP and +/-dp/dtmax were significantly reduced in the I/R group. Administration of U50,488H significantly lowered HR in both control and I/R groups. Compared with the vehicle-treated I/R group, administration of U50,488H had no significant effect on I/R-induced reduction in ABP, LVP, and +/-dp/dtmax. However, this treatment significantly reduced the myocardial infarction size, and markedly decreased the contents of plasma cTnT, CK and LDH. During ischemia and reperfusion, the incidence of ventricular arrhythmia in U50,488H-treated rats was significantly reduced. These effects were independent of the bradycardia induced by U50,488H, as the reducing infarct size and antiarrhythmic effect of U50,488H were still observed in animals in which heart rate was kept constant by electrical pacing. U50,488H and BRL-52537 still produced an antiarrhythmic effect when the rat heart was subjected to a shorter ischemic period of 10 min occlusion of coronary artery, which produced no infarction. IK of the myocytes were inhibited by U50,488H in a dose-dependent manner in normal and hypoxic rat ventricular myocytes. However, the effects of U50,488H on IK did not show any significant difference in normal and hypoxic myocytes. The above-described effects of U50,488H were totally blocked by nor-Binaltorphimine, a selective kappa-opioid receptor antagonist. The results suggest that kappa-opioid agonist U50,48

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Cardiotonic Agents; Electrocardiography; Electrophysiology; Hypoxia; Male; Muscle Cells; Myocardial Reperfusion Injury; Myocardium; Piperidines; Potassium Channels; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Reperfusion Injury; Troponin T; Ventricular Function, Left

Dopamine (DA), released from the lateral olivocochlear (LOC) efferent terminals, the efferent arm of the short-loop feedback in the cochlea, is considered as a protective factor in the inner ear since it inhibits auditory nerve dendrite firing in ischemia- or noise-induced excitotoxicity leading to sensorineural hearing loss (SNHL). In the present study we investigated the effect of oxygen-glucose deprivation (OGD), an in vitro ischemia model, on guinea-pig cochlear [(3)H]DA release in a microvolume superfusion system. We found that OGD alone failed to induce a detectable elevation of [(3)H]DA level, but in the presence of specific D(2) receptor antagonists, sulpiride and L-741,626, it evoked a significant increase in the extracellular concentration of [(3)H]DA. D(2) negative feedback receptors are involved not exclusively in the regulation of synthesis and vesicular release of DA, but also in the activation of its reuptake. Thus, D(2) receptor antagonism interferes with the powerful reuptake of DA from the extracellular space. To explore the underlying mechanism of this DA-releasing effect we applied nomifensine and found that the effect of OGD on cochlear DA release in the presence of D(2) antagonists could be inhibited by this selective DA uptake inhibitor. This finding indicates that the OGD-evoked DA release was mainly mediated through the reverse operation of the DA transporter. The two structurally different D(2) antagonists also augmented the electrical field stimulation-evoked release of DA proving the presence of D(2) autoreceptors on dopaminergic LOC terminals. Our results confirm the presence and role of D(2) DA autoreceptors in the regulation of DA release from LOC efferents, and suggest a protective local mechanism during ischemia which involves the direct transporter-mediated release of DA. Increasing the release of the protective transmitter DA locally in the inner ear may form the basis of future new therapeutic strategies in patients suffering from SNHL.

Topics: Animals; Cochlea; Dopamine; Dopamine Antagonists; Dopamine Uptake Inhibitors; Drug Interactions; Electric Stimulation; Glucose; Guinea Pigs; Hypoxia; In Vitro Techniques; Indoles; Male; Neurons; Nomifensine; Piperidines; Receptors, Dopamine D2; Sulpiride; Tetrodotoxin; Time Factors; Tritium

Group I metabotropic glutamate (mGlu) receptors (i.e. mGlu1 and mGlu5) coupled to phospholipase C have been widely investigated for their possible role in excitotoxic and post-ischemic neuronal death. Recently, phospholipase C has been shown to directly stimulate the activity of poly(ADP-ribose) polymerase (PARP), a nuclear enzyme involved in DNA repair that has been proposed to play a key role in necrotic cell death. In this study, we investigated whether the stimulation of group I mGlu receptors leads to an increase in PARP activity, as detected by flow cytometry, immunodot blot and immunocytochemistry, both in baby hamster kidney cells transfected with mGlu1a or mGlu5a receptors and in cultured cortical cells. Our results show that the group I mGlu receptor agonist DHPG elicited a significant increase in PARP activity that was completely abolished by the administration of the mGlu1 antagonist 3-MATIDA and partially prevented, in cortical neurons, by the mGlu5 antagonist MPEP. To evaluate whether this pathway is involved in post-ischemic neuronal death, we used a sublethal model of oxygen-glucose deprivation in mixed cortical cell cultures. DHPG exacerbated neuronal death, and this effect was significantly prevented by the application of the PARP inhibitor DPQ. This novel pathway may contribute to the effects of mGlu1 receptors in the mechanisms leading to post-ischemic neuronal death.

Topics: Animals; Animals, Newborn; Blotting, Western; Cells, Cultured; Cerebral Cortex; Cricetinae; Drug Interactions; Enzyme Activation; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Fluorescent Antibody Technique; Gene Expression Regulation, Enzymologic; Glial Fibrillary Acidic Protein; Glucose; Hydrogen Peroxide; Hypoxia; Isoquinolines; Methoxyhydroxyphenylglycol; Mice; Neuroglia; Neurons; Piperidines; Poly(ADP-ribose) Polymerases; Pyridines; Receptors, Metabotropic Glutamate; Thiophenes; Time Factors; Transfection

Normoxic and hypoxic ventilation are influenced by chemoreceptor and nonchemoreceptor drives. Although inhalational anesthetics blunt hypoxic ventilation, this effect is reversed by audiovisual stimulation but not by pain. Opioids reduce both normoxic and hypoxic ventilation, but their interaction with pain and audiovisual stimulation has not been fully reported.. Isocapnic, acute hypoxic ventilatory responses (AHRs) were measured in 11 volunteers. AHR and normoxic ventilation were measured under the following conditions: (1) eyes closed, no audio stimulation (low wakefulness); (2) low wakefulness conditions plus painful thermal stimulation; and (3) playing a computer game (high wakefulness), each with and without remifentanil infusion.. The average (+/- sd) remifentanil dose was 0.035 +/- 0.012 microg x kg x min(-1). Both normoxic and hypoxic ventilation were significantly reduced by the remifentanil infusion under all three conditions. The AHR values under low wakefulness conditions were 0.33 +/- 0.19 and 0.89 +/- 0.49 l x min(-1) x sat(-1) with and without remifentanil, respectively (P < 0.05). High wakefulness significantly increased AHR with and without remifentanil, whereas low wakefulness with pain did not. However, high wakefulness with remifentanil did not increase the AHR back to what was observed during low wakefulness without remifentanil.. The computer game was a more potent stimulus than pain in countering the depressant effect of remifentanil on AHR. Although the effect of high wakefulness was more attenuated than was previously observed with respect to inhalational anesthetics, the significance of these findings is underlined by the more clinically relevant scenario of what is experienced in the face of opioid administration.

Topics: Adolescent; Adult; Analgesics, Opioid; Anesthetics, Inhalation; Female; Humans; Hypoxia; Male; Pain; Piperidines; Remifentanil; Respiration; Wakefulness

Angiogenesis is a critical step required for sustained tumor growth and tumor progression. The stimulation of endothelial cells by cytokines secreted by tumor cells such as vascular endothelial growth factor (VEGF) induces their proliferation and migration. This is a prominent feature of high-grade gliomas. The secretion of VEGF is greatly upregulated under conditions of hypoxia because of the transcription factor hypoxiainducible factor (HIF)-1alpha, which controls the expression of many genes, allowing rapid adaptation of cells to their hypoxic microenvironment. Flavopiridol, a novel cyclin-dependent kinase inhibitor, has been attributed with antiangiogenic properties in some cancer cell lines by its ability to inhibit VEGF production. Here, we show that flavopiridol treatment of human U87MG and T98G glioma cell lines decreases hypoxia-mediated HIF-1alpha expression, VEGF secretion, and tumor cell migration. These in vitro results correlate with reduced vascularity of intracranial syngeneic GL261 gliomas from animals treated with flavopiridol. In addition, we show that flavopiridol downregulates HIF-1alpha expression in the presence of a proteasome inhibitor, an agent that normally results in the accumulation and overexpression of HIF-1alpha. The potential to downregulate HIF-1alpha expression with flavopiridol treatment in combination with a proteasome inhibitor makes this an extremely attractive anticancer treatment strategy for tumors with high angiogenic activity, such as gliomas.

Topics: Animals; Blotting, Western; Boronic Acids; Brain Neoplasms; Cell Line, Tumor; Cell Movement; Down-Regulation; Female; Flavonoids; Glioma; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Matrix Metalloproteinase 2; Mice; Neovascularization, Pathologic; Piperidines; Polymerase Chain Reaction; Protease Inhibitors; Proteasome Endopeptidase Complex; Protein Kinase Inhibitors; RNA, Messenger; Transcription Factors; Transcription, Genetic; Vascular Endothelial Growth Factor A

The present study investigated whether activation of vasodilatory mechanisms masks the involvement of endothelin in hypoxic pulmonary vasoconstriction. Rat intrapulmonary arteries were mounted in microvascular myographs. In arteries with endothelium and contracted with phenylephrine, hypoxia, evoked by exchanging 5% CO2 in air for CO2 in N2, caused a transient contraction followed by a sustained contraction. Hypoxia evoked relaxation in preparations without endothelium. An inhibitor of ATP-sensitive K+ channels (KATP), glibenclamide (10 microM), blunted hypoxic relaxation in arteries without endothelium and enhanced the sustained hypoxic vasoconstriction in arteries with endothelium. Hypoxic contraction was more pronounced in endothelin compared with phenylephrine-contracted preparations in the absence, but not in the presence of glibenclamide. Antagonism of the endothelin ETA and ETB receptors with SB217242 or the combination of BQ123 and BQ788 inhibited endothelin and hypoxic contraction, but the latter only in the presence of glibenclamide. An inhibitor of nitric oxide (NO) synthase, N-nitro-L-arginine (100 microM), evoked contractions, which were left unaltered by SB217242 in hypoxic conditions. In conclusion, hypoxic contraction is mediated in part by an unknown endothelium-derived contractile factor and incubation with glibenclamide shows endothelin enhances hypoxic contraction in part through inhibition of KATP channels. Moreover, inhibition of NO formation in pulmonary arteries does not change endothelin receptor activation in severe hypoxia.

Topics: Animals; Anti-Arrhythmia Agents; Carboxylic Acids; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelins; Endothelium, Vascular; Enzyme Inhibitors; Glyburide; Hypoxia; In Vitro Techniques; Indans; Male; Nitric Oxide Synthase; Nitroarginine; Oligopeptides; Oxyhemoglobins; Peptides, Cyclic; Phenylephrine; Pinacidil; Piperidines; Pulmonary Artery; Rats; Rats, Wistar; Receptors, Endothelin; Vasoconstriction; Vasoconstrictor Agents; Vasodilator Agents

Neuroblastoma is the most common extracranial solid tumor of children that arises from the sympathetic nervous system. Survival rates for neuroblastoma patients is low despite intensive therapeutic intervention, and the identification of new effective drugs remains a primary goal. The cyclin-dependent kinase inhibitor, flavopiridol, has demonstrated growth-inhibitory and cytotoxic activity against various tumor types. Our aim was to investigate flavopiridol effects on advanced-stage, N-myc proto-oncogene (MYCN)-amplified human neuroblastomas and the modulation of its activity by hypoxia, a critical determinant of tumor progression and a major challenge of therapy.. Cell viability was monitored by 3-(4,5 dimethyl-2 thiazolyl)-2,5 diphenyl-2H tetrazolium bromide (MTT) and trypan blue dye exclusion assays; DNA synthesis was assessed with the bromodeoxyuridine pulse-labeling technique; apoptosis was studied by Giemsa staining, DNA fragmentation, terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling reaction, flow cytometric determination of hypodiploid DNA content, and evaluation of caspase activity and cytochrome c (CytC) release; MYCN expression was determined by Northern and Western blotting.. Flavopiridol caused dose- and time-dependent decreases in neuroblastoma viability by inducing apoptosis, as confirmed by morphologic and biochemical criteria. Cell death was preceded by DNA synthesis inhibition and G1-G2 arrest, reversed by the pancaspase inhibitor, zVAD-fmk, and associated with caspase-3 and -2 activation and CytC increase. Moreover, flavopiridol strongly down-regulated MYCN mRNA and protein expression. Exposure to hypoxia enhanced both the extent of apoptosis and flavopiridol effects on CytC, caspase 3, and MYCN.. These results indicate that flavopiridol has growth-inhibitory and apoptotic activity against advanced-stage neuroblastomas in vitro and is worthy of further investigation for the treatment of this disease.

Topics: Apoptosis; Bromodeoxyuridine; Caspases; Cell Hypoxia; Cell Survival; Cyclin-Dependent Kinases; Cytochromes c; DNA; Down-Regulation; Enzyme Activation; Enzyme Inhibitors; Flavonoids; G1 Phase; G2 Phase; Genes, myc; Growth Inhibitors; Humans; Hypoxia; In Situ Nick-End Labeling; Neuroblastoma; Piperidines; Proto-Oncogene Mas; Tetrazolium Salts; Thiazoles; Tumor Cells, Cultured

The aims of this study were to investigate the effects of a selective ETA (BQ-123), a selective ETB (BQ-788), and a specific mixed ETA/ETB receptor antagonist (bosentan) on the pulmonary vasoconstriction induced by hypoxia in the isolated perfused rat lung, and the role of nitric oxide, adenosine triphosphate-sensitive (KATP), large conductance Ca+-activated (BKCa) and 4-aminopyridine-sensitive voltage-gated K channels (K+) in the relaxant effects of the selective ETA receptor antagonist BQ-123 and a protein kinase C inhibitor, bisindolylmaleimide I. K+ channels were inhibited by glibenclamide, charybdotoxin, and 4-aminopyridine and nitric oxide synthase by L-NG-nitroarginine methyl ester (L-NAME). Hypoxic ventilation produced a significant pressure response (+57%, p < 0.001). BQ-123, bosentan, and bisindolylmaleimide I induced a concentration-dependent decrease of the hypoxic pressure response (p < 0.001), whereas BQ-788 did not exhibit any inhibitory effect against hypoxic pressure response. Glibenclamide, charybdotoxin, and 4-aminopyridine partially opposed the inhibitory effects elicited by BQ-123 (p < 0.05), but L-NAME did not modify these effects. The effects of bisindolylmaleimide I on hypoxic pressure response were unaffected by glibenclamide, charybdotoxin, or 4-aminopyridine. The authors conclude that (a) ETA receptors and protein kinase C are involved in the modulation of hypoxic pulmonary vasoconstriction; and (b) the ETA antagonist BQ-123 opposes hypoxic pulmonary vasoconstriction through KATP, KV, and BKCa channels, differing in this from the protein kinase C inhibitor bisindolylmaleimide I. These results suggest that BQ-123 operates through a mechanism independent of bisindolylmaleimide I-inhibited protein kinase C isoforms.

Topics: Animals; Bosentan; Drug Interactions; Endothelin Receptor Antagonists; Hypoxia; Indoles; Lung; Male; Maleimides; Nitric Oxide Synthase; Oligopeptides; Peptides, Cyclic; Piperidines; Potassium Channels; Protein Kinase C; Rats; Rats, Wistar; Sulfonamides; Vasoconstriction

The main aim of this study was to determine the effects of endothelium removal on tension and intracellular Ca(2+) ([Ca(2+)](i)) during hypoxic pulmonary vasoconstriction (HPV) in rat isolated intrapulmonary arteries (IPA). Rat IPA and mesenteric arteries (MA) were mounted on myographs and loaded with the Ca(2+)-sensitive fluorophore fura PE-3. Arteries were precontracted with prostaglandin F(2alpha), and the effects of hypoxia were examined. HPV in isolated IPA consisted of a transient constriction superimposed on a second sustained phase. Only the latter phase was abolished by endothelial denudation. However, removal of the endothelium had no effect on [Ca(2+)](i) at any point during HPV. The endothelin-1 antagonists BQ-123 and BQ-788 did not affect HPV, although constriction induced by 100 nM endothelin-1 was abolished. In MA, hypoxia induced an initial transient rise in tension and [Ca(2+)](i), followed by vasodilatation and a fall in [Ca(2+)](i) to (but not below) prehypoxic levels. These results are consistent with sustained HPV being mediated by an endothelium-derived constrictor factor that is distinct from endothelin-1 and that elicits vasoconstriction via Ca(2+) sensitization.

Topics: Animals; Antihypertensive Agents; Calcium; Endothelin Receptor Antagonists; Endothelium, Vascular; Hypoxia; Male; Oligopeptides; Peptides, Cyclic; Piperidines; Pulmonary Artery; Pulmonary Circulation; Rats; Rats, Wistar; Receptor, Endothelin A; Vasoconstriction

Renal vasoconstriction with resultant tissue hypoxia, especially in the renal medulla, has been suggested to play a role in contrast media (CM)-induced nephropathy. Endothelin (ET) is released into the blood stream following CM injection and has been proposed as a potential mediator through its vasoconstrictive properties.. To investigate the possible protective influence of ET-receptor antagonists against CM-induced reduction in renal function, we studied the effects of injection of iopromide with and without pretreatment with BQ123 (ET-A antagonist) or BQ788 (ET-B antagonist) on renal superficial cortical flow (CBF), outer medullary blood flow (OMBF) and outer medullary oxygen tension (pO2) in normal rats.. Administration of CM (1600 mg I/kg b.w.) did not affect CBF in any of the groups. However, a transient decrease in OMBF occurred, which was unaffected by both BQ123 and BQ788. Also a transient decrease in outer medullary pO2 was induced by CM administration. The pO2 reduction was significantly smaller after pretreatment with BQ123, than after injection of CM alone or together with BQ788, and pO2 returned more rapidly to the control level. Neither receptor antagonist had an effect on CM-mediated increases in electrolyte excretion.. In the normal rat, activation of ET-A receptors is partly involved in the depression of outer medullary pO2 caused by injection of iopromide. However, the decrease in OMBF after iopromide injection is not mediated by ET receptors. The beneficial effects of the ET-A receptor antagonist on CM-induced changes in outer medullary pO2 seem therefore not primarily mediated on the hemodynamic level but may rather involve tubular transport mechanisms.

Topics: Animals; Antihypertensive Agents; Contrast Media; Disease Models, Animal; Endothelin Receptor Antagonists; Hypoxia; Iohexol; Kidney Diseases; Kidney Medulla; Male; Oligopeptides; Peptides, Cyclic; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Endothelin; Renal Circulation

Histaminergic modulation of neuronal activity in the respiratory network was investigated under normoxic and hypoxic conditions in the working heart-brainstem preparation of adult mice. Systemic application of histamine, as well as the H-1 and H-3 receptor agonists 6-[2-(4-imidazolyl)ethylamino]- N-(4-trifluoromethylphenyl) heptanecarboxamide (HTMT) and imetit, 0.5-10 micro M, significantly increased the frequency of respiratory burst discharges. Dimaprit, an H-2 receptor agonist, had no effect on respiratory activity. To test for ongoing histaminergic modulation we applied the histamine receptor antagonists pyrilamine (H-1); cimetidine (H-2) and thioperamide (H-3), each 0.5-10 micro M. Only the H-1 receptor antagonist had significant effects, viz. reduction of respiratory frequency and depression of burst amplitude. Underlying effects of histamine receptor activation were identified at the cellular level. Intracellular recordings showed that histamine mediated an increase in synaptic drive potentials in inspiratory neurones while augmentation of inhibitory and excitatory synaptic activity was observed in expiratory neurones. The augmented synaptic depolarisation of inspiratory neurones was blocked by the H-1 receptor antagonist. Histaminergic modulation is also involved in the hypoxic response of the respiratory network. Blockade of H-1 receptors significantly attenuated secondary depression of the biphasic hypoxic responses, while hypoxic augmentation was not affected. We conclude that histamine is a functional neuromodulator, which is tonically active in the respiratory network and is activated further during hypoxia. The data indicate that histaminergic neuromodulation acts predominantly via H-1 receptors.

Topics: Animals; Cimetidine; Histamine; Histamine Agonists; Histamine Antagonists; Histamine H1 Antagonists; Histamine H2 Antagonists; Hypoxia; Medulla Oblongata; Mice; Mice, Inbred C57BL; Nerve Net; Neurons; Phrenic Nerve; Piperidines; Pons; Pyrilamine; Receptors, Histamine H3; Respiratory System

Treatment with richlocaine alone and, especially, in combination with antihypoxant energostim decreased the total content of hydroxyproline in the ischemic skin flap on day 3 after excision. Combination therapy with richlocaine and energostim normalized the redox potential in the energy supply system, improved antioxidant protection, and promoted the recovery of a balance between various components in the antioxidant system. These changes were not accompanied enhanced production of malonic dialdehyde. Our results suggest that combination therapy with richlocaine and energostim maintains the adaptive reserves of detoxifying systems in keratinocytes and prevents endotoxemia. Richlocaine primarily stimulates glycolytic synthesis of ATP, activates nonmitochondrial antioxidant enzymes, and increases RNase activity in lysosomes.

Topics: Adenosine Triphosphate; Animals; Antioxidants; Electron Transport; Endotoxemia; Glycolysis; Hypoxia; Ischemia; Keratinocytes; Lysosomes; Male; Malondialdehyde; Mitochondria; Oxidation-Reduction; Piperidines; Rats; Ribonucleases; Skin; Time Factors

The local anesthetic richlocaine decreased the area of necrosis in the skin flap under conditions of reduced blood flow by 29.5%. Improved survival of skin flap after richlocaine treatment alleviated endogenous intoxication, reduced secondary inflammatory reaction, improved liver function, and normalized the ratio between vasoconstricting and vasodilating prostaglandins. This effect was most pronounced after combination therapy with richlocaine and direct-action antihypoxant energostim.

Topics: Alanine Transaminase; Animals; Antioxidants; Aspartate Aminotransferases; Cell Survival; Cytochromes c; Drug Combinations; Endotoxemia; Erythrocytes; Histamine; Hydroxyproline; Hypoxia; Inflammation; Inosine; Keratinocytes; Lactates; Male; NAD; Necrosis; Piperidines; Rats; Regional Blood Flow; Serotonin; Skin; Surgical Flaps; Time Factors; Vasodilator Agents

Endothelins (ETs) are a group of vasoactive peptides (ET-1, ET-2 and ET-3) produced by many cell types that bind to G-protein-linked transmembrane receptors, ET-A receptors (ET-RAs) and ET-B receptors (ET-RBs). These peptides are expressed in several human tumors, including carcinomas of the breast, and have a mitogenic effect in ovarian cancer cell lines. We investigated ET expression in infiltrating ductal carcinomas (IDCs) of the breast and the relationship between ET and hypoxia. ET staining was increased in human grade II IDC samples compared with normal breast tissue. ET-2 and ET-RB mRNA expression were absent in the majority of normal human breast samples (1 of 5 and 0 of 5, respectively) but was present in the majority of IDC tested (13 of 15 and 12 of 15, respectively). In a murine breast cancer model, HTH-K, ET-2, and ET-RB mRNA were detected in tumor but not normal breast tissue, and ET expression colocalized with areas of hypoxia. In vitro, ET-2, ET-RA, and ET-RB mRNA were increased by incubating HTH-K cells in hypoxia (0.1% oxygen) for 24 h. Hypoxia also up-regulated ET-2 mRNA in several human breast tumor cell lines. ET-2 mRNA increased within 3 h in a hypoxia-inducible factor 1-dependent manner. The ET-RB antagonist BQ-788 increased in hypoxia-associated apoptosis of breast tumor cells in vitro. These effects could be reversed by addition of ET-2 peptide. Intratumoral injection of BQ-788 led to an increase in the development and extent of necrosis within the HTH-K tumor and a decrease in the rate of tumor growth. The ET-RA antagonist, BQ-123, also led to a decrease in tumor growth but without a concomitant increase in necrosis. We propose that modulation of ET-2 production via the hypoxia-inducible factor 1 transcription factor and autocrine signaling via ET-RB is a novel mechanism by which tumor cells can withstand hypoxic stress. Treatment of breast carcinomas with ET receptor antagonists may have a therapeutic benefit.

Topics: Antihypertensive Agents; Blotting, Northern; Breast Neoplasms; Cell Survival; DNA-Binding Proteins; Dose-Response Relationship, Drug; Endothelin-2; Female; Humans; Hypoxia; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor 1, alpha Subunit; Necrosis; Nuclear Proteins; Oligopeptides; Ovarian Neoplasms; Peptides, Cyclic; Piperidines; Receptor, Endothelin B; Receptors, Endothelin; RNA, Messenger; Time Factors; Transcription Factors; Tumor Cells, Cultured; Up-Regulation

We previously demonstrated that the pulmonary vascular response to substance P (SP) increased in chronically hypoxic rats. This study explored the temporal increase in reactivity of the pulmonary vascular response to SP and its underlying mechanisms. First, young female Wistar rats were exposed to sea level (SL) or simulated high altitude (HA) for 15 h/day for 3 days, 1 wk, 2 wk, and 4 wk. Lungs were isolated and perfused with 4% bovine serum albumin in Krebs-Henseleit buffer solution. SP (1.5 x 10(-4) M) induced significant increases in pulmonary arterial pressure (P(pa)), venous pressure (P(v)), capillary pressure (P(c)), arterial resistance (R(a)), and filtration coefficient (K(fc)) in SL lungs. Increases in P(pa) and R(a) were significantly augmented in HA lungs, with a temporal increase trend peaking at 2 wk of HA exposure. The selective neurokinin (NK) type 1 (NK1) receptor antagonist SR-14033 significantly attenuated SP-induced increases in P(pa), P(v), P(c), R(a), and K(fc) in SL lungs. In lungs exposed to HA for 2 wk, SR-14033 suppressed the effect of SP on P(pa). Also, chronic hypoxia induced significant increases in NK1 receptors and NK1 receptor mRNA, with a temporal trend. We conclude that chronic hypoxia temporally augments SP-induced vascular responses, which are closely associated with increases in NK1 receptors and gene expression.

Topics: Altitude; Animals; Blood Pressure; Blood Vessels; Capillaries; Chronic Disease; Female; Hypoxia; In Vitro Techniques; Piperidines; Pulmonary Circulation; Quinuclidines; Rats; Rats, Wistar; Receptors, Neurokinin-1; Receptors, Neurokinin-2; RNA, Messenger; Substance P; Time Factors

We studied whether the contractile responses to potassium chloride (KCI) of rat coronary and femoral arteries differ when perfused with solutions containing varying concentrations of metabolic substrates (glucose, oxygen, insulin) and whether these differences might explain some of the beneficial effects of glucose-insulin-potassium (GIK or polarizing) solution. We also studied the mediation of the endothelium on these effects. Contraction of femoral arteries decreased with low and high glucose while in coronary arteries it increased as the glucose concentrations rose. Endothelin receptor antagonists blocked this increase. The tension increase induced by insulin in both vessels was smaller in the coronary arteries. The ETA receptor antagonist PD51242 blocked most of the insulin effect in the coronary arteries, whereas in the femoral arteries this was blocked by the ET(B) receptor antagonist BQ788. Hypoxia blocked the constrictive responses to glucose and insulin of the coronary but not of the femoral arteries. GIK increased contractile force in hypoxic femoral arteries but reduced that in coronary arteries. The contractile response decreased by GIK in hypoxic coronary arteries was restored by N(G)-nitro-L-arginine methyl ester, suggesting mediation by nitric oxide. We conclude that in the presence of high glucose and/or insulin levels, coronary arteries respond to KCl differently from femoral arteries, their behavior during hypoxia might explain some of the beneficial effects of GIK.

Topics: Animals; Azepines; Blood Glucose; Coronary Vessels; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelium, Vascular; Femoral Artery; Glucose; Hypoxia; Insulin; Male; Oligopeptides; Oxygen; Piperidines; Potassium; Rats; Rats, Wistar; Vasoconstriction

Hypoxia-inducible factor 1 (HIF-1) induces a gene expression program essential for the cellular adaptation to lowered oxygen environments. The intracellular mechanisms by which hypoxia induces HIF-1 remain poorly understood. Here we show that exposure of various cell types to hypoxia raises the intracellular level of phosphatidic acid primarily through the action of diacylglycerol kinase (DGK). Pharmacological inhibition of DGK activity through use of the specific DGK inhibitors and abrogated specifically HIF-1-dependent transcription analyzed with a HIF-1-responsive reporter plasmid. A more detailed analysis revealed that pharmacological inhibition of DGK activity prevented the hypoxia-dependent accumulation of the HIF-1alpha subunit and the subsequent HIF-1-DNA complex formation as well as hypoxia-induced activity of the HIF-1 transactivation domains localized to amino acids 530-582 and 775-826 of the HIF-1alpha subunit. Our results demonstrate for the first time that accumulation of phosphatidic acid through DGK underlines oxygen sensing and provide evidence for the involvement of this lipid kinase in the intracellular signaling that leads to HIF-1 activation.

Topics: Cell Nucleus; Diacylglycerol Kinase; Diglycerides; DNA; DNA-Binding Proteins; Dose-Response Relationship, Drug; Enzyme Inhibitors; HeLa Cells; Humans; Hypoxia; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor 1, alpha Subunit; Immunoblotting; Luciferases; Nuclear Proteins; Oxygen; Phosphatidic Acids; Phospholipids; Piperidines; Plasmids; Pyrimidinones; Quinazolines; Quinazolinones; Recombinant Proteins; Signal Transduction; Thiazoles; Transcription Factors; Transcription, Genetic; Transcriptional Activation; Transfection

Responses to acetylcholine (ACh) and sodium nitroprusside (SNP) were compared in large (LPA) and small pulmonary artery (SPA) rings from normoxic and chronically hypoxic (CH) rats. In addition, the effects of a selective phosphodiesterase (PDE) 5 inhibitor, E-4021, on ACh-induced relaxation were evaluated. Chronic hypoxia markedly decreased both ACh- and SNP-induced relaxations in LPA but not in SPA rings. Pretreatment with E-4021 caused a much greater leftward shift of the concentration-response curve for ACh in hypoxic than in normoxic LPA rings, eliminating the difference in response to ACh between these two vessels. These results suggest that cGMP-dependent relaxation is impaired in the proximal but not in the distal pulmonary artery of CH rats and that increased PDE5 activity could be a mechanism responsible for this impaired responsiveness.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Acetylcholine; Animals; Chronic Disease; Cyclic Nucleotide Phosphodiesterases, Type 5; Dose-Response Relationship, Drug; Hypertension; Hypoxia; In Vitro Techniques; Male; Nitroprusside; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperidines; Pulmonary Artery; Quinazolines; Rats; Rats, Sprague-Dawley; Vasodilation; Vasodilator Agents

Although prior studies suggest that hypoxia may increase pulmonary vascular permeability, the mechanisms responsible for that effect remain uncertain. Neprilysin (neutral endopeptidase) is a cell surface metallopeptidase that degrades several vasoactive peptides including substance P and bradykinin. We hypothesized that hypoxia could reduce lung neprilysin expression, leading to increased vascular leak. Weanling rats were exposed to normobaric hypoxia (inspired O(2) fraction = 0.1). Lung neprilysin activity was significantly decreased after 24 and 48 h of hypoxia (P < 0.006). The decrease in enzyme activity was associated with decreased lung neprilysin protein content and decreased lung neprilysin mRNA expression. Immunohistochemistry showed a predominantly perivascular distribution of neprilysin, with clear reductions in neprilysin immunoreactivity after exposure to hypoxia. Exposure to hypoxia for 24 h also caused marked increases in vascular leak (P = 0.008), which were reversed by the administration of recombinant neprilysin. The hypoxia-induced increase in leak was also reversed by substance P and bradykinin receptor antagonists. We conclude that in young rats hypoxia decreases lung neprilysin expression, which contributes to increased pulmonary vascular leak via substance P and bradykinin receptors.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Gene Expression Regulation, Enzymologic; Hypoxia; Lung; Male; Methionine; Microcirculation; Neprilysin; Neurokinin-1 Receptor Antagonists; Oxygen; Piperidines; Protease Inhibitors; Pulmonary Edema; Quinuclidines; Rats; Rats, Sprague-Dawley; Receptors, Neurokinin-1; RNA, Messenger; Specific Pathogen-Free Organisms; Substance P; Water

The effects on pulmonary artery pressure (PAP) and plasma Endothelin-1 (ET-1) were studied in piglets during severe hypoxemia and reoxygenation for 2 h with selective inhibition of the endothelin receptors. Two groups were subjected to selective ETA (ETA group) or ETB (ETB group) receptor inhibition. During hypoxemia there was an initial increase in PAP to 36.3 and 34.3 mm Hg in the ETA and ETB groups respectively, with a decrease to the end of hypoxemia. During reoxygenation PAP reached a maximum at 5 min with a mean of 29.6 and 38.4 mm Hg in the ETA and ETB groups respectively, and then PAP gradually declined towards baseline. During the 2 h reoxygenation period PAP was higher in the ETB group than in the ETA group (p = 0.02). Plasma ET-1 increased from 1.50 and 1.17 ng/L at baseline to 2.07 and 3.18 ng/L at the end of hypoxemia in the ETA and ETB groups respectively.. ETB receptor inhibition leads to increased pulmonary vasoconstriction during reoxygenation following hypoxemia compared to ETA receptor inhibition. Not only the ETB receptor, but also the ETA receptor plays a role in maintaining plasma ET-1 levels.

Topics: Acid-Base Equilibrium; Animals; Animals, Newborn; Endothelin Receptor Antagonists; Endothelin-1; Hemodynamics; Hypoxia; Lung; Oligopeptides; Peptides, Cyclic; Piperidines; Pulmonary Artery; Receptor, Endothelin A; Receptor, Endothelin B; Swine; Vasoconstriction

The present study was undertaken to test if some cyclohexane dicarboximide derivatives may have a cardioprotective effect against hypoxia/reoxygenation injury. Isolated rat hearts were subjected to 20-min of hypoxia followed by 45-min reoxygenation, and their recovery of post-hypoxic cardiac contractile function was examined. Treatment with agents was carried out from 3 min after the onset of hypoxia to the end of hypoxia (17 min during hypoxia). Among the 17 compounds, 2-[4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]butyl]hexahydro-1H-i soindol-1,3(2H)-dione (ST-6) showed a significant enhancement of post-hypoxic contractile force. This was associated with attenuation of the releases of creatine kinase and purine nucleosides and bases from the perfused heart. Hypoxia-induced increase in myocardial sodium and decrease in potassium ion content was suppressed by ST-6 treatment. The results suggest that ST-6 is capable of protecting the heart against hypoxia/reoxygenation injury possibly through a mechanism by which sodium overload during hypoxia is suppressed.

Topics: Animals; Hypoxia; Imides; Isoindoles; Myocardial Contraction; Myocardial Reperfusion Injury; Piperidines; Rats

These studies document striking pulmonary vasoconstrictor response to nitric oxide synthase (NOS) inhibition in monocrotaline (MCT) pulmonary hypertension in rats. This constriction is caused by elevated endothelin (ET)-1 production acting on ETA receptors. Isolated, red blood cell plus buffer-perfused lungs from rats were studied 3 wk after MCT (60 mg/kg) or saline injection. MCT-injected rats developed pulmonary hypertension, right ventricular hypertrophy, and heightened pulmonary vasoconstriction to ANG II and the NOS inhibitor NG-monomethyl-L-arginine (L-NMMA). In MCT-injected lungs, the magnitude of the pulmonary pressor response to NOS inhibition correlated strongly with the extent of pulmonary hypertension. Pretreatment of isolated MCT-injected lungs with combined ETA (BQ-123) plus ETB (BQ-788) antagonists or ETA antagonist alone prevented the L-NMMA-induced constriction. Addition of ETA antagonist reversed established L-NMMA-induced constriction; ETB antagonist did not. ET-1 concentrations were elevated in MCT-injected lung perfusate compared with sham-injected lung perfusate, but ET-1 levels did not differ before and after NOS inhibition. NOS inhibition enhanced hypoxic pulmonary vasoconstriction in both sham- and MCT-injected lungs, but the enhancement was greater in MCT-injected lungs. Results suggest that in MCT pulmonary hypertension, elevated endogenous ET-1 production acting through ETA receptors causes pulmonary vasoconstriction that is normally masked by endogenous NO production.

Topics: Angiotensin II; Animals; Drug Combinations; Endothelin-1; Endothelins; Enzyme Inhibitors; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; In Vitro Techniques; Lung; Male; Monocrotaline; Oligopeptides; omega-N-Methylarginine; Peptides, Cyclic; Piperidines; Rats; Rats, Sprague-Dawley; Vasoconstriction

Endothelin (ET)-1 has been implicated as a critical mediator in the pathogenesis of hypoxic pulmonary hypertension. We questioned whether, during exposure to chronic hypobaric hypoxia, rat pulmonary artery smooth muscle cells (PASMC) became sensitized to ET-1. Two effects of ET-1, inhibition of voltage-gated K(+) (K(v)) channels and release of intracellular Ca(2+), were studied using whole cell patch clamp and single cell indo 1 fluorescence, respectively. In both normotensive and chronically hypoxic-hypertensive PASMC, ET-1 caused concentration-dependent inhibition of voltage-gated K(+) current [I(K(v))], with maximum inhibition of 12-18% seen at a concentration of 0.1-1 nM. Although the chronically hypoxic-hypertensive PASMC was no more susceptible to ET-1-mediated I(K(v)) inhibition, a switch in coupling between ET-1 and I(K(v)) from ET(B) to ET(A) receptors occurred. This switch in receptor coupling, combined with reduced I(K(v)) density and increased ET-1 production in the hypoxic rat lung, may help explain the ability of ET(A)-receptor blockers to attenuate the development of hypoxic pulmonary hypertension in vivo.

Topics: Animals; Antihypertensive Agents; Calcium; Chronic Disease; Electrophysiology; Endothelin Receptor Antagonists; Endothelin-1; Hypertension; Hypoxia; Male; Muscle, Smooth, Vascular; Oligopeptides; Peptides, Cyclic; Piperidines; Potassium Channel Blockers; Potassium Channels; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptors, Endothelin

Intact Madison (M) rats have greater pulmonary pressor responses to acute hypoxia than Hilltop (H) rats. We tested the hypothesis that the difference in pressor response is intrinsic to pulmonary arteries and that endothelium contributes to the difference. Pulmonary arteries precontracted with phenylephrine (10(-7) M) from M rats had greater constrictor responses [hypoxic pulmonary vasoconstriction (HPV)] to acute hypoxia (0% O(2)) than those from H rats: 473 +/- 30 vs. 394 +/- 29 mg (P < 0.05). Removal of the endothelium or inhibition of nitric oxide (NO) synthase by N(omega)-nitro-L-arginine (L-NA, 10(-3) M) significantly blunted HPV in both strains. Inhibition of cyclooxygenase by meclofenamate (10(-5) M) or blockade of endothelin type A and B receptors by BQ-610 (10(-5) M) + BQ-788 (10(-5) M), respectively, had no effect on HPV. Constrictor responses to phenylephrine, endothelin-1, and prostaglandin F(2alpha) were similar in pulmonary arteries from both strains. The relaxation response to ACh, an NO synthase stimulator, was significantly greater in M than in H rats (80 +/- 3 vs. 62 +/- 4%, P < 0.01), but there was no difference in response to sodium nitroprusside, an NO donor. L-NA potentiated phenylephrine-induced contraction to a greater extent in pulmonary arteries from M than from H rats. These findings indicate that at least part of the strain-related difference in acute HPV is attributable to differences in endothelial function, possibly related to differences in NO production.

Topics: Animals; Blood Pressure; Cyclooxygenase Inhibitors; Endothelin Receptor Antagonists; Endothelium, Vascular; Enzyme Inhibitors; Hypoxia; In Vitro Techniques; Male; Meclofenamic Acid; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Oligopeptides; Piperidines; Pulmonary Artery; Pulmonary Circulation; Rats; Rats, Sprague-Dawley; Species Specificity; Vasoconstriction

The purpose of this study was to determine whether E-4010, a newly synthesized potent and selective orally active phosphodiesterase (PDE) 5 inhibitor, would prevent the development of chronic hypoxia-induced pulmonary hypertension in rats. In conscious, pulmonary hypertensive rats, a single oral administration of E-4010 (1.0 mg/kg) caused an acute, long-lasting reduction in mean pulmonary arterial pressure (PAP), with no significant effects on systemic arterial pressure, cardiac output, and heart rate. In rats that received food containing 0.01 or 0.1% E-4010 during the 3-wk exposure to hypoxia, mean PAP was significantly decreased (mean PAP 24.0 +/- 0.9, 16.2 +/- 0.8, and 12.8 +/- 0.5 mmHg in rats treated with 0, 0.01, and 0.1% E-4010-containing food, respectively), whereas mean systemic arterial pressure was unchanged and cardiac output was slightly increased compared with chronically hypoxic control rats. Right ventricular hypertrophy, medial wall thickness in pulmonary arteries corresponding to the respiratory and terminal bronchioles, and the degree of muscularization of more distal arteries were less severe in E-4010-treated rats. Long-term treatment with E-4010 caused an increase in cGMP levels in lung tissue and plasma but not in aortic tissue and no significant change in cAMP levels in either lung, aorta, or plasma. These results suggest that long-term oral treatment with E-4010 reduced the increase in PAP, right ventricular hypertrophy, and pulmonary arterial remodeling induced by exposure to chronic hypoxia, probably through increasing cGMP levels in the pulmonary vascular smooth muscle.

Topics: Animals; Aorta; Cyclic GMP; Hemodynamics; Hypertension, Pulmonary; Hypoxia; Lung; Male; Nitriles; Phosphodiesterase Inhibitors; Piperidines; Rats; Rats, Sprague-Dawley; Time Factors

The electrophysiological effects of N-[1-[4-(4-fluorophenoxy)butyl]-4-piperidinyl]-N-methyl-2-benzothiazo lamine (R56865), a drug which protects heart cells from ischemia-induced arrhythmias, was studied on intracellularly-recorded CA1 neurons of the rat hippocampal slice under normal or hypoxic conditions. On normoxic cells R56865 (1 microM) reduced firing accommodation without changing passive membrane properties, spike characteristics or synaptic transmission. On hypoxic cells R56865 selectively reduced the amplitude of hypoxia-induced membrane depolarization and partly counteracted the depression of synaptic transmission evoked by Schaffers collateral stimulation. Despite its influence on repetitive firing properties, R56865 might be useful to limit the extent of cellular depolarizing responses to hypoxia.

Topics: Animals; Benzothiazoles; Calcium Channel Blockers; Electric Stimulation; Electrophysiology; Hippocampus; Hypoxia; In Vitro Techniques; Neurons; Piperidines; Rats; Reference Values; Synaptic Transmission; Thiazoles

We have investigated the effects of flavopiridol, a novel protein kinase inhibitor that is selective for cyclin-dependent kinases, on hypoxia-induced vascular endothelial growth factor (VEGF) expression in human monocytes. We found that hypoxia induces a time-dependent increase of VEGF mRNA expression and protein levels in human monocytes. Flavopiridol showed a minimal effect on the constitutive levels of VEGF mRNA but completely blocked hypoxia-induced VEGF mRNA and protein expression. The inhibitory effects of flavopiridol on VEGF mRNA induction also occurred in the presence of cycloheximide. The transcriptional activation of either a VEGF promoter-luciferase construct or a hypoxia-inducible factor 1 reporter plasmid was not affected by addition of flavopiridol in transient transfection experiments. In contrast, actinomycin D experiments demonstrated that flavopiridol dramatically decreased VEGF mRNA stability. These data provide the first evidence that flavopiridol can affect gene expression by altering mRNA stability. We propose that flavopiridol may interfere with one or more signaling events, leading to hypoxia-induced, protein kinase-modulated, RNA protein binding activity. An important clinical implication of our results is that flavopiridol, presently under investigation in clinical trials, might have antiangiogenic as well as direct antiproliferative effects.

Topics: Blotting, Northern; Dose-Response Relationship, Drug; Down-Regulation; Endothelial Growth Factors; Enzyme Inhibitors; Flavonoids; Humans; Hypoxia; Luciferases; Lymphokines; Monocytes; Piperidines; Protein Kinase Inhibitors; RNA, Messenger; Time Factors; Transcriptional Activation; Transfection; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Nonselective nitric oxide synthase (NOS) inhibition has detrimental effects in sepsis because of inhibition of the physiologically important endothelial NOS (eNOS). The authors hypothesized that selective inducible NOS (iNOS) inhibition would maintain eNOS vasodilation but prevent acetylcholine- and bradykinin-mediated vasoconstriction caused by lipopolysaccharide-induced endothelial dysfunction.. Rats were administered intraperitoneal lipopolysaccharide (15 mg/kg) with and without the selective iNOS inhibitors L-N6-(1-iminoethyl)-lysine (L-NIL, 3 mg/kg), dexamethasone (1 mg/kg), or the nonselective NOS inhibitor Nomega-nitro-L-arginine methylester (L-NAME, 5 mg/kg). Six hours later, the lungs were isolated and pulmonary vasoreactivity was assessed with hypoxic vasoconstrictions (3% O2), acetylcholine (1 microg), Biochemical Engineering, and bradykinin (3 microg). In additional lipopolysaccharide experiments, L-NIL (10 microM) or 4-Diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP, 100 microM), a selective muscarinic M3 antagonist, was added into the perfusate.. Exhaled nitric oxide was higher in the lipopolysaccharide group (37.7+/-17.8 ppb) compared with the control group (0.4+/-0.7 ppb). L-NIL and dexamethasone decreased exhaled nitric oxide in lipopolysaccharide rats by 83 and 79%, respectively, whereas L-NAME had no effect. In control lungs, L-NAME significantly decreased acetylcholine- and bradykinin-induced vasodilation by 75% and increased hypoxic vasoconstrictions, whereas L-NIL and dexamethasone had no effect. In lipopolysaccharide lungs, acetylcholine and bradykinin both transiently increased the pulmonary artery pressure by 8.4+/-2.0 mmHg and 35.3+/-11.7 mmHg, respectively, immediately after vasodilation. L-NIL and dexamethasone both attenuated this vasoconstriction by 70%, whereas L-NAME did not. The acetylcholine vasoconstriction was dose-dependent (0.01-1.0 microg), unaffected by L-NIL added to the perfusate, and abolished by 4-DAMP.. In isolated perfused lungs, acetylcholine and bradykinin caused vasoconstriction in lipopolysaccharide-treated rats. This vasoconstriction was attenuated by administration of the iNOS inhibitor L-NIL but not with L-NAME. Furthermore, L-NIL administered with lipopolysaccharide preserved endothelium nitric oxide-dependent vasodilation, whereas L-NAME did not.

Topics: Acetylcholine; Animals; Bradykinin; Dexamethasone; Enzyme Inhibitors; Hypoxia; In Vitro Techniques; Lipopolysaccharides; Lung; Lysine; Male; Muscarinic Antagonists; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitroprusside; Piperidines; Pulmonary Circulation; Rats; Rats, Sprague-Dawley; Salmonella typhimurium; Vasoconstriction

The N-methyl-D-aspartate (NMDA) subtype of glutamate receptor is one pathway through which excessive influx of calcium has been suggested to trigger ischemia-induced delayed neuronal death. NMDA receptors are heterooligomeric complexes comprised of both NR1 and NR2A-D subunits, in various combinations. NR2B-containing NMDA complexes exhibit larger, more prolonged conductances than those lacking this subunit. We tested the ability of the non-competitive, NR2B-selective NMDA antagonist eliprodil to (a) protect synaptic transmission in in vitro hippocampal slices from hypoxia, and (b) reduce ischemic delayed neuronal death in hippocampal organotypic slice cultures. Eliprodil markedly improved the recovery of Schaffer collateral-CA1 excitatory postsynaptic potentials following a 15 min hypoxic insult, with an EC50 of approximately 0.5 microM. In contrast to this functional protection, eliprodil did not reduce delayed death of CA1 pyramidal neurons in organotypic hippocampal slice cultures treated with severe hypoxia plus hypoglycemia, though it did potently protect CA3 pyramidal neurons in the same cultures. These data indicate that NMDA receptors containing NR2B subunits may play a role in long-term recovery of hippocampal synaptic function following ischemia/hypoxia. Furthermore, the selective protection of CA3, but not CA1, pyramidal neurons suggests that NR2B-containing NMDA receptors may preferentially contribute to an excitotoxic component of ischemia-induced delayed neuronal death.

Topics: Animals; Excitatory Amino Acid Antagonists; Hippocampus; Hypoxia; In Vitro Techniques; Ischemia; Male; N-Methylaspartate; Neuroprotective Agents; Piperidines; Pyramidal Cells; Rats; Rats, Sprague-Dawley

To test whether a potent cGMP-specific phosphodiesterase inhibitor, E 4021, is a selective pulmonary vasodilator in pulmonary hypertension, we studied its acute hemodynamic effects in conscious, chronically hypoxic pulmonary hypertensive rats. Chronically hypoxic pulmonary hypertension was induced by keeping adult Sprague-Dawley rats in a hypobaric chamber for 3 weeks. Two days after catheterization. E 4021 was injected intravenously at doses of 3, 10, 30, 100, 300, and 1,000 micrograms/kg at 10-min intervals. E 4021 caused significant decreases in mean pulmonary arterial pressure of 11 +/- 5, 12 +/- 6, and 18 +/- 5% at doses of 100, 300, and 1,000 micrograms/kg, respectively. In contrast to its depressor effect on mean pulmonary arterial pressure, E 4021 decreased mean systemic arterial pressure significantly (by 9 +/- 2%) at a dose of 1,000 micrograms/kg only. Heart rate and cardiac output were unchanged after the administration of E 4021. Tissue cGMP-specific phosphodiesterase activity was markedly higher in lung than in aorta. These results indicate that E 4021 is a relatively selective pulmonary vasodilator in chronically hypoxic pulmonary hypertensive rats. We conclude E 4021 may be useful for the treatment of pulmonary hypertension.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Blood Pressure; Chronic Disease; Hypertension, Pulmonary; Hypoxia; Lung; Male; Phosphodiesterase Inhibitors; Piperidines; Pulmonary Artery; Quinazolines; Rats; Rats, Sprague-Dawley; Vasodilator Agents

Pigs were subjected to acute, intermittent hypoxia (fraction of inhaled O2 0.1, n = 10). The increase in mean pulmonary artery pressure during hypoxia was not altered after i.v. administration of the selective endothelin ETB receptor antagonist BQ-788 (N-cis-2,6-dimethylpiperidinocarbonyl-L-gamma-methylleucyl-D -1- methoxycarbonyltryptophanyl-D-norleucine) (1 mg). However, the vasodilatory effect of endothelin-1 (25 ng/kg per min) infused into the pulmonary artery during hypoxia was attenuated by BQ-788. The present results suggest that the pulmonary vasodilator effect of exogenously administered endothelin-1 during acute hypoxia is mediated by endothelin ETB receptors in the pig. Furthermore, endothelin ETB receptor antagonism with BQ-788 does not influence the pulmonary vascular response to acute hypoxia.

Topics: Analysis of Variance; Animals; Blood Pressure; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Hypoxia; Injections, Intravenous; Oligopeptides; Piperidines; Pulmonary Artery; Pulmonary Wedge Pressure; Rats; Receptor, Endothelin B; Swine; Vascular Resistance; Vasodilation

1. The effects of the calcium channel blockers, nicardipine and ifenprodil, on the brain free arachidonic acid level and learning ability in rats exposed to hypoxia were examined. 2. Adult rats were injected with 0.003; 0.01; 0.03; 0.1; 0.3 or 1.0 mg/kg of tested drugs i.p. Thirty min later the learning ability was tested in a passive avoidance task according to the step-through procedure. Immediately after the training trial, the animals were subjected to a period of oxygen deprivation hypoxia until the loss of the righting reflex. The retention trial was carried out 24 hr later. 3. The other groups of animals were pretreated with mentioned substances before hypoxia-exposure. Fifteen min after the loss of the righting reflex they were decapitated and brains were frozen in liquid nitrogen. The brain free arachidonic acid level was quantified by gas chromatography. 4. Both nicardipine and ifenprodil were effective in preventing a memory decline in hypoxia-exposed rats but did not prevent the accumulation of the brain free arachidonic acid in hypoxia-exposed rats. 5. The protective effects of both substances in behavioral studies during acute brain damage caused by hypoxia could not be explained by the prevention of the increase of the brain free arachidonic acid, but by some other mechanism.

Topics: Animals; Arachidonic Acid; Brain; Female; Hypoxia; Learning; Nicardipine; Piperidines; Rats; Rats, Wistar; Vasodilator Agents

We investigated the effect of systemic hypoxia (Krebs-Henseleit solution gassed with 5% CO2/95% N2) on an isolated, perfused rat lung. Hypoxia resulted in a slowly developing sustained increase in pulmonary perfusion pressure (PPP) accompanied by an increase in lung weight (LW). The endothelin (ET) receptor antagonists BQ123 (3 and 10 microM), BQ788 (3 microM) and bosentan (1.5 and 5 microM) all attenuated the hypoxia-induced increases in LW and PPP. In addition, phosphoramidon (1 microM), an ET-converting enzyme inhibitor, also significantly attenuated the hypoxia-induced increases in PPP and LW. The use of two agents that alter peptide secretion, phalloidin (10 and 50 nM) and colchicine (100 nM), and the peptide synthesis inhibitor cycloheximide (5 microM) all significantly attenuated the hypoxia-induced increases in PPP and LW. The increase in PPP and LW after the onset of hypoxia was accompanied by an increase in perfusate levels of ET-1 compared with normoxic time-matched controls. The results show that in this model, systemic hypoxia is capable of causing a sustained vasoconstriction and increased LW. The fact that these increases can be attenuated by an ET-converting enzyme inhibitor, ET receptor antagonists and agents that block peptide synthesis and secretion, together with the increase in perfusate levels of ET-1, suggests that ET production and release contribute to the changes seen.

Topics: Animals; Colchicine; Cycloheximide; Endothelins; Hypoxia; Lung; Oligopeptides; Peptides, Cyclic; Perfusion; Piperidines; Rats; Rats, Wistar; Vasoconstriction

While it is known that nitric oxide (NO) is an important modulator of tone in the hypertensive pulmonary circulation, the roles of cyclic 3'-5'-guanosine monophosphate (cGMP) and cGMP-phosphodiesterase (PDE) are uncertain. We found that isolated lung perfusate levels of cGMP were over ninefold elevated in hypertensive vs. normotensive control rats. 98-100% of lung cGMP hydrolytic activity was cGMP-specific PDE5, with no significant decrease in PDE activity in hypertensive lungs, suggesting that the elevation in cGMP was due to accelerated production rather than reduced degradation. In pulmonary hypertensive rat lungs, in vitro, cGMP-PDE inhibition by E4021[1-(6-chloro-4-(3,4-methylbenzyl) amino-quinazolin-2-yl)piperdine-4-carboxylate], increased perfusate cGMP threefold, reduced hypoxic vasoconstriction by 58 +/- 2%, and reduced baseline pulmonary artery pressure by 37 +/- 5%. In conscious, pulmonary hypertensive rats, intravenous administration of E4021 reduced hypoxic vasoconstriction by 68 +/- 8%, pulmonary artery pressure by 12.6 +/- 3.7% and total pulmonary resistance by 13.1 +/- 6.4%, with no significant effect on cardiac output, systemic pressure, and resistance. Comparison of E4021 to inhaled nitric oxide demonstrated that cGMP-PDE inhibition was as selective and as effective as inhaled NO.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Calcium Channel Blockers; Cyclic GMP; Diltiazem; Hemodynamics; Hypertension, Pulmonary; Hypoxia; In Vitro Techniques; Lung; Male; Nitric Oxide; Perfusion; Phosphodiesterase Inhibitors; Piperidines; Pulmonary Circulation; Purinones; Quinazolines; Rats; Rats, Sprague-Dawley; Vasodilation

Topics: Acetyl Coenzyme A; Acetylcholine; Animals; Azepines; Carotid Body; Carrier Proteins; Cats; Cell Hypoxia; Choline; Choline O-Acetyltransferase; Enzyme Inhibitors; Glossopharyngeal Nerve; Hemicholinium 3; Hypoxia; Membrane Transport Proteins; Models, Neurological; Naphthylvinylpyridine; Nerve Tissue Proteins; Piperidines; Pyridines; Receptors, Presynaptic; Signal Transduction; Synaptic Vesicles

Anoxic depolarization (AD) and failure of ion homeostasis play an important role in ischemia-induced neuronal injury. In the present study, different drugs with known ion-channel-modulating properties were examined for their ability to interfere with cardiac-arrest-elicited AD and with the changes in the extracellular ion activity in rat brain. Our results indicate that only drugs primarily blocking membrane Na+ permeability (NBQX, R56865, and flunarizine) delayed the occurrence of AD, while compounds affecting cellular Ca2+ load (MK-801 and nimodipine) did not influence the latency time. The ischemia-induced [Na+]e reduction was attenuated by R56865. Blockade of the ATP-sensitive K+ channels with glibenclamide reduced the [K+]e increase upon ischemia, indicating an involvement of the KATP channels in ischemia-induced K+ efflux. The KATP channel opener cromakalim did not affect the AD or the [K+]e concentration. The ischemia-induced rapid decline of extracellular calcium was attenuated by receptor-operated Ca2+ channel blockers MK-801 and NBQX, but not by the voltage-operated Ca2+ channel blocker nimodipine, R56865, and flunarizine.

Topics: Adenosine Triphosphate; Animals; Benzothiazoles; Calcium; Dizocilpine Maleate; Flunarizine; Glyburide; Heart Arrest; Hypoxia; Ion Channels; Male; Nimodipine; Piperidines; Potassium; Potassium Channels; Quinoxalines; Rats; Rats, Wistar; Sodium; Thiazoles

Remifentanil is a new mu opioid analgesic of the synthetic phenylpiperidine class. It has an extremely short half-life (10-20 min) due to its breakdown by nonspecific estrases. We studied the effects of continuous infusion of remifentanil, compared with alfentanil, on the respiratory response to hypoxia. In addition, we examined the efficacy of naloxone to reverse remifentanil-mediated depression of respiration. Spontaneous recovery after the end of the infusion was also assessed. Twelve adult males participated in the study. On three sessions, separated by 7 to 14 days, the participants received continuous infusion over 240 min of alfentanil (0.5 microgram/kg/min), remifentanil (0.025 microgram/kg/min) or remifentanil (0.1 microgram/kg/min). Naloxone (6 micrograms/kg) was given at 95 min. On a fourth session, remifentanil (0.1 microgram/kg/min) was infused and placebo was given instead of naloxone. Base-line hypoxic challenge was induced at 30 min before starting the infusion. Eight hypoxic challenges were conducted at 10 min after starting the infusion and half-hourly thereafter. Two postinfusion challenges were performed at 250 and 280 min. The slope (liter/min/SPO2) of the ventilatory response and the predicted ventilation at SPO2 of 80% (VE80) (liter/min) significantly decreased during the infusion with remifentanil and alfentanil. A significant difference was noted between the two doses of remifentanil. Naloxone administration was associated with reversal of the depressed hypoxic responses during the infusion of alfentanil and the low dose of remifentanil. Termination of remifentanil infusion was associated with a prompt spontaneous recovery of the blunted hypoxic responses that was not detected with alfentanil.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Alfentanil; Analgesics, Opioid; Humans; Hypoxia; Infusions, Intravenous; Male; Naloxone; Piperidines; Reference Values; Remifentanil; Respiration

Several new bioanalogues of (+/-)-N-methyl-N-(1-[3-(4-fluorophenoxy)-2-hydroxy-propyl]piperidin++ +-4-yl) benzothiazol-2-amine (1, sabeluzole, CAS 104383-17-7) were prepared by reacting 1,2-epoxy-3-aryloxypropanes with 4-arylaminopiperidines. Some of these derivatives showed enhanced activity in the potassium cyanide hypoxia test and in the pentetrazol convulsion test in mice compared to 1.

Topics: Animals; Anticonvulsants; Cell Survival; Cyanides; Hypoxia; Male; Mice; Mice, Inbred Strains; Pentylenetetrazole; Piperidines; Seizures; Thiazoles

Studies have shown that the rise in intracellular ionized calcium, [Ca2+]i, in hypoxic myocardium is driven by an increase in sodium, [Na+]i, but the source of Na+ is not known.. Inhibitors of the voltage-gated Na+ channel were used to investigate the effect of Na+ channel blockade on hypoxic Na+ loading, Na(+)-dependent Ca2+ loading, and reoxygenation hypercontracture in isolated adult rat cardiac myocytes. Single electrically stimulated (0.2 Hz) cells were loaded with either SBFI (to index [Na+]i) or indo-1 (to index [Ca2+]i) and exposed to glucose-free hypoxia (PO2 < 0.02 mm Hg). Both [Na+]i and [Ca2+]i increased during hypoxia when cells became inexcitable following ATP-depletion contracture. The hypoxic rise in [Na+]i and [Ca2+]i was significantly attenuated by 1 mumol/L R 56865. Tetrodotoxin (60 mumol/L), a selective Na(+)-channel blocker, also markedly reduced the rise in [Ca2+]i during hypoxia and reoxygenation. Reoxygenation-induced cellular hypercontracture was reduced from 83% (45 of 54 cells) under control conditions to 12% (4 of 32) in the presence of R 56865 (P < .05). Lidocaine reduced hypercontracture dose dependently with 13% of cells hypercontracting in 100 mumol/L lidocaine, 42% in 50 mumol/L lidocaine, and 93% in 25 mumol/L lidocaine. The Na(+)-H+ exchange blocker, ethylisopropylamiloride (10 mumol/L) was also effective, limiting hypercontracture to 12%. R 56865, lidocaine, and ethylisopropylamiloride were also effective in preventing hypercontracture in normoxic myocytes induced by 75 mumol/L veratridine, an agent that impairs Na+ channel inactivation. Ethylisopropylamiloride prevented the veratridine-induced rise in [Ca2+]i without affecting Na(+)-Ca2+ exchange, suggesting that amiloride derivatives can reduce Ca2+ loading by blocking Na+ entry through Na+ channels, an action that may in part underlie their ability to prevent hypoxic Na+ and Ca2+ loading.. Na+ influx through the voltage-gated Na+ channel is an important route of hypoxic Na+ loading, Na(+)-dependent Ca2+ loading, and reoxygenation hypercontracture in isolated rat cardiac myocytes. Importantly, the Na+ channel appears to serve as a route for hypoxic Na+ influx after myocytes become inexcitable.

Topics: Amiloride; Animals; Benzofurans; Benzothiazoles; Calcium; Calcium Channel Blockers; Cell Separation; Ethers, Cyclic; Fluorescent Dyes; Hypoxia; Lidocaine; Myocardial Contraction; Myocardium; Piperidines; Rats; Sodium; Sodium Channel Blockers; Sodium-Hydrogen Exchangers; Tetrodotoxin; Thiazoles

6-[6-(4-Hydroxypiperidinyl)hexyloxy]-3-methylflavone HCI, (NPC 16377), a potent and highly selective sigma-site ligand, was evaluated in tests predictive of antipsychotic and neuroprotective potential and for toxicity. Like haloperidol, clozapine and remoxipride, and the sigma-ligands BMY 14802, ifenprodil and rimcazole, NPC 16377 reversed amphetamine-induced hyperactivity and apomorphine-induced climbing in mice. Additional evidence for antipsychotic activity was obtained in rats with NPC 16377, clozapine, BMY 14802, ifenprodil, haloperidol and rimcazole, all of which reduced conditioned avoidance responses at doses that did not reduce escape behavior. NPC 16377 did not induce catalepsy in mice, suggesting a decreased liability for producing extrapyramidal side effects. NPC 16377 extended survival time for mice exposed to a hypoxic environment. In a model of global ischemia using conscious gerbils, NPC 16377 prevented damage to hippocampal CA1 neurons after either intraperitoneal or oral administration. NPC 16377 did not disrupt prepulse inhibition or block the disruption of prepulse inhibition induced by the phencyclidine site-selective ligand (+)MK-801. In rats trained to discriminate phencyclidine from saline, NPC 16377 did not substitute for the psychotomimetic. These data are consistent with the notion that selective sigma-agents may possess antipsychotic and neuroprotective activities. Moreover, the results from prepulse inhibition and drug discrimination experiments suggest that NPC 16377 is devoid of phencyclidine-like effects.

Topics: Amphetamine; Animals; Antipsychotic Agents; Apomorphine; Avoidance Learning; Brain; Flavonoids; Hypoxia; Lethal Dose 50; Male; Mice; Motor Activity; Nervous System; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, sigma

To determine if NIP-121, a new antihypertensive agent with K+ channel-opening activity, would be an effective vasodilator in pulmonary hypertension, we studied its acute hemodynamic effects under normoxic conditions in conscious chronically hypoxic pulmonary hypertensive rats and in control pulmonary normotensive rats. In contrast to no pulmonary vasodilation by NIP-121 in control rats, the K+ channel activator (10-100 mg/kg i.v.) decreased both mean pulmonary arterial pressure (from 42 +/- 2 to 33 +/- 2 mmHg; P < 0.05) and total pulmonary resistance (from 278 +/- 30 to 213 +/- 32 mmHg.l-1 x min; P < 0.05) in hypertensive rats. NIP-121 produced similar dose-related decreases in mean systemic arterial pressure and total systemic resistance in both groups of rats. Both the pulmonary and the systemic vasodilations to NIP-121 were inhibited by pretreatment with the blocker of ATP-sensitive K+ channels, glibenclamide (20 mg/kg), but not with the inhibitor of endothelium-derived relaxing factor synthesis, nitro-L-arginine (10 mg/kg). The L-type voltage-gated Ca2+ channel blocker, nifedipine (10-1,000 mg/kg i.v.), failed to cause pulmonary vasodilation in normoxic hypertensive rats, although there was dose-related systemic vasodilation. These results show that in contrast to the Ca2+ channel blocker, nifedipine, the K+ channel activator, NIP-121, is a potent vasodilator of chronic hypoxia-induced pulmonary hypertension in the rat. The mechanism of its hypotensive action in the hypertensive pulmonary vasculature might be more than simply membrane hyperpolarization and indirect inhibition of the L-type voltage-gated Ca2+ channel.

Topics: Altitude; Animals; Chronic Disease; Glyburide; Hemodynamics; Hypertension, Pulmonary; Hypoxia; Male; Nifedipine; Oxadiazoles; Piperidines; Pulmonary Circulation; Rats; Rats, Sprague-Dawley; Vasoconstriction; Vasodilation

1. Microelectrode recording techniques were used to study the effects of several potassium channel blockers which are considered to be Class III antiarrhythmic compounds. The effects of (+)-sotalol, UK-66,914, UK-68,798 and E-4031 on action potential duration (APD) were determined in guinea-pig isolated papillary muscles. The compounds were evaluated under normoxic or hypoxic/ischaemic conditions at 36.5 degrees C and compared to glibenclamide, which is considered to be a blocker of ATP-dependent potassium channels. Prolongation of action potential duration at 90% repolarization (APD90) was taken as an indirect measure of potassium channel blockade. 2. Under normoxic conditions, the Class III compounds prolonged APD in a concentration-dependent manner. According to EC15 values, the order of potency of the Class III compounds was found to be UK-68,798 > E-4031 > UK-66,914 > (+)-sotalol. Glibenclamide did not significantly prolong APD90 under normoxic conditions. 3. Perfusion with an experimental hypoxic or ischaemic bathing solution produced qualitatively similar effects on action potentials. Over a period of 20-25 min in either of the experimental solutions, there was a small decrease in action potential amplitude (APA) and a prominent shortening of APD. The ischaemic solution also depolarized the resting membrane potential by about 15 mV. 4. (+)-Sotalol and UK-66,914 did not reverse the shortening of APD induced by perfusion with hypoxic Krebs solution. High concentrations of glibenclamide (10 microM) and UK-68,798 (30 and 60 microM) partially reversed the hypoxia-shortened APD. Glibenclamide was more potent and exhibited a greater time-dependent action than UK-68,798. 5. During experimental ischaemia, the Class III compound E-4031 (10 microM, n = 7) produced small, but significant, increases in the APD90 (11 +/-3 ms after 20 min) which were not clearly time-dependent(14 +/- 4 ms after 30 min). UK-68,798 (10 microM) also produced a small, but insignificant, increase in APD90(12 =/-6 ms at 20 min, n = 4). Higher concentrations of UK-68,798 (30 and 60 microM, n = 4) did not produce a consistently significant increase in APD90 during ischaemia: significance was only attained after 20 min in the presence of 60 microM UK-68,798 (24 +/- 12 ms). However, in marked contrast to the effects of the Class III compounds, glibenclamide (10 microM) produced large time-dependent increases in ischaemic APD90 (34 +/- 11 ms at 7 min, n = 9) which were significant 15 min or

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Electrophysiology; Glyburide; Guinea Pigs; Heart; Hypoxia; In Vitro Techniques; Microelectrodes; Myocardial Ischemia; Papillary Muscles; Piperidines; Potassium Channels; Pyrazines; Pyridines; Sotalol

The recent finding that ifenprodil binds with high affinity to sigma sites suggests that other sigma agents may have ifenprodil-like cerebroprotectant and functional N-methyl-D-aspartate (NMDA) antagonist effects. The present study, compared the in vivo effects of ifenprodil and the sigma agents, BMY 14802, caramiphen and haloperidol, in three tests sensitive to NMDA antagonists and purported cerebroprotectant drugs. When administered at or below the rotorod TD50 dose, all four compounds significantly increased survival time in an hypoxic environment (4% O2 in nitrogen). Caramiphen and ifenprodil (ED50 = 52 and 61 mg/kg, respectively) also blocked maximal electroshock-induced seizures, whereas BMY 14802 and haloperidol were ineffective. Finally, caramiphen (ED50 = 95 mg/kg) antagonized seizures and lethality induced by administration of NMDA (250 mg/kg, IP). BMY 14802, haloperidol and ifenprodil only partially antagonized NMDA-induced seizures, but did enhance the anticonvulsant potency of the noncompetitive NMDA antagonist, MK-801. Together, these findings suggest that sigma agents may have cerebroprotective effects.

Topics: Animals; Anticonvulsants; Brain Diseases; Electroshock; Haloperidol; Hypoxia; Male; Mice; Mice, Inbred Strains; N-Methylaspartate; Nimodipine; Piperidines; Postural Balance; Pyrimidines; Receptors, Opioid; Receptors, sigma; Seizures

Cimetidine blunts the increase in cerebral blood flow (CBF) normally observed during hypoxia. It is important, therefore, to know whether other H2-blockers also affect the cerebral circulation adaptation to hypoxia. Cerebral blood flow was measured in 24 awake dogs after an intravenous injection of either saline (control) or one of three H2-blockers: 1 mg/kg ranitidine, 0.4 mg/kg famotidine, or 1 mg/kg roxatidine. These doses are equipotent blockers of H2-gastric receptors. Each dog was studied during normoxia and after 2 and 4 h of normocapnic hypoxia (FIO2, 0.10; FICO2, 0.035). During each set of experimental conditions, a bolus of either saline or one of the anti-H2 drugs was administered, and, 15 min later, radiolabeled microspheres (ruthenium 103, scandium 46, and cerium 141) were injected into the left atrium for measurement of regional CBF. After death by an overdose of thiopental, each dog's brain was excised and fixed in 10% formaldehyde; it was then weighed and dissected by region, with the radioactivity measured in each region using a gamma counter. During hypoxia, PaO2 ranged from 45 to 50 mm Hg, and pH, PaCO2, and hematocrit were within the normal limits. In the control group CBF increased 34% above normoxic baseline levels after 2 h and 31% after 4 h of hypoxia. Ranitidine (1 mg/kg) did not prevent the increase in CBF during hypoxia, but famotidine and roxatidine prevented it. When the dose of ranitidine was doubled (2 mg/kg), it too abolished the increase of CBF induced by hypoxia. In conclusion, H2-receptor blockers could interfere with the adaptation of CBF during hypoxia.

Topics: Animals; Cerebrovascular Circulation; Dogs; Famotidine; Hemodynamics; Histamine H2 Antagonists; Hypoxia; Injections, Intravenous; Microspheres; Piperidines; Pulmonary Gas Exchange; Ranitidine; Respiration

The effects of the new and potent methanesulfonanilide class III antiarrhythmic agents (E-4031, UK-66,914, and UK-68,798) on myocardial refractoriness and contractility were compared to those of d-sotalol in ferret isometrically contracting right ventricular papillary muscle preparations. During 1 Hz pacing at 37 degrees C, the four class III agents elicited concentration-dependent increases in ventricular effective refractory period (ERP), with a relative order of potency of UK-68,798 greater than E-4031 greater than UK-66,914 much greater than d-sotalol. EC25 values (effective concentration required to increase ERP 25% above baseline) were (in microM) UK-68,798, 0.018; E-4031, 0.058; UK-66,914, 0.501; and d-sotalol, 43.76. Maximal increases in ERP relative to baseline (% of baseline value) for the class III agents at 37 degrees C (range of 44.5 +/- 4.5 to 63.0 +/- 3.1%) were greater than the maximal increases observed at 27 degrees C (range of 15.0 +/- 3.3 to 31.2 +/- 4.8%), whereas the maximal absolute (ms) increases in ERP above baseline were comparable for the class III agents at both temperatures. Increases in ERP produced by the four class III agents at 37 degrees C were significantly greater at a pacing frequency of 1 Hz (range of 70.0 +/- 7.6 to 102.0 +/- 2.3 ms) than at 3 Hz (range of 18.3 +/- 4.4 to 31.BBB/- 4.8 ms). During a temporary period of hypoxic perfusion at 37 degrees C, increases in ERP produced by the four class III agents were reversed, such that "hypoxic" ERP values approximated pretreatment, baseline values.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Cardiac Pacing, Artificial; Ferrets; Heart; Hypoxia; In Vitro Techniques; Male; Myocardial Contraction; Phenethylamines; Piperidines; Pyrazines; Pyridines; Refractory Period, Electrophysiological; Sotalol; Sulfonamides; Temperature

Cognitive deficits resulting from neuropathological brain changes such as Alzheimer's Disease or normal aging are most likely due to alterations in multiple neurotransmitter systems. While the majority of preclinical studies have focused on the effects of acetylcholine (ACh), it has been shown that activation of the serotonergic (5-HT) pathways in the central nervous system interferes with passive avoidance retention in rats. In contrast, decreased 5-HT activity has been shown to improve learning and memory in rats using similar procedures. In the present experiment, 5-HT antagonists were evaluated for their effects on performance in a delayed match to sample task (DMTS) in two groups of squirrel monkeys: one in which the baseline level of performance was low (less than 65% correct, N = 5; group 1) and another in which DMTS performance was high (greater than 80% correct, N = 3; group 2) but impaired by exposure to hypoxia. Initial parametric tests exposing group 2 to various levels of oxygen deprivation were conducted to determine optimal conditions for performance deficits. Each monkey in both normoxia (group 1) and hypoxia (group 2) served as his own control and received an individualized range of doses for each test compound. For both groups, ketanserin and mianserin, the 5-HT2-selective antagonists, produced dose-dependent increases in DMTS performance at 0.3-1.5 mg/kg PO and 0.05-1.5 mg/kg PO, respectively. Pirenperone, another 5-HT2-selective antagonist, was active in improving performance in group 1 at 0.001 to 0.2 mg/kg PO but was not effective against hypoxia-induced performance deficits.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Avoidance Learning; Cognition; Dose-Response Relationship, Drug; Hypoxia; Ketanserin; Male; Memory; Mianserin; Piperidines; Psychomotor Performance; Reinforcement Schedule; Saimiri; Serotonin Antagonists

The pure and selective serotonin blocking agent ketanserin (5-HT2 receptor blocker) was used to evaluate a possible role for serotonin as a mediator of the pulmonary vasoconstrictor response to alveolar hypoxia. Isolated and ventilated lungs (FiO2 = 0.21) from rats were perfused at 310 degrees (K) with homologous blood at constant volume inflow, and pressor responses to standardized periods of ventilation hypoxia (FIO2 = 0.02) were recorded. Pressor responses to pulmonary arterial bolus-injections of serotonin were tested both before and after administration of ketanserin for comparison with the responses to hypoxia. We found that ketanserin in doses adequate to block the response to serotonin, had no effect on the pulmonary vasoconstrictor response to hypoxia.

Topics: Animals; Hypoxia; In Vitro Techniques; Ketanserin; Lung; Perfusion; Piperidines; Pulmonary Circulation; Rats; Rats, Inbred Strains; Vasoconstriction

Here I have reviewed evidence from electron microscopic studies showing that each of several sustained limbic seizure syndromes is associated with a type of acute brain damage which is ultrastructurally indistinguishable from the brain damage induced by Glu and other excitotoxins. In addition, I have presented evidence that persistent stimulation of specific axonal tracts that use Glu as transmitter results in Glu-like excitotoxic degeneration of postsynaptic neurons innervated by such tracts. Phencyclidine and ketamine, which powerfully block the neurotoxicity of the Glu analog NMA, protect against seizure-related brain damage. This may be explained by either an anticonvulsant or antiexcitotoxic mechanism, or both. Recent evidence suggests that an excitotoxic mechanism (excessive activation of Glu/Asp receptors) may underlie both seizure-mediated and anoxic brain damage. The acute fulminating type of neuronal degeneration induced by Glu is a Na+ and Cl- but not Ca2+ dependent phenomenon. According to a recent study, however, Glu may induce neuronal necrosis not only by an acute Ca2+ independent process but by a more slowly evolving Ca2+ dependent process. If, as these data suggest, an excitotoxic mechanism underlies brain damage associated with anoxia and epilepsy, a better understanding of excitotoxic mechanisms may lead eventually to prophylactic approaches for preventing such forms of brain damage.

Topics: Action Potentials; Animals; Brain; Cell Survival; Chick Embryo; Cholinergic Fibers; Disease Models, Animal; Edema; Epilepsies, Partial; Folic Acid; Hippocampus; Hypoxia; Kainic Acid; Ketamine; Microscopy, Electron; Parasympathomimetics; Phencyclidine; Piperidines; Seizures; Synaptic Transmission; Thalamus

A persistent pulmonary artery hypertension, increased airways resistance, increased vascular permeability to protein, and hypoxia are characteristic of sepsis-induced ARDS in humans and are present in the late phase injury response seen in sheep after endotoxin. Our purpose was to determine the role of serotonin, 5-HT, in the steady-state pulmonary hypertension and decreased arterial oxygen tension seen beginning approximately 3 h after Escherichia coli endotoxin injury (2 micrograms/kg) in the adult sheep. Plasma 5-HT levels remained constant, whereas lung lymph values increased from a baseline of 60 +/- 40 to 180 +/- 70 and 270 +/- 90 ng/ml at 1-h and at 3- to 5-h periods, respectively, after endotoxin. Platelet count decreased significantly only at the 3-h time period. Ketanserin, a 5-HT antagonist, was infused (0.15 mg/kg/h) in 7 sheep during endotoxin injury. The degree of early pulmonary hypertension and hypoxia was not affected by ketanserin. Mean values for pulmonary artery pressure and arterial oxygen tension were 40 +/- 8 mmHg and 70 +/- 8 torr for endotoxin alone and 38 +/- 7 mmHg and 72 +/- 7 torr for the ketanserin group. Steady-state, protein-rich pulmonary perfusion was also not altered, being increased 3-fold in both groups. Pulmonary hypertension and hypoxia were significantly attenuated, however, at the 3- to 5-h period with ketanserin, compared with endotoxin alone, the pulmonary artery pressure decreasing from 29 +/- 5 to 22 +/- 4 mmHg and the PaO2 increasing from 75 +/- 4 to 83 +/- 5 torr.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Pressure; Endotoxins; Escherichia coli; Hypertension, Pulmonary; Hypoxia; Ketanserin; Lung; Lymph; Oxygen; Piperidines; Platelet Count; Pulmonary Artery; Serotonin; Serotonin Antagonists; Sheep

The authors measured changes in pulmonary and systemic haemodynamics in seven patients following oxygen inhalation, nifedipine and Ketanserin administration. A significant decrease in mean pulmonary artery pressure, cardiac index and heart rate could be observed following 30-min oxygen inhalation. No significant changes were found in pulmonary haemodynamics 1 hour after sublingual administration of 20 mg Corinfar (nifedipine). Long-term treatment (6 months) with Corinfar (30-60 mg per day) was not followed by a significant change in mean pulmonary artery pressure. However, in 3 patients a decrease in mean pulmonary artery pressure (6-11 mmHg) could be observed. Ketanserin (10 mg intravenously) did not significantly change the mean pulmonary artery pressure in patients with hypoxic pulmonary hypertension.

Topics: Adult; Carbon Dioxide; Cardiac Output; Female; Heart Rate; Humans; Hypertension, Pulmonary; Hypoxia; Ketanserin; Lung Diseases, Obstructive; Lung Volume Measurements; Male; Middle Aged; Nifedipine; Oxygen; Oxygen Inhalation Therapy; Piperidines; Pulmonary Wedge Pressure; Serotonin Antagonists

The effects of intracarotid (i.c.) injections of 5-hydroxytryptamine (5-HT; 1-50 micrograms) on carotid chemoreceptor activity recorded from the carotid sinus nerve have been studied in anaesthetized cats. Three separate components in the complex response of the chemoreceptors to injected 5-HT were identified. Firstly, a transient burst of activity was obtained during the injection period in 56% of the recordings. Secondly, in all the recordings a period of chemodepression commenced a few seconds after completing the injection and was usually dose-related. Thirdly, a delayed longer-lasting chemoexcitation occurred in many experiments, concomitant with a fall in systemic blood pressure. The neuronal 5-HT receptor antagonist MDL 72222 (10-100 micrograms kg-1, i.c.) virtually abolished the transient chemoexcitation evoked during 5-HT injections and also significantly increased the mean ID50 for 5-HT-induced chemodepression; in 37% of recordings 5-HT caused a dose-related chemoexcitation after the high dose of MDL 72222. Neither the delayed chemoexcitation nor the hypotension caused by 5-HT were much affected by the antagonist. MDL 72222 itself had a biphasic effect on chemosensory discharge, causing depression followed by a delayed excitation. The 5-HT2-receptor antagonist ketanserin (100 micrograms kg-1, i.c.) had no appreciable effect on the transient chemoexcitation evoked during 5-HT injections and caused a slight but significant increase in the mean ID50 for 5-HT-induced chemodepression. The delayed chemoexcitation and accompanying hypotension associated with 5-HT were both substantially reduced or abolished by the antagonist. Ketanserin itself caused a short-lasting period of chemoexcitation. All the effects of injected 5-HT on chemosensory discharge could be abolished by the combination of MDL 72222 and ketanserin (100 micrograms kg-1, i.c.). Neither MDL 72222 nor ketanserin had any significant effect upon the response of the carotid chemoreceptors to hypoxia. The rate at which discharge increased, and also the steady-state discharge before and during hypoxia, were unaffected by the antagonists, alone or in combination. At least two types of 5-HT receptor appeared to be involved in the response of carotid body chemoreceptors to 5-HT. Transient excitation and chemodepression were mediated via MDL 72222-sensitive (peripheral neuronal) receptors whereas the delayed chemoexcitation and associated hypotension involved a ketanserin-sensitive, presumably 5-H

Topics: Action Potentials; Animals; Carotid Body; Cats; Chemoreceptor Cells; Domperidone; Dopamine; Electrophysiology; Female; Hypoxia; Ketanserin; Male; Piperidines; Serotonin; Serotonin Antagonists; Tropanes

We have analyzed a conditioned avoidance response (CAR) in rats, under both normoxia and hypobaric hypoxia (300 torr), to try to elucidate the mechanism of apomorphine's protective effect against hypoxia. The resistance to hypoxia is markedly increased by apomorphine (1 mg/kg i.p.) and, to a lesser degree, by an alpha-adrenergic pre-synaptic (yohimbine 1 mg/kg i.p.) or post-synaptic (phenoxybenzamine 1 mg/kg i.p.) blocker. The anti-hypoxic property of apomorphine is not altered when associated with domperidone (0.5 mg/kg i.p.), a peripheral blocker of the dopaminergic receptors. Resistance to hypoxia is decreased by propranolol (1 mg/kg i.p.) and pimozide (1 mg/kg i.p.). It is not modified by tylciprine (2 mg/kg i.p.) or by metergoline (2.5 mg/kg i.p.), a blocker of the 5-hydroxytryptamine (5 H T) receptors. However, the association of any of the above pharmacological agents with apomorphine destroys apomorphine's anti-hypoxic effect. There has even been shown a positive potentialisation ( i.e. an increase of the inhibitory effect) between apomorphine, hypoxia, and the added drug. This potentialisation is already noticeable under normoxia for the association of each of the drugs with apomorphine. Free alpha, beta adrenergic, cerebral dopaminergic, and serotoninergic receptors and an intact amine metabolic pathway therefore seem required for apomorphine to develop its anti-hypoxic activity.

Topics: Animals; Apomorphine; Atmospheric Pressure; Avoidance Learning; Benzimidazoles; Domperidone; Female; Hypoxia; Monoamine Oxidase Inhibitors; Phenoxybenzamine; Pimozide; Piperidines; Propranolol; Rats; Yohimbine

Topics: Acetophenones; Alkaloids; Animals; Cell Survival; Cells, Cultured; Cricetinae; Cyclic N-Oxides; Diamide; Hypoxia; In Vitro Techniques; Piperidines; Radiation-Sensitizing Agents

Pharmacological effects of ifenprodil (IP), 4-benzyl-alpha-(p-hydroxyphenyl)-beta-methyl-1-piperidineethanol-L-(+)-tartrate monohydrate (Funai Pharmaceutical), a potential vasodilator, were studied in the dog, rabbit, guinea-pig and mouse. 1) Intravenous administration of IP (0.1 approximately 1 mg/kg) exhibited a continuous fall in blood pressure, an increase in heart rate and an increase in cardiac contractile force in the dog. The depressor and chronotropic effects of IP appeared likewise in the pithed dog, and the depressor responses were slightly more evident in the rabbit. The cardiovascular responses to IP were not affected by pretreatment with atropine or diphenhydramine, however, the chronotropic and inotropic effects were completely removed and the depressor response was depressed to some extent by propranolol. On the contrary, a pressor response to adrenaline was reversed to a depressor one after IP in the dog. 2) In heart-lung preparation of dogs, IP brought about slight cardiac stimulating effects, such as an increase in contractile force and a rise in aortic pressure. 3) IP induced a transient slight excitation in in situ movements of the rabbit intestine, and a similar excitation followed with a inhibition in movements of isolated intestine (10(-6), 2.5 X 10(-5) g/ml. This slight excitation was not affected by pretreatment with atropine, whereas the inhibition was depressed to a certain degree by simultaneous pretreatment with phenoxybenzamine and propranolol. IP produced a slight tonic increase in the guinea-pig isolated intestine and inhibited markedly the excitatory effect of histamine in the intestine. 4) IP did not affect the bronchial muscle but inhibited prominently a contractile respose of the muscle to histamine in in situ experiments on guinea-pig. 5) Locomotor activity was reduced dose-dependently and thiopental hypnosis was potentiated similarly after subcutaneous administration of IP (5 approximately 40 mg/kg), while skeletal muscle relaxant effects were not observed. 6) Survival time under a condition of acute anoxia was not changed with a dose of 0.5 and 1 mg/kg, but shortened with a dose of 5 mg/kg. The results suggest that IP has a alpha-blocking, a beta-stimulating and a moderate antihistaminic effects, and shows some cardiovascular effects, such as continuous depressor and chronotropic effects, and a moderate central inhibition.

Topics: Animals; Blood Pressure; Bronchi; Dogs; Guinea Pigs; Heart; Heart Rate; Hypoxia; In Vitro Techniques; Intestines; Locomotion; Male; Mice; Muscles; Phenylpropanolamine; Piperidines; Rabbits; Sleep; Vasodilator Agents

Topics: Aerobiosis; Carcinoma, Squamous Cell; Cell Line; Cell Survival; Cells; Culture Techniques; Cyclic N-Oxides; Dose-Response Relationship, Radiation; Female; Humans; Hypoxia; Oxygen; Piperidines; Radiation Dosage; Radiation Effects; Radiation-Sensitizing Agents; Uterine Cervical Neoplasms

Topics: Aminobutyrates; Analgesics; Animals; Barbiturates; Cats; Cerebral Cortex; Drug Synergism; Hexobarbital; Hypoxia; Lethal Dose 50; Mice; Morphine; Piperidines; Rabbits; Rats; Seizures; Thiopental; Thiosemicarbazones; Visual Cortex

Topics: Anesthetics; Animals; Cerebrovascular Circulation; Haplorhini; Hypercapnia; Hypoxia; Intracranial Pressure; Macaca; Phencyclidine; Piperidines

Topics: Anesthesia; Anesthesia, Endotracheal; Blood Gas Analysis; Chlorpromazine; Hemodynamics; Hibernation; Humans; Hypothermia, Induced; Hypoxia; Intubation; Muscle Relaxants, Central; Neoplasms; Phenothiazines; Piperidines; Surgical Procedures, Operative

Topics: Animals; Argon; Atmospheric Pressure; Electroshock; Gas Poisoning; Helium; Hypoxia; Nitrogen; Piperidines; Rats; Unconsciousness