Cardiac and lung VEGF mRNA expression in chronically hypoxic and monocrotaline-treated rats.
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Animals↗
Biomedical subjects
B Raffestin
Publications and source records attributed to B Raffestin.
Treatment with 5-HT potentiates development of pulmonary hypertension in chronically hypoxic rats.
The aim of this study was to investigate the potential role of 5-hydroxytryptamine (5-HT) on development of pulmonary hypertension during chronic exposure to mild (15% O2) and severe (10% O2) hypoxia. In isolated lungs from normoxic rats preconstricted with U-46619, 5-HT (10(-12)-10(-8) M) induced dose-dependent vasodilation (n = 6), which was suppressed by the NO synthesis inhibitor nitro-L-arginine methyl ester (L-NAME, 10(-4) M, n = 5) and reduced by the 5-HT3-receptor antagonist MDL-7222 (10(-5) M, n = 6). The vasoconstriction that was observed with higher concentrations of 5-HT (10(-7)-10(-4) M) was inhibited by ketanserin (10(-5) M) and methiothepin (10(-5) M, n = 6 each). The vasodilator response to 5-HT was suppressed in lungs from rats exposed to 10% O2 but not 15% O2 (n = 6 each). In conscious rats, intravenous administration of 5-HT potentiated the pulmonary pressor response to acute hypoxia (10% O2, n = 5), an effect that remained unchanged after pretreatment with a 5-HT1 and a 5-HT2 antagonist (n = 4) but was attenuated after treatment with the cyclooxygenase inhibitor meclofenamate (n = 4). Treatment with 5-HT (5 nmol/h i.v. by osmotic pumps) for 2 wk in rats simultaneously exposed to 10% O2 increased pulmonary arterial pressure, right ventricular hypertrophy, and muscularization of pulmonary vessels in comparison with their hypoxic controls (n = 12 each). No changes occurred in 15% O2 hypoxic rats (n = 12 each). The present findings show that 5-HT potentiates development of pulmonary hypertension in rats exposed to chronic hypoxia.
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
Induction of nitric oxide synthase activity in pulmonary arteries from normoxic and chronically hypoxic rats.
Chronic hypoxia has recently been shown to upregulate inducible nitric oxide synthase (iNOS) gene expression in rat lung. In the present study, we questioned whether induction of NO synthesis could alter the reactivity of pulmonary arteries (PA) from chronically hypoxic (CH) rats. Dose-response curves to phenylephrine (PE) 10(-9) to 5 x 10(-6) M) were examined in PA rings as well as response to L-arginine analogues in isolated lungs from CH or normoxic (N) rats after various incubation times. Although maximal contraction to PE did not differ in PA from CH rats compared to N rats at time 0 (361 +/- 53 vs 506 +/- 52 mg, respectively), it was markedly decreased after prolonged incubation (149 +/- 28 vs 386 +/- 47 mg, respectively, at 4 h; p < 0.001). This phenomenon persisted after endothelial-denudation, but was reversed by NG-monomethyl-L-arginine (L-NMMA) (5 x 10(-4) M) and prevented by actinomycin D (2 x 10(-6) M). In contrast, maximal contraction to PE in aorta from CH rats was similar at time 0 and 4 h. After a short incubation, PA contraction to L-NMMA was greater in CH than in N rats (96 +/- 17 vs 33 +/- 9 mg at 90 min; p < 0.05), was abolished after endothelial denudation, but persisted in CH rats in the presence of calmidazolium (5 x 10(-4) M). At 4 h, contraction to L-NMMA was abolished in endothelium-denuded PA from N rats but only attenuated in those from CH rats. In salt solution perfused lungs, L-NMMA added 30 or 90 min after isolation did not alter baseline pressure in N rats but caused its increase in CH rats. Whereas iNOS messenger ribonucleic acid (mRNA) was detectable by reverse-transcriptase polymerase chain reaction in the PA wall of N or CH rats after 4 h of incubation, it was absent in both at the time of isolation. In contrast, there was evidence of iNOS mRNA in lungs from CH rats at the time of isolation but no signal in those from N rats. In conclusion, there is induction of nitric oxide synthase activity in pulmonary arteries from normoxic and chronically hypoxic rats after prolonged incubation, but this effect is more pronounced in pulmonary arteries from chronically hypoxic rats.
Animals↗
Pulmonary hypertension: NO therapy?
Endothelium-derived nitric oxide (NO) is a powerful pulmonary vasodilator which also prevents adhesion and aggregation of platelets, controls growth of smooth muscle, and influences the expression of growth promoting and vasoactive substances. Impaired endothelial NO production contributes to pulmonary vasoconstriction and vascular remodelling in several forms of pulmonary hypertension. Exogenous NO gas delivered via the airspaces is a selective pulmonary vasodilator now used as treatment in various lung disorders.
Humans↗
Hypoxia-reoxygenation impairs NO-mediated vasodilation in rat lungs.
Isolated rat lungs subjected to hypoxia-reoxygenation (H/R) were used to study NO-mediated pulmonary vasodilation during oxidant-induced vascular injury. After ventilation with 3% O2, reoxygenation with 21% (H/R 21%) or 95% O2 (H/R 95%) caused lung edema and lipid peroxidation. Vasodilation to A23187 was attenuated after H/R 21% and abolished after H/R 95%. The vasodilator-response curve to NO was more shifted to the right after H/R 95% than after H/R 21%. Pretreatment with superoxide dismutase (SOD; 150 U/ml) and catalase (120 U/ml) prevented impairment of A23187- and NO-mediated vasodilation. SOD and catalase added after reoxygenation restored vasodilation to NO but not to A23187. In lungs obtained from chronically hypoxic rats but studied under conditions of normoxic ventilation, vasodilation to A23187 was abolished, but vasodilation to NO remained unchanged. The data suggest that generation of oxygen-derived reactive species after H/R produces impairment of NO formation as well as direct inactivation of NO. This does not explain the decreased endothelial NO-mediated pulmonary vasodilation in chronically hypoxic rats.
Animals↗
Short-term variability of blood pressure during sleep in snorers with or without apnea.
In normal subjects, the level and variability of blood pressure decrease during non-rapid eye movement (non-REM) sleep. In contrast, sleep apnea is associated with large swings in nocturnal pressure. In this study, we evaluated a computer-derived index of all-night blood pressure variability in normotensive snorers with or without sleep apnea. We also examined this index in snorers receiving medical treatment for coexistent ischemic heart disease. Beat-to-beat blood pressure was recorded with a photoplethysmographic device (Finapres) throughout polysomnography. Subjects were categorized into four groups: those without cardiovascular disease without or with sleep apnea (> or = 15 apnea plus hypopnea per hour of sleep), and those with ischemic heart disease without or with sleep apnea. A frequency distribution histogram of all increases and decreases of blood pressure according to their amplitudes was drawn and the SD of the distribution used as an estimation of variability. Mean systolic and diastolic pressures during the total sleep time were not different among the four groups. In contrast, the SD of the distribution of systolic and diastolic pressure variations that were higher in the apneic than in the nonapneic groups (P < .05) correlated with apnea plus hypopnea (P < .0001) and transient electroencephalographic arousal number per hour of sleep (P < .0001). In both apneic and nonapneic subjects, blood pressure variability as assessed by SD decreased during stages 3 and 4 of non-REM sleep compared with stages 1 and 2 and REM sleep (P < .001). Blood pressure variability was similarly increased in apneic subjects with or without ischemic heart disease. We speculate that in apneic individuals with coexistent ischemic heart disease, pressure variability that is increased despite treatment with beta-blockers or calcium antagonists may be a risk factor for acute coronary events.
Adult↗
Nitric oxide in the pulmonary circulation.
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Administration, Inhalation↗
NO in the lung.
In the lung, nitric oxide (NO) derives from several cellular sources, forming networks of paracrine communication. In pulmonary vessels, NO produced by endothelial cells is a powerful vasodilator. In the airways, NO originates from epithelial cells and from adventitial nerve endings to induce smooth muscle relaxation. Activated macrophages can also produce large quantities of NO during lung immunological reactions. In the normal pulmonary circulation, NO not only mediates vasodilation, but also opposes vasoconstriction, prevents platelet adhesion, controls growth of smooth muscle and influences the composition of the extracellular matrix. During exposure to chronic hypoxia, impaired endothelial NO production contributes to the increased vasomotor tone and vascular remodelling leading to sustained pulmonary hypertension. Exogenous NO gas delivered via the airspaces is a selective pulmonary vasodilator. Inhaled NO is now used as a therapy to treat various forms of pulmonary hypertension and to improve arterial oxygenation during lung injury.
Animals↗
Protection from pulmonary hypertension with an orally active endothelin receptor antagonist in hypoxic rats.
The aim of this study was to investigate the potential role of endothelin (ET) in the development of chronic hypoxic pulmonary hypertension. Pulmonary vascular reactivity to ET-1 was first examined in isolated perfused lungs from normoxic and chronically hypoxic rats in the presence of bosentan, a new nonpeptide mixed antagonist of ETA and ETB receptors. The effect of chronic treatment with bosentan was then examined in rats that were exposed to chronic hypoxia and developed pulmonary hypertension. In lungs from normoxic rats, bosentan (10(-5) M) abolished the vasodilator responses to ET-1 (10(-10) M) or to the ETB-selective agonist IRL-1620 (10(-10) M) and attenuated the vasoconstrictor responses to 10(-9) M ET-1 (from 8.7 +/- 0.7 to 1.8 +/- 0.3 mmHg, P < 0.01) or 10(-9) M IRL-1620 (from 1.5 +/- 0.4 to 0.4 +/- 0.1 mmHg, P < 0.05). In lungs from chronically hypoxic rats, the pressor response to 3 x 10(-10) M ET-1 was abolished by bosentan and partially reduced by the selective ETA antagonist BQ-123. In conscious rats previously exposed to hypoxia for 15 days, pretreatment with bosentan (100 mg.kg-1.day-1 by gavage) for 3 days attenuated the increase in systemic arterial pressures and the concomitant decrease of cardiac output in response to an intravenous bolus of ET-1 (3 x 10(-10) M). In rats exposed to hypoxia for 15 days and simultaneously treated with bosentan, pulmonary arterial pressure was lower (P < 0.05) and right ventricular hypertrophy was less severe (P < 0.01) than in control hypoxic rats treated with vehicle.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Inhaled nitric oxide as a screening vasodilator agent in primary pulmonary hypertension. A dose-response study and comparison with prostacyclin.
To investigate the capacity of the pulmonary vascular bed to acutely vasodilate, we examined in 35 consecutive patients with primary pulmonary hypertension (PPH), the hemodynamic effects of incremental inhalation periods of an air-NO mixture at different concentrations (10, 20, and 40 ppm), and compared them with those of an acute infusion of prostacyclin (PGI2). An individual pulmonary vasodilator response was defined by a fall in total pulmonary resistance (TPR) > or = 30% relative to mean TPR baseline value. Thirteen patients were responders and 22 were nonresponders to both drugs, and they did not significantly differ in overall baseline characteristics except for mean right atrial pressure (p < 0.03). In responders, both drugs produced similar individual vasodilator response. Changes in mean pulmonary arterial pressure and TPR observed during NO and PGI2 were closely correlated (r2 = 0.9, p < 0.001, and r2 = 0.7, p < 0.01, respectively). The vasodilator response to NO was not concentration-related with a maximal effect obtained at 10 ppm. Combination of both drugs did not lead to any additive vasodilator response. Unlike PGI2, NO did not induce any systemic effect, no adverse reaction, but a moderate increase in methemoglobin. Inhaled NO at low dose (10 ppm) appears to be an effective, safe, and reliable substitute for PGI2 in screening for acute pulmonary vasodilator responsiveness during therapeutic assessment of patients with PPH.
Adult↗
Evaluation of an ambulatory device, CID 102, in the diagnosis of obstructive sleep apnoea syndrome.
Diagnosis of obstructive sleep apnoea syndrome (OSAS) is usually performed during overnight polysomnography in the sleep laboratory. In an attempt to simplify the diagnostic strategy, we compared an ambulatory device, CID 102, with polysomnography during the same night in the laboratory in 50 consecutive patients referred for polysomnography. The CID 102 device monitors oxygen saturation, heart rate, body position and tracheal breath sounds. An acoustic pressure sensor is placed on the suprasternal notch. Signals coming from this sensor are amplified and analysed in three different channels, according to their frequency and energy. CID respiratory disturbance index is defined as the number, per hour of analysis time, of apnoeas lasting more than 10 s plus episodes of desaturation by 4% or more associated with pauses lasting from 7-10 s or snores. The polysomnographic data were recorded on paper (Reega 2000, Alvar) and analysed manually. Polysomnographic apnoea-hypopnoea index (AHIp) was defined as the number of apnoeas plus hypopnoeas per hour of sleep. The sensitivity, specificity, positive predictive value and negative predictive value of various CID respiratory disturbance index (> or = 5, > or = 10, > or = 15 and > or = 20 per hour) in diagnosing obstructive sleep apnoea syndrome were determined. When OSAS was diagnosed as AHIp > or = 15, sensitivity and specificity of a CID respiratory disturbance index > or = 5 were 73 and 62%, respectively. Positive predictive value of CID respiratory disturbance index > or = 10 for AHIp > or = 10 was 94%. CID 102 false negative patients had only hypopnoeas without any desaturation.(ABSTRACT TRUNCATED AT 250 WORDS)
Equipment Design↗
Brain magnetic resonance imaging before and after percutaneous mitral balloon commissurotomy.
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Atrial Fibrillation↗
Continuous inhalation of nitric oxide protects against development of pulmonary hypertension in chronically hypoxic rats.
Exposure to hypoxia and subsequent development of pulmonary hypertension is associated with an impairment of the nitric oxide (NO) mediated response to endothelium-dependent vasodilators. Inhaled NO may reach resistive pulmonary vessels through an abluminal route. The aim of this study was to investigate if continuous inhalation of NO would attenuate the development of pulmonary hypertension in rats exposed to chronic hypoxia. In conscious rats previously exposed to 10% O2 for 3 wk, short-term inhalation of NO caused a dose-dependent decrease in pulmonary artery pressure (PAP) from 44 +/- 1 to 32 +/- 1 mmHg at 40 ppm with no changes in systemic arterial pressure, cardiac output, or heart rate. In normoxic rats, acute NO inhalation did not cause changes in PAP. In rats simultaneously exposed to 10% O2 and 10 ppm NO during 2 wk, right ventricular hypertrophy was less severe (P < 0.01), and the degree of muscularization of pulmonary vessels at both alveolar duct and alveolar wall levels was lower (P < 0.01) than in rats exposed to hypoxia alone. Tolerance to the pulmonary vasodilator effect of NO did not develop after prolonged inhalation. Brief discontinuation of NO after 2 wk of hypoxia plus NO caused a rapid increase in PAP. These data demonstrate that prolonged inhalation of low concentrations of NO induces sustained pulmonary vasodilation and reduces pulmonary vascular remodeling in response to chronic hypoxia.
Administration, Inhalation↗
[Nitric oxide, from vascular physiology to therapeutics].
Nitric oxide (NO) synthesised by endothelial cells, plays a key role in the control of vascular tone. Its synthesis from L-arginine is assured by NO-synthase, the activity of which is dependent on intracellular calcium concentrations, which are themselves modulated by pharmacological (acetylcholine, serotonin, bradykinin...) or physical factors (shearing forces exerted by blood flow). NO acts by stimulating a soluble guanylate-cyclase of the smooth muscle cells in the vessel wall. Its vasodilator effect is therefore mediated by an increase in intracellular cyclic GMP concentration. The synthesis or liberation of NO by the endothelium may be decreased or abolished during many pathological processes (hypercholesterolaemia, atherosclerosis, systemic or pulmonary hypertension...). The significance of this abnormality of NO-mediated endothelium-dependent vasodilation in different pathological conditions has not been established. However, it is probably significant in view of the different properties of NO: vaso-relaxation, antiaggregant and inhibition of vascular smooth muscle growth. It is not yet known whether this abnormality is a cause or a consequence of the underlying disease. From the therapeutic point of view, NO is an active metabolite of nitrate derivatives, sodium nitroprussiate and molsidomine which therefore share the same mode of action as the so-called "endothelium-dependent" vasodilatoe agents. The inhalation of NO, which is increasingly used in neonatal and adult intensive care units, is an alternative therapeutic approach in many conditions associated with pulmonary hypertension.
Administration, Inhalation↗
Early radionuclide detection of intrapulmonary shunts in children with liver disease.
UNLABELLED: In order to detect and quantify intrapulmonary shunts in children with liver disease, a radionuclide method was developed and evaluated in such a population. METHODS: We studied 135 children in whom the severity of liver disease, in most cases, justified consideration of liver transplantation. Patients were separated into two groups according to their resting PaO2 values under room air: 109 children were normoxic and 26 were hypoxic. A radionuclide scan was performed immediately after intravenous injection of human albumin macroaggregates. Activity of the lungs (L) and brain (B) was counted. A shunt index (SI) was calculated as SI = 100.B/L. We compared this index with blood gases and clinical follow-up. RESULTS: In the normoxic group, SI was 0.43 +/- 0.30 (mean +/- s.d.); none of the 102 children with SI < 1 developed hypoxemia during their follow-up. Two of the six children with SI > 1 developed subsequent hypoxemia. In the hypoxic group, the nine children with SI < 1 did not aggravate their hypoxemia during follow-up. The 17 hypoxic children with SI > 1 later developed severe hypoxemia. CONCLUSIONS: Scintigraphy with intravenous human albumin macroaggregates is more accurate than measuring arterial blood gases to detect IPS in children with cirrhosis.
Arteriovenous Fistula↗
Loss of endothelium-dependent relaxation in proximal pulmonary arteries from rats exposed to chronic hypoxia: effects of in vivo and in vitro supplementation with L-arginine.
To explore endothelium-dependent relaxation and the L-arginine (L-ARG)-nitric oxide (NO) pathway during chronic hypoxia, we examined isolated rings from large conduit pulmonary arteries and aorta from rats exposed to either room air (N), 3-week hypoxia (H), or 3-week H followed by 72-h recovery to normoxia (room air). We examined the vasodilatory actions of acetylcholine (ACh), ionophore A23187, and endothelin-3 (ET-3) on extrapulmonary left and right branches of pulmonary arteries and thoracic aorta precontracted by phenylephrine (PE 10(-6) M). Endothelium-dependent relaxation of N rat pulmonary arteries and aorta to ACh and A23187 was abolished in the presence of L-NG nitroarginine methyl ester (L-NAME 10(-4) M) or methylene blue (MB 10(-5) M) but was suppressed only partially by NG-monomethyl-L-arginine (L-NMMA 5 x 10(-4) M). In pulmonary arteries but not in aorta, ET-3 induced endothelium-dependent relaxation that was suppressed by L-NAME, MB, and L-NMMA. Pulmonary arteries from H rats did not relax with ET-3. As compared with those of N rats, they exhibited less relaxation to ACh and A23187, (47 +/- 3 vs. 89 +/- 2 and 53 +/- 2 vs. 85 +/- 4%, p < 0.001, respectively) but exhibited similar relaxation to the nonendothelium-dependent vasodilator linsidomine. In contrast, endothelial-relaxation did not differ between N and H rat aorta.2+ pretreatment with L-ARG.
Acetylcholine↗
Cardiopulmonary and carotid baroreflex control of splanchnic and forearm circulations.
The objective was to determine whether a rise in carotid sinus transmural pressure by neck suction (NS) would counteract vasoconstriction secondary to inhibition of discharge of arterial and cardiopulmonary baroreceptors by simultaneous lower body negative pressure (LBNP). NS alone was applied to seven normal human subjects at -40 mmHg for 400-600 ms at each heartbeat during a 6-min period. NS reduced mean arterial pressure (MAP) from 94 +/- 6 to 86 +/- 9 mmHg and heart rate (HR) from 64 +/- 5 to 60 +/- 4.7 beats/min but did not affect vascular resistance in the splanchnic region (flow by constant infusion of indocyanine green; assumed constant extraction) or in the forearm (venous occlusion plethysmography). The same NS stimulus was applied during 23 min of continuous LBNP at -40 mmHg. LBNP alone before NS significantly reduced central venous pressure (CVP) from 5 +/- 0.3 to 1 +/- 0.5 mmHg and raised splanchnic (+34%) and forearm (+70%) vascular resistances and HR (from 64 to 74 beats/min) without reducing MAP. NS plus LBNP reduced MAP from 103 +/- 8 to 95 +/- 6 mmHg and HR from 74 +/- 6 to 67 +/- 5 beats/min without changing CVP but did not alter vascular resistances, which remained elevated and constant throughout LBNP before and after NS. Increments in plasma concentrations of renin (240%), aldosterone (70%), epinephrine (112%), and norepinephrine (46%) accompanied LBNP and NS; a separate influence of NS was not discernible. We conclude that vasoconstriction in response to combined cardiopulmonary and aortic inhibition is not overpowered by carotid sinus stimulation.
Adult↗
Dilator effect of endothelins in pulmonary circulation: changes associated with chronic hypoxia.
To investigate dilator effects of endothelins (ETs) on the pulmonary circulation and possible changes induced by chronic hypoxia, we examined vascular responses to ET-1 and ET-3 as well as ET binding to receptor subtypes ETA and ETB in the lungs from rats exposed to either room air (controls), hypoxia (10% O2) for 3 wk (3 WH), or 3 WH followed by recovery to room air (3 WH+R). In controls, both ETA and ETB receptor binding was present in smooth muscle of airways and vessels. Infusion of ET-1 or ET-3 (3-100 pM) to isolated perfused lungs preconstricted by U-46619 produced dose-dependent vasodilation with a greater potency of ET-3 (P < 0.01). The vasodilator responses to ET-1 and ET-3 were potentiated by the cyclooxygenase blocker meclofenamate (3 x 10(-6) M) or by the thromboxane synthetase inhibitor R-68070. In meclofenamate-treated lungs, the vasodilator responses to ET-1 and ET-3 remained unaffected by the inhibitor of nitric oxide synthesis, NG-monomethyl-L-arginine (5 x 10(-4) M) or by the guanylate cyclase inhibitor, methylene blue (10(-4) M). Conversely, the K+ channel blockers glibenclamide (10(-4) M) and tetraethylammonium (10(-4) M) attenuated the vasodilator responses to both ET-1 and ET-3. The selective ETA receptor antagonist BQ-123 did not alter ET-induced vasodilation, whereas it attenuated ET-induced vasoconstriction. Vasodilation to both ET-1 and ET-3 was abolished in lungs from 3 WH rats (P < 0.01) but was fully restored in lungs from 3 WH+R rats. Pulmonary vasodilation induced by the K+ channel opener pinacidil, which was suppressed by glibenclamide, did not differ between controls and 3 WH rat lungs. We found no change in ETA and ETB receptor binding from pulmonary vessels in H rat lungs compared with controls. In conclusion, endothelin-induced pulmonary vasodilation which may involve activation of K+ channels is abolished during chronic hypoxia. This abolition does not appear to be related to alterations in ET-receptor subtypes or to unresponsiveness of K+ channels in the pulmonary circulation.
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗