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J Baribeau

Publications and source records attributed to J Baribeau.

At least 19 recordsLinked to original sources
PubMed2001

Role of protein kinase C and phosphatases in the pulmonary vasculature of neonatal piglets.

OBJECTIVE: Persistent pulmonary hypertension of the newborn is characterized by the presence of intense vasoconstriction and vascular remodeling. Protein tyrosine phosphorylation has been recognized as a critical regulatory element in signal transduction, because it is dynamically regulated by the opposing actions of protein tyrosine kinases and protein tyrosine phosphatases. The objectives of this study were to investigate the role of protein kinase C and phosphatases in the neonatal pulmonary vasculature of normoxic and chronically hypoxic piglets. DESIGN: Prospective, randomized, unblinded study. SETTING: Hospital research laboratory. SUBJECTS: Newborn Yorkshire-Landrace piglets. INTERVENTIONS: Normoxic animals were 3-6 days old. Hypoxic animals were exposed to hypoxia (Fio2 0.10) between 1 and 15 days of age to induce pulmonary hypertension and then were studied. MEASUREMENTS AND MAIN RESULTS: In isolated perfused lungs from normoxic piglets, we measured the perfusion pressure to assess the vasoconstrictor response to protein kinase C activation with phorbol 12,13-dibutyrate or 1-oleyl-2-acetyl-glycerol. We also assessed the effect of protein kinase C inhibition with staurosporine (2 x 10-6M) and chelerythrine (5 x 10-5M) on endothelin-1-induced pulmonary vasoconstriction. We then examined the effect of chelerythrine and phosphatase inhibition with phenylarsine oxide on the baseline perfusion pressure of normoxic and chronically hypoxic piglets. Phorbol 12,13-dibutyrate and 1-oleyl-2-acetyl-glycerol caused a sustained, dose-dependent increase in perfusion pressure, with relative potencies about 100- and 1000-fold less than endothelin-1, respectively. Protein kinase C inhibitors, chelerythrine and staurosporine, decreased the constrictor response to endothelin-1. Chelerythrine did not affect baseline perfusion pressure in the normoxic animal, whereas it lowered pulmonary vascular tone in chronically hypoxic animals. With respect to phosphatases, phenylarsine oxide significantly increased perfusion pressure in normoxia as well as in hypoxia. CONCLUSIONS: These findings confirm that protein kinase C activation causes sustained vasoconstriction in the neonatal pulmonary vasculature and mediates the vasoconstrictor action of potent peptides, like endothelin-1. These findings also confirm that protein kinase C activation could be induced by hypoxic exposure in the neonatal piglet pulmonary vasculature. Phosphatases appear to modulate pulmonary vascular tone in the normoxic and hypoxic newborn piglet.

Analysis of Variance↗
PubMed2001

TBC3711, an ET(A) receptor antagonist, reduces neonatal hypoxia-induced pulmonary hypertension in piglets.

The pulmonary vasculature of newborns with persistent pulmonary hypertension is characterized by active vasoconstriction and vascular remodeling. It has been suggested that endothelin-1 (ET-1), a potent vasoconstrictor and growth promoter, may be involved in the pathogenesis of persistent pulmonary hypertension of the newborn. To determine whether treatment with an ET(A) receptor antagonist can reverse pulmonary hypertension in the neonate, 1-d-old piglets were exposed to hypoxia for 3 d to induce pulmonary hypertension and then treated for the remainder of the 14 d with an orally active, nonpeptidic ET(A) antagonist (TBC3711, 22 mg x kg(-1) x d(-1)). At the end of the exposure, Hb, pulmonary artery pressure, right ventricle to left ventricle plus septum weight ratio, percentage wall thickness, ET-1 circulating levels, perfusion pressure, and dilator response to the nitric oxide (NO) donor, SIN-1 (3-morpholinosydnonimine-N-ethylcarbamide) in isolated perfused lungs were determined. Exhaled NO and hemodynamic variables were also examined in an intact anesthetized animal preparation that had undergone the same treatment. By 3 d of exposure to hypoxia, piglets had already developed significant pulmonary hypertension as estimated by their pulmonary artery pressure (24.0 +/- 1.3 mm Hg versus 14.2 +/- 3.4 mm Hg) and percentage wall thickness (26.6 +/- 5.9% versus 18.7 +/- 2.4% for vessels 0-30 microm). Whereas further exposure to hypoxia for 14 d did not enhance the increase in pulmonary artery pressure and percentage wall thickness, it did augment the right ventricle to left ventricle plus septum weight ratio (0.71 +/- 0.09 versus 0.35 +/- 0.01). ET-1 circulating levels were increased only when exposure to hypoxia was prolonged to 14 d (5.1 +/- 2.4 pg/mL versus 1.0 +/- 0.4 pg/mL). Treatment with TBC3711 from d 3 to d 14, once pulmonary hypertensive changes were established and while hypoxic exposure persisted, caused significant reduction in the right ventricle to left ventricle plus septum weight ratio (0.60 +/- 0.06), pulmonary artery pressure (20.0 +/- 4.8 mm Hg), and percentage wall thickness (18.5 +/- 3.3%) and restored the dilator response to the NO donor SIN-1. Prolonged hypoxia markedly reduced exhaled NO concentrations (0.3 +/- 0.6 ppb), although treatment of hypoxic animals with TBC3711 restored the concentration of exhaled NO (4.4 +/- 2.8 ppb) to the level of normoxic controls (4.9 +/- 3.0 ppb). Lastly, treatment with TBC3711 increased ET-1 circulating levels in both the normoxic (5.4 +/- 2.8 pg/mL) and hypoxic (13.0 +/- 6.3 pg/mL) groups. In conclusion, the specific ET(A) receptor antagonist, TBC3711, can significantly ameliorate the morphologic changes encountered in hypoxia-induced pulmonary hypertension in the newborn piglet and may improve the dilator response to NO.

Animals↗
PubMed2000

Decreased synthesis and vasodilation to nitric oxide in piglets with hypoxia-induced pulmonary hypertension.

Nitric oxide (NO) is thought to play an important role in the regulation of neonatal pulmonary vasculature. It has been suggested that neonates with pulmonary hypertension have a defective NO pathway. Therefore, we measured in 1-day-old piglets exposed to hypoxia (fraction of inspired O(2) = 0.10) for 3 or 14 days to induce pulmonary hypertension 1) the activity of NO synthase (NOS) via conversion of L-arginine to L-citrulline and the concentration of the NO precursor L-arginine in isolated pulmonary vessels, 2) the vasodilator response to the NO donor 3-morpholinosydnonimine-N-ethylcarbamide (SIN-1) and the cGMP analog 8-bromo-cGMP in isolated perfused lungs, and 3) the production of cGMP in response to SIN-1 in isolated perfused lungs. After 3 days of exposure to hypoxia, endothelial NOS (eNOS) activity was unaffected, whereas, after 14 days of hypoxia, eNOS activity was decreased in the cytosolic fraction of pulmonary artery (P < 0.05) but not of pulmonary vein homogenates. Inducible NOS activity was decreased in the cytosolic fraction of pulmonary artery homogenates after both 3 (P < 0.05) and 14 (P < 0.05) days of hypoxia but was unchanged in pulmonary veins. Pulmonary artery levels of L-arginine were unaffected by hypoxic exposure. After 3 days of exposure to hypoxia, the reduction in the dilator response to SIN-1 (P < 0.05) coincided with a decrease in cGMP production (P < 0.005), suggesting that soluble guanylate cyclase activity may be altered. When the exposure was prolonged to 14 days, dilation to SIN-1 remained decreased (P < 0.05) and, although cGMP production normalized, the dilator response to 8-bromo-cGMP decreased (P < 0.05), suggesting that, after prolonged exposure to hypoxia, cGMP-dependent mechanisms may also be impaired. In conclusion, neonatal hypoxia-induced pulmonary hypertension is associated with multiple disruptions in the NO pathway.

Animals↗
PubMed1999

Vasoconstrictor effect of endothelin-1 in human skin: role of ETA and ETB receptors.

The aim of this project was to investigate the role of ETA and ETB receptors in the mediation of endothelin (ET)-1-induced vasoconstriction in human skin. This information should provide important insights into the design of pharmacological intervention against skin vasospasm induced by ET-1 in peripheral vascular disease or surgical trauma. Vasoconstriction in response to intra-arterial drug infusion in isolated perfused human skin flaps (8 x 18 cm) derived from dermolipectomy specimens was assessed by studying changes in skin perfusion and perfusion pressure under constant flow rate in each drug treatment (n = 4). It was observed that ET-1 (10(-10) to 10(-8) M) and norepinephrine (NE, 10(-8) to 10(-5) M) caused skin vasoconstriction in a concentration-dependent manner, with the vasoconstrictor potency of ET-1 approximately 200-fold higher than NE. The ETA-receptor antagonist BQ-123 but not the ETB-receptor antagonist BQ-788 blocked the vasoconstrictor effect of ET-1. This observation was confirmed by studying skin perfusion using the dermofluorometry technique. In addition, ETB-receptor agonists BQ-3020 and sarafotoxin S6c (10(-9) to 10(-6) M) did not evoke skin vasoconstriction. BQ-3020 also did not elicit skin vasoconstriction even in the presence of 10(-5) M of Nomega-nitro-L-arginine methyl ester and indomethacin. Furthermore, results from saturable and competitive ET-1 radioligand membrane receptor binding assays revealed that high-affinity and capacity binding sites are predominantly the ETA receptor subtype in endothelium-denuded skin arteries and veins of 0.5-1.5 mm diameter, with an ETA-to-ETB receptor ratio of 83:17 in arteries (n = 5) and 78:22 in veins (n = 7). Results from the present functional and radioligand receptor binding studies clearly indicate that ET-1 is a very potent vasoconstrictor in human skin and its vasoconstrictor effect is primarily mediated by ETA receptors, with no significant participation from ETB receptors.

Adult↗
PubMed1997

Ketamine increases the amplitude of the 40-Hz auditory steady-state response in humans.

The auditory middle latency response (AMLR) and the 40-Hz auditory steady-state response (40-Hz ASSR) are evoked potentials which possibly arise from the same generators in the primary auditory cortex. Both responses are attenuated by most general anaesthetics. Ketamine, however, has been reported to have no effect on the AMLR. Our aim was to evaluate the effects of ketamine on the 40-Hz ASSR. Spectral analysis of the electroencephalogram (EEG) was also conducted to independently examine the effects of ketamine. Ketamine 1.5 mg kg-1 was given to 12 patients for induction of general anaesthesia. Recordings of the 40-Hz ASSR and EEG were obtained every minute from 3 min before administration of ketamine to 5 min after injection, when the study was terminated. Similar recordings were obtained in three control subjects under identical conditions except that no medication was administered. Consciousness, defined as responsiveness to verbal commands, was assessed before each recording. Ketamine caused an increase in the amplitude of the 40-Hz ASSR (P < 0.01). Using published AMLR data, we conducted a simulation experiment that suggested that the effect of ketamine on the AMLR can explain its effects on the amplitude of the 40-Hz ASSR. There was a pronounced increase in relative theta (3.9-7.9 Hz) EEG power and a decrease in relative alpha (8.0-12.8 Hz) power (P < 0.001). These changes were not observed in the control group. Ketamine produced unconsciousness until the end of the study in five patients and transient unconsciousness in five patients. Two patients did not lose consciousness after administration of ketamine. The 40-Hz ASSR and EEG revealed no consistent differences between conscious and unconscious patients. No relationship could be demonstrated between the increase in amplitude of the 40-Hz ASSR or of relative theta power (the hallmark of ketamine effect) and loss of responsiveness to commands. We conclude that ketamine, unlike other anaesthetics, increases the amplitude of the 40-Hz ASSR.

Acoustic Stimulation↗
PubMed1997

ANF system in the newborn piglet pulmonary vessels.

The atrial natriuretic factor (ANF) induces diuresis, natriuresis, and vasodilation. Although it was originally found to be secreted from the atria, ANF synthesis has been demonstrated in other organs. The adult lung is not only the first target organ for ANF, but it also expresses the ANF gene and synthesizes, releases, and clears ANF from the circulation. We have shown the presence of ANF in human fetal lungs and also demonstrated that these lungs can release bioactive ANF. However, the role of the ANF system in the newborn lung is unknown. Therefore we studied the ANF system in pulmonary vessels (arteries and veins dissected from the hilum down to a 100-microm diameter), in isolated perfused lungs, and in the plasma from pulmonary artery and vein of 1- and 7-day-old piglets. High-performance liquid chromatography (HPLC) revealed the presence of both the mature peptide and the ANF prohormone in pulmonary vein microsomes, but in pulmonary arteries, only the mature form was identified. Furthermore, in the veins, the ANF content tended to be higher in 7- than in 1-day-olds. ANF caused a dose-dependent decrease in perfusion pressure (p < 0.05). In veins and arteries, most of the ANF receptors were of the type A guanylate cyclase as opposed to clearance receptors. Interestingly, the ANF receptors were fewer in veins, where synthesis takes place, than in arteries (p < 0.05). Significant circulating ANF plasma levels were measured by radioimmunoassay in both pulmonary artery and vein. However, there was no site difference in ANF plasma levels, suggesting that ANF is cleared and synthesized in the pulmonary vessels. In conclusion, the entire ANF system is present in the newborn piglet pulmonary vessels. The paucity of clearance receptors compared with functional receptors potentiates the role of ANF in the regulation of postnatal pulmonary vascular resistance.

Animals↗
PubMed1997

Endothelin receptor changes in hypoxia-induced pulmonary hypertension in the newborn piglet.

Endothelin (ET)-1, a potent vasoconstrictor and mitogen, acts through ETA and ETB receptors and may be involved in the pathogenesis of persistent pulmonary hypertension of the newborn. We hypothesized that hypoxia-induced pulmonary hypertension in the newborn is associated with increased ET-1 release and modified ET receptor characteristics leading to vasoconstriction and vascular remodeling. Therefore, we studied 1-day-old piglets exposed for 3 or 14 days to hypoxia (fraction of inspired O2 = 0.10) or normoxia (controls). ET-1 circulating levels in pulmonary artery and vein were measured. Pulmonary vascular reactivity to ET-1 was evaluated using isolated-perfused lungs. ET binding characteristics were examined in microsomes from pulmonary arteries (down to 100 microns). ET-1 circulating levels are low and are not altered by hypoxia. The magnitude of the initial dilator response to ET-1 decreases after 3 days of hypoxia (P < 0.05), whereas the number of ETB receptors is reduced by 40% in the pulmonary arteries (P < 0.05). ETA receptors are predominant (65-90%) in pulmonary arteries. ETA receptors decrease by 50% after 14 days of exposure to hypoxia (P < 0.05), whereas the constrictor response to ET-1 remains unchanged. The fact that the reduction in vasodilator response parallels the decrease in ETB receptors suggests a decrease in receptor expression. We speculate that the maintenance of the vasoconstrictor response to ET-1 despite a reduction in the number of binding sites is likely due to receptor occupancy. In conclusion, in the newborn piglet pulmonary vasculature, ETA and ETB receptors may be affected differently by hypoxia.

Animals↗
PubMed1997

Reduced vasodilator response to ANF in hypoxia-induced pulmonary hypertension in the newborn piglet.

Recent evidence suggests that, in adult animals with hypoxia-induced pulmonary hypertension, atrial natriuretic factor (ANF) may modulate pulmonary vascular tone and may have a protective effect. However, its role in the pathogenesis of pulmonary hypertension of the newborn is unknown. We hypothesized that, in the newborn, hypoxia-induced pulmonary hypertension would result in ANF receptor downregulation, resulting in decreased dilator response, favoring pulmonary vasoconstriction and vascular remodeling. Therefore, we studied, in 1-day-old piglets exposed to hypoxia (fraction of inspired O2 0.10) for 3 or 14 days to induce pulmonary hypertension, 1) ANF release by measuring circulating levels of ANF by radioimmunoassay in pulmonary artery and veins, 2) pulmonary vascular reactivity to ANF using isolated perfused lungs, and 3) binding characteristics by examining the concentration dependence of ANF binding and competitive binding of 125I-labeled ANF with ANF, brain natriuretic peptide, C-type natriuretic peptide, and the specific ligand for ANF clearance receptor on microsomes from pulmonary arteries (down to 100 microns). ANF circulating levels are increased after exposure to hypoxia compared with normoxia, reaching significance at 14 days (P < 0.005). The magnitude of ANF dilator response is diminished after exposure to hypoxia (P < 0.05). Saturation studies reveal that the number of ANF receptors is diminished in hypoxia after 3 days but reaches significance after 14 days (P < 0.01) compared with their respective normoxic control. At either condition, the majority of these receptors are of the functional type, whereas clearance receptors are virtually undectable. These results suggest that hypoxia increases circulating ANF and causes a decreased responsiveness of the pulmonary vasculature to ANF. Receptor down-regulation may explain part of the reduced dilator response, although the involvement of other mechanisms is not excluded.

Animals↗
PubMed1996

Performance of subclinical compulsive checkers on putative tests of frontal and temporal lobe memory functions.

Previous research suggests that compulsive checking is associated with a deficit in memory for actions. In addition, evidence indicates frontal lobe involvement in both obsessive-compulsive disorder and in the monitoring of self-ordered actions. We examined the relationship between compulsive checking and performance on tests putatively related to frontal and temporal lobe memory functions. Subjects consisted of two groups of 14 university students identified as checkers or noncheckers according to the checking subscale of the Maudsley Obsessional-Compulsive Inventory. Checkers demonstrated significantly poorer ability to monitor their responses on the frontal task and a trend toward better long-term visuospatial memory. When the effect of trait anxiety was controlled for, the frontal effect was reduced to a trend, but the visuospatial memory advantage was enhanced. Although both a frontal deficit and enhanced long-term visuospatial memory may contribute to compulsive checking, trait anxiety seems to play a moderating role.

Adult↗
PubMed1995

Characterization of endothelin receptors in newborn piglet lung.

Endothelins (ET-1, ET-2, and ET-3) cause dilation and constriction as a result of binding to different ET receptors. ETA receptor is responsible for the vasoconstrictor response, while ETB receptors lead to vasodilation (ETB1) or vasoconstriction (ETB2). Although the effects of ETs have been described in the neonatal pulmonary vasculature, ET receptors have not been characterized extensively. Therefore, in newborn piglets we aimed to characterize ET receptors by studying 1) in isolated perfused lungs the effects of ET-1, ET-3, and the ETB receptor agonists sarafotoxin S6c (S6c) and BQ-3020 on perfusion pressure with or without an ETA antagonist, BQ-123, or an ETB1 antagonist, RES-701-1, and 2) the concentration-dependence of ET-1 and ET-3 on their binding to microsomes from arteries and veins of piglet lungs. ET-1, ET-3, S6c, and BQ-3020 cause an early-onset dilation followed by a late-onset constriction. The dilator response to ET-3 is blunted by RES-701-1 (P < 0.005), while the inhibition of the dilator response of ET-1 almost reaches significance (P = 0.06). BQ-123 inhibits incompletely (P < 0.05) the constrictor response to ET-1, while it does not alter the response to ET-3. This suggests that constriction may follow binding to ETA as well as ETB2 receptors. Binding studies reveal that ET receptors are abundant in pulmonary vessels. ETA receptors are predominant, but ETB1 and likely ETB2 receptors are also present. Also, receptor affinities are higher in veins than in arteries.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗