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M Clozel

Publications and source records attributed to M Clozel.

86 records · Page 5Linked to original sources
PubMed1989

Human cultured endothelial cells do secrete endothelin-1.

Endothelin-1 (ET-1) has been identified in the conditioned medium of porcine endothelial cells. Human endothelin (ET-1) cloned from a placenta cDNA library is similar to porcine, but it is not known whether endothelin itself is secreted by human endothelial cells. To answer this question, a conditioned medium taken every 48 h from confluent cultures of umbilical vein endothelial cells was analyzed by HPLC and all fractions were tested for their ability to inhibit [125I]ET-1 binding on human placenta membranes. Only one fraction did inhibit [125I]ET-1 binding. When the conditioned medium was spiked with ET-1, the same single fraction inhibited [125I]ET-1 binding showing that ET-1, itself, is present in the conditioned medium of human endothelial cells. ET-1 accumulates with time, reaching a plateau at 48 h. ET-1 secretion is not increased by a 24-h incubation of endothelial cells with phorbol myristate acetate, interleukin-1, tumor necrosis factor, thrombin or neuropeptide Y.

Endothelins↗
PubMed1989

Effects of endothelin on the coronary vascular bed in open-chest dogs.

The goal of the present study was to evaluate the effects of endothelin, a newly discovered very potent vasoconstrictor secreted by endothelial cells, on the coronary vascular bed. For this purpose, the effects of endothelin injected intracoronarily were tested in open-chest anesthetized dogs with the circumflex coronary artery cannulated and perfused at a constant pressure of 100 mm Hg. Circumflex blood flow, transmural distribution of coronary blood flow (radioactive microspheres), circumflex coronary artery diameter (piezoelectric crystals), and circumflex luminal surface area were measured. Endothelin decreased coronary blood flow by 30% and 61% with doses of 1 and 3 micrograms, respectively. A dose of 10 micrograms was lethal. The decrease of coronary blood flow was larger in the subepicardium than in the subendocardium, which explains that the endocardial-epicardial blood flow ratio increased from 1.27 +/- 0.05 to 1.98 +/- 0.23 (p less than 0.001) with a dose of 3 micrograms endothelin. Circumflex surface area decreased by 7% (p = NS) and 20% (p less than 0.01) with doses of 1 and 3 micrograms endothelin, respectively. The action of endothelin was not modified by the concomitant alpha-adrenergic blockade, serotonergic blockade, angiotensin converting enzyme inhibition, or cyclooxygenase inhibition. We conclude that endothelin is a potent coronary vasoconstrictor with a selective effect on the subepicardium. At least part of the increase of coronary vascular resistance is due to a constriction of the large coronary arteries. Further studies are required to determine the physiopathological role of endothelin, especially in coronary vasospasm.

Animals↗
PubMed1989

Specific binding of endothelin on human vascular smooth muscle cells in culture.

Endothelin is a newly discovered, potent vasoconstrictor peptide secreted by endothelial cells. The binding of endothelin was studied on cultured human vascular smooth muscle cells obtained from umbilical veins. A single specific binding site for 125I-endothelin was identified, with an apparent Kd of 126 pM and a maximal binding capacity of approximately 10,000 sites per smooth muscle cell. At room temperature the binding was saturable, reached equilibrium at 2 h (using 20 pM endothelin), and was slowly and only partially reversed by unlabeled endothelin. The calcium antagonists nifedipine, nicardipine, and diltiazem did not compete for the same binding site. Conditioned medium from cultured human umbilical vein endothelial cells inhibited the binding of 125I-endothelin dose dependently. This effect was antagonized by anti-endothelin antiserum. We conclude that human umbilical vein smooth muscle cells possess specific binding sites for endothelin, and that human endothelial cells secrete an endothelinlike material.

Binding, Competitive↗
PubMed1989

Effects of endothelin on regional blood flows in squirrel monkeys.

Endothelin is a newly described potent vasoconstrictor produced by endothelial cells. The aim of the present study was to evaluate the effects of i.v. injection of human endothelin on regional blood flows (RBFs) and hemodynamic parameters in nonhuman primates. For this purpose, in a first series of experiments, anesthetized squirrel monkeys were instrumented with Doppler flow-probes in order to measure RBF continuously in the renal, mesenteric and iliac vascular beds. Endothelin at 0.03 and 0.1 microgram/kg produced no effect. After 0.3 and 1 microgram/kg, renal and mesenteric blood flow decreased, but iliac blood flow increased transiently. With 3 micrograms/kg all the three vascular beds were constricted. In the kidney, blood flow was almost abolished and the effect of endothelin sustained for up to 2 hr and more. In a second series of experiments, radioactive microspheres were used to measure RBFs in most organs 3 to 4 min after endothelin (0.3, 1 and 3 microgram/kg), or after vehicle alone. Endothelin induced a dose-dependent increase in systemic vascular resistance and increase in mean arterial blood pressure. The vasoconstrictor effect was selective for some vascular beds. The splanchnic vascular bed (except stomach) was most affected, with a 96% decrease in renal and splenic blood flow after 3 micrograms/kg of endothelin. The coronary blood flow decreased by 46% after 3 micrograms/kg, with a greater effect in subepicardium than subendocardium. In contrast, the blood flow to the brain and stomach was not decreased by endothelin. We conclude that endothelin is a potent vasoconstrictor in squirrel monkeys selective for some vascular beds.

Animals↗
PubMed1987

Effects of tolazoline on regional blood flows in the newborn piglet.

To assess the effects of intravenous tolazoline on hemodynamics and regional blood flow distribution, 12 anesthetized newborn piglets were studied. Six piglets received saline and served as controls, the other 6 received two bolus doses of tolazoline (1 and 2 mg/kg). Mean arterial blood pressure decreased from control levels of 69.4 +/- 5.6 to 54.6 +/- 7.0 and 47.0 +/- 5.6 mm Hg, respectively, after 1 and 2 mg/kg of tolazoline, and heart rate increased from 220 +/- 9 to 270 +/- 13 and 282 +/- 8 beats/min, respectively. Cardiac output and regional blood flows were measured 15 min after tolazoline by the radioactive microsphere technique. Cardiac index did not change significantly. There was a redistribution of cardiac output toward the coronary circulation, with an increase in coronary blood flow from a control value of 249.3 +/- 39.9 to 361.0 +/- 56.4 ml/min/100 g of tissue after 1 mg/kg of tolazoline. Bronchial blood flow was also significantly increased. After a dose of 2 but not 1 mg/kg, the renal blood flow was markedly decreased from 139.8 +/- 17.8 to 104.4 +/- 24.5 ml/min/100 g. The other regional blood flows were not significantly modified. We conclude that tolazoline is a potent coronary vasodilator during the neonatal period. In addition we speculate that the decrease in renal blood flow might play a role in the renal toxicity of tolazoline.

Animals↗
PubMed1986

Indomethacin metabolism in liver microsomes during postnatal development in the rat.

Indomethacin is now widely used during the neonatal period, but few data exist concerning its metabolism during this period. Thus, we studied the maturational changes in the metabolism of indomethacin into desmethylindomethacin by isolated liver microsomes from 1- to 60-day-old rats. From 8 days of age on, there was a progressive increase in enzymatic activity which was inversely correlated with the change in Michaelis-Menten constant. However, the maximal velocity was not significantly affected by the age. These findings suggest that the deficient metabolism of indomethacin in the newborn rat is due to decreased affinity between enzyme and substrate, or presence of competitive inhibitors. To determine the substrate specificity of the monooxygenase-catalyzing inducers, sodium phenobarbital and beta-naphthoflavone given during 3 days in neonatal rats were also studied. Although beta-naphthoflavone did not exhibit any significant effect, phenobarbital significantly increased the activity and maximal velocity of indomethacin O-demethylation.

Aging↗
PubMed1986

Effect of diltiazem on hemodynamics and regional blood flows in the newborn piglet.

The aim of our study was to evaluate the effects of the calcium antagonist diltiazem (DTZ) on hemodynamics and regional blood flows measured with radioactive microspheres during the neonatal period. For this purpose, two bolus doses (0.5 and 1 mg/kg) of intravenous DTZ were injected in six 2- to 6-day-old urethan-anesthetized piglets. Six other piglets were injected with saline and served as controls. DTZ arterial plasma concentrations measured by high-pressure liquid chromatography were 0.521 +/- 0.034 and 1.141 +/- 0.073 microgram/ml, respectively, after 0.5 and 1 mg/kg. The only significant hemodynamic effects of DTZ were a decrease in mean arterial blood pressure and in heart rate. The main effect of DTZ on regional blood flow was a striking increase in coronary blood flow (by 54%) after both 0.5 and 1 mg/kg. To a lesser extent, DTZ increased significantly the blood flow to the brain, liver, ileum, diaphragm, and lungs. In contrast, DTZ at a dose of 1 mg/kg induced a significant decrease in renal blood flow (by 37%). We conclude that DTZ in the neonatal period is a nonspecific vasodilator. However, the decrease in renal blood flow induced by a dose of 1 mg/kg might be detrimental and requires further investigation.

Animals↗
PubMed1985

Regional cerebral blood flow during bicuculline-induced seizures in the newborn piglet: effect of phenobarbital.

The changes in cerebral blood flow (CBF) during and after bicuculline-induced seizures were studied by the radioactive microsphere technique in 12 newborn, urethan-anesthetized piglets, 6 piglets pretreated with phenobarbital (10 mg/kg) and 6 without phenobarbital. The mean arterial blood pressure (MABP), PaO2, PaCO2 and the cerebral tissue pH (CtpH) were measured. CBF was increased during seizure, more in basal ganglia (98 and 106% in the control and phenobarbital group, respectively) than in brainstem, cerebellum and cortex. 15 min after seizure, CBF has returned to preseizure values. There was no significant difference at any time between the control and phenobarbital group. The increase in CBF was correlated with an increase in MABP (r = 0.753, p less than 0.01), suggesting a loss of cerebral autoregulation. CBF was significantly correlated with PaCO2 before and after seizure, but not during seizure. Finally, the increase in CBF was significantly correlated with an early increase in CtpH (r = 0.570, p less than 0.05), suggesting that brain acidosis is not involved in the pathogenesis of the increased CBF during seizures.

Acid-Base Equilibrium↗
PubMed1985

Thromboxane is not responsible for the high pulmonary vascular resistance in fetal lambs.

The factors responsible for the high pulmonary vascular resistance in the fetus are not well known. Thromboxane (TX) A2 is a potent pulmonary vasoconstrictor. To determine whether TXA2 may play a role in fetal pulmonary vasoconstriction, we infused the specific TX synthetase inhibitor U63,557A into eight chronically instrumented fetal lambs (134-137 days gestational age, full term 145 days) and measured pulmonary blood flow, pulmonary and systemic arterial pressure, and heart rate. U63,557A (3 mg/kg as a bolus then 3 micrograms/kg/min for 120 min infused in the main pulmonary artery) did not change pulmonary blood flow, pulmonary mean arterial pressure, and pulmonary vascular resistance during the infusion and during 2 h following the end of the infusion. During the infusion, TXB2 arterial plasma concentrations decreased from 106.1 +/- 17.5 to 8.7 +/- 2.9 pg/ml. In three of the fetal lambs, immediately after the 2-h infusion of U63,557A, we infused the leukotriene end-organ antagonist FPL 57231 into the main pulmonary artery (1 mg/kg/min for 60 min). TXA2 synthesis inhibition did not prevent the pulmonary vasodilation induced by FPL 57231. Pulmonary blood flow increased from 64.8 +/- 24.4 to 669.5 +/- 65.6 ml/min/100 g lung tissue during the FPL 57231 infusion. We conclude that TXA2 does not play a role in the maintenance of elevated fetal pulmonary vascular tone, either directly or as a mediator of leukotriene action.

Animals↗
PubMed1983

Effect of caffeine on thyroid and pituitary function in newborn rats.

The possibility that caffeine, a central nervous system stimulant used in neonatal apnea, may produce acute or chronic changes in growth hormone (GH), thyroxine (T4) and thyrotropin (TSH) was studied in the newborn rat. Five-day-old rats were separated into three groups: control (0) group receiving saline, Group I (low dose caffeine) receiving 5 mg/kg and Group II (high dose caffeine) receiving 50 mg/kg. Acute effects were studied at 2, 4, and 24 h after injection. Chronic effects were studied 24 h after the last of 10 daily injections. GH, T4, and TSH were measured by radioimmunoassay and caffeine by high pressure liquid chromatograph. GH was increased at all times and all doses after a single injection of caffeine. After chronic therapy, the increase in GH was small, suggesting depletion of pituitary reserve. A high dose of caffeine had a biphasic effect on T4 with an increase at 4 h and a decrease at 24 h. Thyrotropin-releasing hormone (TRH)-induced TSH release at 24 h was not influenced by caffeine administration. Chronic caffeine therapy stimulated both T4 and TSH; however, TRH-stimulated TSH release was decreased, suggesting that chronic therapy may blunt pituitary TSH response.

Animals↗
PubMed1981

Adverse effects of caffeine and theophylline in the newborn infant.

The desirable effects of methylxanthine use in the neonate, appropriately prescribed and monitored, outweigh the importance of adverse effects. This view assumes that pharmacologic manipulation of apnea of prematurity is in itself a desirable goal and clearly superior to treatment of apneic episodes when they occur. While a considerable body of evidence supports this current practice, conclusive documentation awaits long-term follow-up studies.

Apnea↗
PubMedDate not supplied

Effect of seizures on brain phenobarbital concentration in newborn piglets.

Phenobarbital (PB) brain and blood concentrations were measured together with brain and blood pH in newborn piglets before and at the end of seizure activity induced by pentylenetetrazol or bicuculline. Seizures induced a significant elevation of arterial blood pressure and profound changes in the blood gases and in the acid-base balance, with a marked reduction in brain tissue pH. Despite an intense brain acidosis, however, and a significant rise in blood/brain [H+] gradient, phenobarbital brain concentrations were not reduced during seizures but, on the contrary, were increased in 7 of 11 piglets. These data suggest that contrary to the pH partition hypothesis, brain uptake of PB is concomitantly increased during seizures and brain acidosis.

Animals↗