Biomedical subjects

A H Stephenson

Publications and source records attributed to A H Stephenson.

52 records · Page 3Linked to original sources

PubMed1988

Relationship of leukotriene C4 and D4 to hypoxic pulmonary vasoconstriction in dogs.

Leukotrienes C4 and D4 have been implicated as possible mediators of hypoxic pulmonary vasoconstriction. To test this hypothesis, the relationship between pulmonary leukotriene (LT) synthesis in response to hypoxia and alterations in pulmonary hemodynamics was evaluated in pentobarbital sodium-anesthetized, neuromuscular-blocked, male, mongrel dogs. A reduction in the fraction of inspired O2 (FIO2) in vehicle-treated animals (n = 12) from 0.21 to 0.10 was associated with increases in LTC4 and LTD4 in bronchoalveolar lavage fluid (BALF). After 30 min of continuous hypoxia, LTC4 and LTD4 increased from control values of 59.4 +/- 10.4 and 91.7 +/- 18.1 ng/lavage to 142.7 +/- 31.8 (P less than 0.05) and 156.3 +/- 25.3 (P less than 0.01) ng/lavage, respectively. Concomitantly, mean pulmonary arterial pressure (Ppa) and pulmonary vascular resistance (PVR) were increased over control by 67 +/- 7 (P less than 0.001) and 62 +/- 7% (P less than 0.001), respectively. In contrast, in animals treated with diethylcarbamazine (n = 5), a leukotriene A4 synthase inhibitor, identical reductions in FIO2 were not associated with increases in LTC4 and LTD4 in BALF, although at the same time period, Ppa and PVR were increased over control by 60 +/- 13 (P less than 0.05) and 112 +/- 31% (P less than 0.05), respectively. These results, therefore, do not support the contention that leukotrienes mediate hypoxic pulmonary vasoconstriction in dogs.

Animals↗

PubMed1988

Increased concentrations of leukotrienes in bronchoalveolar lavage fluid of patients with ARDS or at risk for ARDS.

The sulfidopeptide leukotrienes (LT) C4 and D4 have been reported to promote the formation of pulmonary edema when administered into the pulmonary circulation of laboratory animals. As a first step in the evaluation of the hypothesis that these leukotrienes participate in the edema formation of the adult respiratory distress syndrome (ARDS), we investigated whether LTC4 and LTD4 were present in the bronchoalveolar lavage (BAL) fluid of patients with ARDS compared to nonsmoker control subjects and to patients with acute respiratory failure exhibiting no radiographic evidence of widespread pulmonary infiltrates but having a clinical predisposition for developing ARDS, i.e., the "at risk" group. Bronchoscopic lavage was performed with sterile 0.9% NaCl on 32 control subjects, nine patients with ARDS, and nine patients "at risk" for ARDS. Leukotrienes were measured in BAL fluid by radioimmunoassay after methanol extraction and HPLC purification of a 20-ml aliquot of the BAL sample. LTC4 and LTD4 (mean +/- SE) increased from 1.1 +/- 0.2 and 1.2 +/- 0.5 ng/lavage in the BAL fluid of control subjects to 6.3 +/- 2.3 and 20.1 +/- 5.9 ng/lavage in patients "at risk" for ARDS and to 12.5 +/- 3.0 and 30.5 +/- 7.8 ng/lavage in patients with ARDS, respectively. The sulfidopeptide LTs correlated with BAL fluid protein content. These results suggest that increased amounts of LTs in BAL fluid are a general finding in patients with ARDS and those "at risk" for ARDS.

Acute Disease↗

PubMed1987

Increased leukotriene C4 in ethchlorvynol-induced acute lung injury in dogs.

We investigated whether ethchlorvynol (ECV)-induced acute lung injury (ALI) is associated with an increase in leukotriene C4 (LTC4) production. In six pentobarbital sodium-anesthetized dogs, ECV (15 mg/kg iv) introduced into the pulmonary circulation resulted in a 164 +/- 31% increase in extravascular lung water 120 min after ECV administration. Concomitantly, the mean (+/- SE) concentration of LTC4 in arterial plasma measured by radioimmunoassay following 80% EtOH precipitation, XAD-7 extraction and high-pressure liquid chromatography purification was 5.0 +/- 1.3 pg/ml, unchanged from control (pre-ECV) values. In contrast, in pulmonary edema fluid 120 min post-ECV, the LTC4 concentration was 35.2 +/- 10.8 pg/ml, sevenfold greater than those values found in the arterial plasma (P less than 0.01). In six additional dogs, 120 min after unilateral ALI had been induced with ECV (9 mg/kg iv), LTC4 in the bronchoalveolar lavage (BAL) of the uninjured lung was 12.1 +/- 1.5 pg/ml, unchanged from pre-ECV values, whereas, LTC4 in the BAL of the injured lung increased from a control value of 10.2 +/- 1.6 to 24.2 +/- 3.5 pg/ml (P less than 0.01) 120 min after ECV administration. These results demonstrate that, in ECV-induced acute lung injury, LTC4 concentrations in pulmonary edema fluid are considerably greater than those found in arterial plasma in the case of bilateral acute lung injury and significantly greater in the BAL of the injured lung compared with the uninjured lung in the case of unilateral acute lung injury. The results are a necessary first step in support of the hypothesis that leukotrienes participate in the altered permeability of ECV-induced acute lung injury.

Acute Disease↗

PubMed1987

Effects of ibuprofen on the hypoxemia of established ethchlorvynol-induced unilateral acute lung injury in anesthetized dogs.

Nonsteroidal anti-inflammatory agents, given prior to induction of unilateral acute lung injury with ethchlorvynol (ECV) in anesthetized dogs, prevent the decreases in systemic oxygen tension (PaO2) which are observed when ECV is given alone. We investigated whether ibuprofen, administered after acute lung injury, would result in improvement in arterial oxygenation. In animals not receiving ibuprofen after unilateral acute lung injury with ECV, PaO2 decreased and venous admixture increased significantly from control values at all experimental time-periods. In those animals receiving ibuprofen, significant decreases in venous admixture were noted. The decrease in PaO2 after ECV administration was significantly less than that observed in animals that did not receive ibuprofen after acute lung injury (p less than 0.05). Ibuprofen had no effect on extravascular lung water. These results demonstrate that in an ECV model of acute lung injury the administration of ibuprofen, after the acute lung injury, results in significant decreases in venous admixture.

Animals↗

PubMed1986

Effect of cyclooxygenase inhibition on ethchlorvynol-induced acute lung injury in dogs.

In anesthetized dogs ethchlorvynol (ECV, 9 mg/kg) was selectively administered into the right pulmonary circulation to produce unilateral acute lung injury (ALI) characterized by nonhydrostatic pulmonary edema and systemic hypoxemia. To investigate the hypothesis that products of cyclooxygenase activity are mediators of the arterial hypoxemia, but not the edema formation in this injury, animals were pretreated with one of two chemically dissimilar cyclooxygenase inhibitors, indomethacin (5 mg/kg), or ibuprofen (12.5 mg/kg), or vehicle (0.1 M sodium carbonate) prior to the administration of ECV. Pretreatment with either inhibitor prevented the ECV-induced systemic hypoxemia observed in animals pretreated with vehicle (P less than 0.01). Despite this protection of systemic oxygenation, there was no redistribution of blood flow to the uninjured lung following unilateral ECV administration. Cyclooxygenase inhibition prior to ALI did not attenuate the accumulation of lung water. In the ibuprofen group, left atrial pressure increased significantly following ECV administration. We conclude that a product(s) of cyclooxygenase-mediated arachidonic acid metabolism is responsible for the altered vascular reactivity and consequent systemic hypoxemia in this model, but that the edema formation following ECV is not related to cyclooxygenase activity. In addition, ibuprofen, administered prior to the induction of ALI, exhibits properties not shared by indomethacin but is not different in its capacity to attenuate hypoxemia or in its failure to limit edema formation.

Animals↗

PubMed1984

Prostaglandin I2 supports blood flow to hypoxic alveoli in anesthetized dogs.

In an animal model of unilateral alveolar hypoxia, inhibition of cyclooxygenase activity, estimates of immunoreactive 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha), and administration of prostaglandin I2 (PGI2) were used to evaluate the hypothesis that endogenous PGI2 opposes hypoxic pulmonary vasoconstriction, thereby producing redistribution of blood flow to hypoxic alveoli and reductions in systemic PO2. In anesthetized dogs, one lung was ventilated with 100% N2 and the other with 100% O2. Thermal dilution coupled with electromagnetic flow measurements permitted estimates of blood flow to each lung. Indomethacin or meclofenamate reduced flow to the N2-ventilated lungs (P less than 0.05) and increased systemic PO2 (P less than 0.05). Simultaneously, aortic concentrations of immunoreactive 6-keto-PGF1 alpha decreased 63 +/- 8% (P less than 0.001). Following cyclooxygenase inhibition, incremental doses of PGI2 (0.01, 0.025, and 0.10 micrograms X kg-1 X min-1) increased flow to the N2-ventilated lungs and reduced systemic PO2 (P less than 0.001) without affecting mixed venous PO2. These results suggest that systemic PO2 was reduced because of increased venous admixture. We conclude that PGI2 attenuates hypoxic vasoconstriction which allows flow to be maintained to hypoxic alveoli, resulting in reduced systemic PO2.

Animals↗

PubMed1984

Unilateral acute lung injury induced by ethchlorvynol in anesthetized dogs.

Ethchlorvynol (ECV) was used to induce unilateral acute lung injury in anesthetized dogs. Measurements of extravascular thermal volume by double-indicator (thermal-dye) dilution with and without left main pulmonary arterial occlusion permitted sequential estimates of extravascular lung water (EVLW) for each lung. Determinations of EVLW by thermal-dye and gravimetric methods were highly correlated (r = 0.80). ECV (9-15 mg/kg) administered into the right pulmonary circulation produced progressive increases in right lung EVLW, which by 120 min post-ECV was increased 152 +/- 22% (SE) over control (P less than 0.001). Left lung EVLW remained unchanged. Similarly, right, but not left, peak airway pressure was increased. Thermal dilution, coupled with electromagnetic methods, permitted estimates of blood flow to each lung. Despite redistribution of flow to the uninjured lung, systemic PO2 decreased (P less than 0.001) and venous admixture increased (P less than 0.05), suggesting impaired matching of ventilation and perfusion. In summary, introduction of ECV into one lung produced unilateral acute lung injury. EVLW increased solely in the injured lung as did peak airway pressure. Although there was a partial redistribution of blood flow away from the injured lung to the uninjured one, it was apparently inadequate to prevent impaired oxygenation of the blood.

Animals↗

PubMed1984

Differential response of the pulmonary circulation to prostaglandins E2 and F2 alpha in the presence of unilateral alveolar hypoxia.

Pulmonary hemodynamic responses to several prostaglandins (PGs) are augmented by hypoxia. To test whether responses to vasoconstrictor PGs would be enhanced in hypoxic areas of the lung, resulting in redistribution of blood flow to well-oxygenated areas, the effects of PGE2 and PGF2 alpha were evaluated in anesthetized dogs with divided ventilation, one lung being ventilated with 100% N2 and the other with 100% O2. Thermal dilution techniques coupled with electromagnetic flow measurements permitted estimates of blood flow to each lung. After indomethacin (5 mg/kg i.v.), PGE2 at 0.01, 0.025 and 0.10 micrograms/kg/min i.v. produced significant increases in flow to the O2-ventilated lung at each dose. In addition, PGE2 increased total pulmonary blood flow, but only at the two larger doses. Concomitantly, systemic arterial PO2 increased from 104 +/- 21 to 138 +/- 26 mm Hg (P less than .001). Identical results were obtained when meclofenamate (5 mg/kg i.v.) was used to block PG synthesis. PGF2 alpha increased total pulmonary blood flow (P less than .01) only at the largest dose (0.10 micrograms/kg/min), but did not redistribute flow or increase PO2. Atrial pacing increased total pulmonary blood flow (P less than .001) and flow to both O2 (P less than .001)- and N2 (P less than .05)-ventilated lungs with no change in PO2. We conclude that PGE2 redistributes pulmonary blood flow to well-oxygenated alveoli through mechanisms not related solely to its vasoconstrictor properties or to its capacity to increase cardiac output.

Animals↗

PubMed1982

Effect of ventilatory rate on renal venous PGE2 and PGF2 alpha efflux in anesthetized dogs.

In anesthetized laparotomized male mongrel dogs with ventilatory rate set at 10 breath.min-1, tidal volume was adjusted so that control arterial pH and PCO2 were within the normal range for unanesthetized dogs. Control renal venous PGE2 and PGF2 alpha concentrations were comparable to those of unanesthetized dogs, namely, 57 +/- 10 and 114 +/- 18 pg.ml-1, respectively. In contrast, control arterial plasma renin activity (PRA), 6.6 +/- 1.2 ng.ml-1.h-1, was considerably greater than in unanesthetized dogs. Stepwise increases in ventilatory rate increased renal venous PGE2 and PGF2 alpha to 109 +/- 18 and 205 +/- 41 pg.ml-1, respectively. Hyperventilation reduced PCO2 and increased pH and PRA but had no effect on renal blood flow, arterial blood pressure, or arterial PGE2 and PGF2 alpha concentrations. When the ventilatory rate was returned to control levels, pH, PCO2, PRA, and renal venous PGE2 and PGF2 alpha concentrations returned to control. Ventilatory rate or some consequence of altering ventilatory rate is, therefore, a determinant of renal venous efflux of PGE2 and PGF2 alpha. Moreover, it may be a more important determinant of "resting" concentrations of prostaglandins in renal venous blood than anesthesia, laparotomy, or PRA.

Animals↗

PubMed1981

Alterations in the fraction of oxygen in inspired gas affect rates of renal prostaglandin E2 synthesis in anesthetized dogs.

Reductions of oxygen in inspired gas from 20% to 15%, in anesthetized dogs, reduced arterial PO2 and increased the renal efflux of PGE2 but not PGF2a. Renal blood flow, blood pressure, plasma renin activity as well as arterial pH and PCO2 were unaffected PGs may mediate the renal hemodynamic or excretory consequences of alterations in PO2. In addition, minor variations in PO2 might account, in part, for the variable renal venous PGE2 concentrations reported under basal conditions.

Animals↗

PubMed1978

Furosemide exhibits physicochemical properties similar to prostaglandins and interferes with their bioassay.

The parallel pharmacological assay system has been of inestimable value in the identification and quantification of prostaglandins. A greater degree of specificity is conferred on the bioassay system by the preparative techniques of extraction and chromatography, for substances which might interfere with the assay of prostaglandins are usually eliminated by these procedures. It would be highly unlikely for a substance to survive the extraction procedure, to exhibit chromatographic properties similar to the prostaglandins and to interfere with their bioassay. We report here such an occurrence. Thus, furosemide not only survived the acidic lipid extraction, but, in addition, it exhibited chromatographic properties identical to those of the prostaglandins of the E series and finally, furosemide, at a dose which in and of itself was without effect on the assay tissues, inhibited the responses to prostaglandins. The quantification of prostaglandins by radioimmunoassay was, on the other hand, not altered by the presence of furosemide. This latter method appears to be the one of choice when interrelations between prostaglandins and furosemide are being examined.

Animals↗

PubMed1978

Inhibition of prostaglandin synthesis by indomethacin augments the renal vasodilator response to bradykinin in the anesthetized dog.

It has been proposed that the increase in renal blood flow (RBF) produced by bradykinin (BK) is mediated or amplified by the intrarenal generation of prostaglandins. The present investigation was designed to explore these relationships further. In anesthetized dogs, the renal arterial infusion of BK (100 ng/kg per min), prior to the intravenous administration of indomethacin, produced a 93 +/- 14% increase in RBF and an increase in the renal venous concentration of a prostaglandin E-like substance ("PGE") from 51 +/- 23 to 235 +/- 73 pg/ml as determined by bioassay. Following indomethacin (5 mg/kg), the same dose of BK produced a 151 +/- 18% increase in RBF (P less than 0.001 compared to the preindomethacin increase) and the concentration of "PGE" remained largely below the threshold of sensitivity of the bioassay system. In three experiments, a highly sensitive and specific radioimmunoassay technique was used to obtain better quantitative estimates of concentrations of E2-like ("PGE2") and F2alpha-like ("PGF2alpha") substances so that determinations of renal efflux could be made. Thus, prior to indomethacin, BK administration increased RBF by 142 +/- 39 ml/min and was associated with a 26-fold increase in renal efflux of "PGE2" and a 12-fold increase in "PGF2alpha." After indomethacin, the effluxes of both "PGE2" and "PGF2alpha" decreased to negligible levels and were not influenced by BK infusion, although RBF increased by 225 +/- 75 ml/min. These results are not compatible with the hypothesis that intrarenal prostaglandins mediate or amplify the renal vasodilator response to BK.

Animals↗

PubMedDate not supplied

Receptor-mediated activation of the heterotrimeric G-protein Gs results in ATP release from erythrocytes.

BACKGROUND: Adenosine triphosphate (ATP), released from the erythrocyte in response to mechanical deformation, decreased oxygen tension or reduced pH, has been suggested to be an important determinant of vascular resistance in several vascular beds. Mechanical deformation-induced ATP release from rabbit and human erythrocytes was reported to require the activity of the cystic fibrosis transmembrane conductance regulator (CFTR), suggesting that a signal transduction pathway involving CFTR mediates ATP release from erythrocytes. Here we investigate the hypothesis that the heterotrimeric G-protein Gs is also involved in this signal transduction pathway. MATERIALS AND METHODS: The heterotrimeric G-protein Gs was identified in rabbit and human erythrocyte membranes, using gel electrophoresis. The concentration of ATP released into a suspension of erythrocytes, incubated with iloprost or epinephrine, was measured using the luciferin/luciferase assay. RESULTS: The 45 kDa form of the heterotrimeric G-protein Gs was identified in rabbit and human erythrocyte membranes. Incubation of rabbit erythrocytes with iloprost (n=18) or epinephrine (n=6) increased the ATP concentration by 106+/-16% and 156+/-54%, respectively. Epinephrine-induced changes in ATP concentrations were prevented by pretreatment with propranolol. CONCLUSIONS: The heterotrimeric G-protein Gs is present in erythrocyte membranes. Receptor-mediated activation of Gs results in ATP release. These results are consistent with the hypothesis that Gs is a component of a signal transduction pathway for ATP release from erythrocytes.

Adenosine Triphosphate↗

PubMedDate not supplied

Endothelium-dependent relaxation to arachidonic acid in porcine coronary artery: is there a fourth pathway?

Endothelium-dependent relaxations to bradykinin (BK) in U46619-contracted, indomethacin (INDO)-treated porcine coronary artery (PCA) rings are modestly attenuated by the nitric oxide (NO) synthase inhibitor, N omega-nitro-l-arginine methyl ester (L-NAME); whereas, when contracted with KCl, L-NAME abolishes BK relaxations. In contrast, endothelium-dependent arachidonic acid (AA) relaxations of U46619-contracted, INDO-treated PCA rings are not affected by L-NAME. AA does not relax KCl-contracted rings. Since BK is known to release AA, we postulated that the non-NO component of BK relaxation of the PCA is mediated by AA or an AA metabolite. Changes in tension of PCA rings to BK and AA were determined in the presence and absence of phospholipase (PLA), cyclooxygenase (CO), lipoxygenase (LO) and cytochrome P-450 (cP450) inhibitors. Responses to BK were attenuated by PLA inhibitors. No other inhibitors, however, eliminated responses to either BK or AA. The results suggest that relaxation to BK in PCA rings requires PLA activity, but relaxation to AA is independent of PLA, CO, LO or cP450 activity. We conclude that relaxation to BK and AA in the PCA is mediated by a product of an unidentified pathway of AA metabolism or by an unknown second messenger system resident within the endothelium and responsive to AA.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMedDate not supplied

Inhibition of nitric oxide synthesis results in a selective increase in arterial resistance in rabbit lungs.

Endogenous nitric oxide (NO) opposes the vasoconstriction that occurs when lungs are ventilated with a hypoxic gas mixture. However, the contribution of NO to pulmonary vascular resistance when alveolar gas tension is not reduced remains to be defined. Here, we investigated the hypothesis that endogenous NO is a determinant of pulmonary vascular resistance in isolated perfused rabbit lungs ventilated with a normoxic gas mixture. Moreover, we wished to establish that, as flow rate increases, the contribution of NO to vascular resistance increases. In addition, we examined the contribution of NO to the longitudinal distribution of pulmonary vascular resistance. Pressure-flow curves were generated in isolated blood perfused rabbit lungs by varying flow rate from 50 ml/min to 300 ml/min in the presence and absence of the cyclooxygenase inhibitor, indomethacin (100 microM) and the inhibitor of NO synthesis, NG-nitro-L-arginine methyl ester (L-NAME, 100 microM). Indomethacin did not alter total pulmonary vascular resistance or the longitudinal distribution of resistance. In contrast, L-NAME administration resulted in significant, flow-related increases in total vascular resistance, i.e., after L-NAME, as flow rate increased, the increment in resistance increased. L-NAME-induced increases in total pulmonary vascular resistance were the result of flow-related increases in the arterial component of vascular resistance. These results provide support for the hypothesis that NO is an important determinant of pulmonary vascular resistance in the rabbit and that the major site of NO activity resides in the arterial side of that circulation.

Animals↗

PubMedDate not supplied

Inhibition of nitric oxide synthesis improves arterial oxygenation in ethchlorvynol-induced acute lung injury in dogs.

In both humans and in experimental animals, acute lung injury (ALI) is characterized by the development of pulmonary edema and arterial hypoxemia. It has been reported that the hypoxemia of ALI is related to the failure of those mechanisms that result in the diversion of blood flow away from hypoxic (edematous) lung units to those that are well oxygenated. One such mechanism is hypoxic pulmonary vasoconstriction (HPV). In the pulmonary circulation, endogenous nitric oxide (NO) has been shown to oppose HPV and, thereby, to support blood flow to hypoxic alveoli. In the present work we investigated the hypothesis that, in ALI, endogenous NO, by virtue of its ability to oppose HPV, supports blood flow to hypoxic lung units resulting in increases in venous admixture (Qva/Qt) and decreases in arterial oxygen tension (PaO2). In anesthetized and mechanically ventilated dogs, the intravenous administration of ethchlorvynol (ECV, 15 mg/kg) resulted in an increase in extravascular lung water (EVLW) of 10 +/- 1 ml/kg body wt (p < 0.001) as well as a 120 +/- 45% increase in Qva/Qt (p < 0.01) and a 23 +/- 5% decrease in PaO2 (p < 0.01) (n = 3). L-NAME (1 mg/kg iv, followed by 5 mg/kg/h, iv), administrated 60 min after ethchlorvynol (ECV), prevented entirely the ECV-induced increase in Qva/Qt and fall in PaO2 with minimal effect on EVLW (n = 3). We conclude that, in this model of ALI, endogenous NO is present in the lung and acts to support blood flow to poorly oxygenated lung units resulting, thereby, in reductions in PaO2.

Animals↗