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Biomedical subjects

J R Fletcher

Publications and source records attributed to J R Fletcher.

At least 73 records · Page 4Linked to original sources
PubMed1981

Beneficial effect of indomethacin on acid-induced esophagitis in cats.

Acid-induced esophageal injury in the cat, produced by infusion of 0.1 N HCl (1 ml/min for 30 min) on 4 consecutive days, has been shown previously to adversely affect lower esophageal sphincter (LES) pressure. We studied the role of prostaglandins in acid-induced esophagitis and the associated LES hypotension by simultaneous treatment of some animals with indomethacin (150 micrograms/kg intravenous), a specific inhibitor of prostaglandin synthesis, either during production of esophagitis or during recovery. LES pressures and esophageal histology were compared to control groups which received acid alone. Indomethacin treatment resulted in more rapid healing of the esophageal inflammation and prevented or promptly corrected the esophagitis-associated LES hypotension. These studies provide further evidence that prostaglandins play an important role in the pathogenesis of acid-induced esophagitis and LES hypotension and raise the possibility that indomethacin, a prostaglandin synthetase inhibitor, may be of benefit in prevention or therapy of esophagitis.

Animals↗
PubMed1981

Prostaglandin E1 effects on resting and cholinergically stimulated lower esophageal sphincter pressure in cats.

Intraluminal esophageal manometry with a sleeve catheter was used to compare the magnitude of decrease in lower esophageal sphincter (LES) pressure produced by an arterial or venous infusion of prostaglandin E1 in cats. Arterial PGE1 produced significantly lower LES pressures than venous PGE1 (p less than 0.05). Maximal decrease of 75% in basal LES pressure occurred with an associated 15% decrease in systolic blood pressure. The site of action of PGE1 in producing LES hypotension was studied by injection of either edrophonium, or bethanechol during the maximal PGE1 effect. Bethanechol, which acts directly on sphincteric smooth muscle, produced an increase in LES pressure during both saline and PGE1 infusion, while the increases in LES pressure seen with edrophonium during saline infusion were blocked during the PGE1 infusion. From these studies, we conclude that PGE1 produces LES hypotension in the cat by an inhibitory effect on the cholinergic pathway responsible for maintaining LES tone. These studies pharmacologically reproduce the LES pressure abnormality previously reported in the cat during acid-induced esophagitis and support the hypothesis that PGE1 may be involved in the pathogenesis of acute acid-induced lower esophageal sphincter abnormalities.

Animals↗
PubMed1981

Indomethacin improves survival in gram-negative sepsis.

A clinically relevant rat model of peritoneal sepsis was developed through the use of (a) intraperitoneal insertion of rat fecal pellets or (b) live E. coli intraperitoneal injections. Therapy with indomethacin and lidocaine were evaluated in this model. Indomethacin alone, or in combination with appropriate antibiotics, significantly improved survival. Lidocaine did not show an increase in survival. These findings suggest that indomethacin may be beneficial in treatment of human sepsis.

Animals↗
PubMed1981

Thromboxane, prostacyclin, and hemodynamic events in primate endotoxin shock.

Prostaglandins participate in the pathophysiology of septic shock; however, their exact role is unclear. In this study we investigated the possibility that thromboxane and prostacyclin, the most recently discovered prostaglandins, may be related to the pulmonary arterial hypertension (thromboxane) and systemic arterial hypotension (prostacyclin) during endotoxin shock in the baboon. There are no previously reported studies in the subhuman primate. In this study ten male baboons received an LD70 dose of E. coli endotoxin. Cardiac output, mean systemic arterial pressure, pulmonary arterial pressure, blood gases, WBC and platelet counts, and prostaglandins were determined at 0, 15, 60, 120, 180, and 240 minutes. Thromboxane and prostacyclin levels were significantly (P less than 0.05) increased after the endotoxin injection. Systemic arterial PGI values increased within 15 minutes, peaked at two hours, and was directly related to the fall in systemic arterial pressure (r = 0.93). In contrast, thromboxane values peaked at 15 minutes and directly related (r = 0.90) to the rise in pulmonary artery pressure. Thromboxane and prostacyclin are significantly increased in subhuman primate endotoxin shock. The temporal relationship of thromboxane and pulmonary arterial pressure suggests that thromboxane may mediate the effects of endotoxin on the pulmonary vasculature.

Animals↗
PubMed1980

The role of prostaglandins in endotoxemia: comparisons in response in the nonpregnant, maternal, and fetal models. I. Prostaglandins and the pulmonary effect of experimental endotoxemia.

The mechanism of respiratory distress in sepsis is unknown. Previous work has shown elevations of prostaglandins during sepsis. This study reveals a correlation between levels of prostaglandins F 2 alpha and E and pulmonary hypertension and other parameters of respiratory distress in oophorectomized ewes subjected to endotoxin. The use of prostaglandin synthetase inhibitors prior to endotoxin prevented the rise in prostaglandins and the development of respiratory distress.

Animals↗
PubMed1980

Lidocaine increases prostacyclin in the rat.

In the rat, the effect of intravenous lidocaine was evaluated on plasma prostacyclin concentration as well as the concentration of prostacyclin in aortic ring incubation chambers and in the effluent of isolated perfused lungs. Prostacyclin was assayed using a radioimmunoassay for its stable product 6-Keto PGF1 alpha. Lidocaine in therapeutic doses (2 mg/kg) will significantly increase 6-Keto PGF1 alpha in plasma as well as in aortic ring incubation chambers and in the effluent of isolated perfused lungs when compared to saline treated controls.

6-Ketoprostaglandin F1 alpha↗
PubMed1980

The effects of prostacyclin (PGI2) on endotoxin shock and endotoxin-induced platelet aggregation in dogs.

Prostacyclin (PGI2) is a major metabolite of arachidonic acid and is synthesized in vascular endothelial cells. It is a potent inhibitor of platelet aggregation and a known vasodilator. Because of the effects of PGI2 on platelet function, this study was designed to determine the efficacy of prostacyclin in endotoxin shock and on endotoxin-induced platelet aggregation in dogs. Thrombocytopenia is characteristic of septic shock and is believed to be related to platelet clumping, and thereby, to participate in the pathophysiology of endotoxin shock. Twenty-four males dogs were given an LD50 dose of Escherichia coli endotoxin (1 mg/kg). Twelve of these animals were treated with PGI2 (20 ng/kg/min) by continuous infusion from 15 minutes before, and for 4 hours after the injection of endotoxin. Parameters determined were mean arterial pressure, cardiac output, pulmonary arterial pressure, heart rate, platelet and white blood cell counts, and arterial blood gases. In animals given endotoxin alone, only 42% (5/12) survived, whereas, with PGI2 treatment, 83% (10/12) survived (P < 0.05). Prostacyclin therapy did not alter the rise in pulmonary arterial pressure, but did further decrease the mean systemic arterial pressure. There was a transient attenuation of the thrombocytopenia, and minimal effects on the granulocytopenia. Despite the fact that the PGI2-treated animals had greater decreases in blood pressures, 83% of the animals did survive. These findings suggest that PGI2 may have some protective effects in endotoxin shock. Serratia marcescens endotoxin caused dose-dependent platelet aggregation in canine platelet-rich plasma in vitro. Antiaggregating agents such as indomethacin (0.2-1 microgram/ml), and aspirin (0.2-1 microgram/ml), PGE1 (0.1-1 microgram/ml) and PGI2 (0.1-1 microgram/ml), added 1 minute before endotoxin (1 microgram/ml), had no apparent effect on the endotoxin-induced platelet aggregation. These findings suggest that endotoxin-induced platelet aggregation may be caused by a mechanism that is unrelated to cAMP and/or the arachidonic acid prostaglandin system.

Animals↗
PubMed1980

Indomethacin treatment following baboon endotoxin shock improves survival.

Baboons treated with one or two doses of indomethacin (1.5 mg/kg) after shock from endotoxin were randomly compared to untreated controls in an LD73 E coli endotoxin (6 mg/kg) model. Survival, systemic and pulmonary arterial pressures, cardiac output, white blood cell and platelet counts, and blood gases were determined. Baboons receiving indomethacin had a significantly (P less than 0.05) better survival at 72 hours than did the controls. Circulatory function was improved with indomethacin treatment; however, white blood cell and platelet counts were similar. Arterial oxygen tension was significantly (P less than 0.02) better with indomethacin treatment. The mechanism by which indomethacin improves the survival in baboon endotoxin shock may be related to its effect on circulatory function.

Animals↗