PubMed Health⌕ Search

Biomedical subjects

G B Bulkley

Publications and source records attributed to G B Bulkley.

At least 73 records · Page 4Linked to original sources
PubMed1992

Lung injury produced by pancreatic proteases in dogs.

With an isolated, blood-perfused canine lung-lobe preparation, the potential role of reactive oxygen metabolites and neutrophils in pancreatic protease (alpha-chymotrypsin)-induced acute lung injury was studied. Administration of alpha-chymotrypsin caused a low-pressure pulmonary edema (mean lung lobe weight increased from 71 to 197 gm). Pretreatment with superoxide dismutase alone did not attenuate the injury (58 to 166 gm), but when combined with catalase, the injury was significantly ameliorated (64 to 107 gm). However, depletion of circulating leukocytes did not attenuate the injury (69 to 200 gm). These findings suggest that circulatory proteases can cause lung injury by a mechanism that is mediated, at least in part, by toxic oxygen metabolites that are not of neutrophil origin.

Animals↗
PubMed1991

Free radical ablation for the prevention of post-ischemic renal failure following renal transplantation.

The toxic metabolites of oxygen, including those which are free radicals, have been found to constitute a fundamental common pathway of tissue injury in a wide variety of disease processes, including injury in many organs resulting from post-ischemic reperfusion. Research efforts designed to prevent or ameliorate tissue injury have therefore centered on the pharmacologic inhibition of free radical-mediated mechanisms. This approach has particular application to post-ischemic renal failure seen in renal transplantation, after a well-defined period of graft ischemia, followed by reperfusion.

Acute Kidney Injury↗
PubMed1991

Pharmacologic approach to tissue injury mediated by free radicals and other reactive oxygen metabolites.

Highly toxic metabolites of oxygen are generated normally by aerobic metabolism in most cells, and this generation is often greatly increased in pathologic conditions. When this oxidant flux exceeds the capability of the multiple endogenous antioxidant mechanisms, tissue injury ensues. The pharmacologic modification of this injury process, with agents that scavenge these reactive oxygen metabolites, block their generation, or enhance the endogenous antioxidant capability, has shown great promise in animal models of common clinical conditions, and has already been successfully applied in controlled clinical trials. This approach represents an interruption of tissue injury at its most basic level.

Animals↗
PubMed1991

Evidence for an early free radical-mediated reperfusion injury in frostbite.

Frostbite is characterized by acute tissue injury induced by freezing and thawing. Initial complete ischemia is followed by reperfusion and later, tissue necrosis. These vascular events support the hypothesis that free radical-mediated reperfusion injury at thawing might contribute to tissue necrosis after frostbite in a manner similar to that seen after normothermic ischemia. To test this hypothesis, rabbit ears were frozen at -21 degrees C for 30, 60, 90, or 120 s and rewarmed at room temperature (22 degrees C). Rabbits were treated "blindly" with saline alone, highly purified, pharmaceutical grade superoxide dismutase (SOD), allopurinol, or deferoxamine. The area of ear necrosis was determined 3 weeks after frostbite by "blinded" morphometry. The administration of SOD at the time of thawing significantly improved viability in ears frozen for 60 and 90 s, but not in those frozen for 30 or 120 s. Deferoxamine also improved viability in ears frozen for 60 s. Allopurinol did not significantly affect ear survival. Electron micrographs showed the appearance of severe endothelial cell injury beginning during freezing and extending through early reperfusion. Later, neutrophil adhesion, erythrocyte aggregation, and microvascular stasis were seen. These findings suggest that free radical-mediated reperfusion injury has a role in frostbite, and quantitate the proportion of the injury that is due to this mechanism.

Allopurinol↗
PubMed1991

Preoperative lumbar epidural morphine improves postoperative analgesia and ventilatory function after transsternal thymectomy in patients with myasthenia gravis.

OBJECTIVE: To test the hypothesis that preoperative lumbar epidural morphine improves postoperative pain control and ventilatory function after transsternal thymectomy in patients with myasthenia gravis. DESIGN: The study design was randomized, placebo-controlled, and double-blind. SETTING: After surgery, all patients were admitted to the Neuroscience Critical Care Unit for evaluation and treatment. PATIENTS: All patients with myasthenia gravis who presented to the hospital for thymectomy were asked to participate in the study. Twenty patients were randomized to either the placebo or epidural morphine groups. INTERVENTIONS: Patients received either epidural morphine (7 mg in 14 mL of sterile saline) or saline (14 mL) before induction of anesthesia. Supplemental iv opioids were administered intraoperatively, with need determined by the anesthesiologist. MAIN OUTCOME MEASURES: The main outcome measures were indicators of postoperative pain (e.g., Visual Analog Pain Score, requirement for supplemental opioid administration, respiratory rate) and ventilatory function (e.g., forced vital capacity, negative inspiratory pressure). RESULTS: Immediately after surgery, the Visual Analog Pain Score in the placebo group was twice as high as the score in the epidural morphine group (placebo 7.0 +/- 1.3; epidural morphine 3.5 +/- 1.2, p less than or equal to .05). During the first eight postoperative hours, the placebo group required more opioids (0.22 +/- 0.03 vs. 0.12 +/- 0.04 mg/kg morphine equivalents, p less than or equal to .06) than the epidural morphine group. Later, both groups received similar amounts of opioids. Patients receiving epidural morphine had better initial recovery of forced vital capacity (at 8 hrs: 55 +/- 6% [epidural morphine] vs. 34 +/- 5% [placebo] of preoperative value, p less than or equal to .05). Respiratory rate was lower for the first 12 postoperative hours in the epidural morphine group, without a difference in PaCO2. There was no difference between groups for the duration of postoperative intubation or ventilation. CONCLUSIONS: Preoperative lumbar epidural morphine facilitates postoperative analgesia and improves initial postoperative ventilatory performance.

Adult↗
PubMed1991

Effect of inhibition of oxygen free radical on ovulation and progesterone production by the in-vitro perfused rabbit ovary.

The potential role of oxygen free radicals in hCG-induced ovulation was investigated using the free radical scavenging enzymes superoxide dismutase (SOD) and/or catalase with the in-vitro perfused rabbit ovary preparation. SOD (25 micrograms/ml) and SOD + catalase (25 micrograms/ml) significantly reduced the % of large follicles that ovulated during perfusion (P less than 0.005). Neither maturity nor degeneration of ovulated ova and follicular oocytes was affected by SOD and/or catalase. Progesterone concentration in the perfusate was significantly increased in the SOD + catalase treatment group (P less than 0.01). These results indicate a significant role for oxygen free radicals in the process of ovulation.

Animals↗
PubMed1990

Decreased mesenteric vascular response to angiotensin II in portal hypertension.

We studied the mesenteric and systemic vascular response to angiotensin II in normotensive and portal hypertensive (PHT) rabbits, because of the documented poor tolerance of hemorrhagic shock in PHT. Normally, the hemodynamic response to angiotensin II (AII) is characterized by selective and disproportionate splanchnic vasoconstriction. We postulated that the response to AII could be diminished in PHT. Chronic PHT was induced by partial portal vein ligation 3 weeks prior to graded angiotensin II infusion. Baseline hemodynamic measurements showed markedly elevated portal pressure (PPV) and superior mesenteric artery blood flow (QSMA) compared with those of normotensive animals (P less than 0.01). Superior mesenteric artery resistance (RSMA) was markedly reduced in PHT compared to that in controls (P less than 0.05). Angiotensin II infusion in normals resulted in a marked selective rise in RSMA compared with the rise in systemic resistance (RSYS) (P less than 0.01). AII infusion in PHT resulted in a rise in RSMA and RSYS, but the disproportionate in RSMA was attenuated. Furthermore, in both normal and PHT, AII caused a significant rise in PPV (P less than 0.01). We conclude that the findings indicate that the splanchnic vasoconstrictive response to AII is substantially impaired in PHT, and that AII will paradoxically cause a rise in PPV, possibly aggravating the tendency to hemorrhage in PHT.

Angiotensin II↗
PubMed1990

Molecular biology of circulatory shock. Part II. Expression of four groups of hepatic genes is enhanced after resuscitation from cardiogenic shock.

Despite an initially successful resuscitation from circulatory shock, multiple organ failure (MOF) develops in some patients. The marked biochemical alterations associated with shock and MOF include clinically important changes in gene expression, such as altered rates of albumin and procoagulant synthesis. To characterize the MOF-associated changes at the cellular level, sequential liver biopsies were obtained from a swine model of cardiogenic shock associated with MOF. Preshock and postresuscitation biopsies were used not only to create a complementary DNA (cDNA) library but also to screen, to confirm, and, in nine out of 12 cases, to specifically identify genes whose expression is enhanced at least fivefold after resuscitation. The twelve genes thus characterized can be separated according to function into distinct groups, including the acute-phase genes and the heat-shock genes. Expression of acute-phase genes is liver specific and is essential for systemic homeostasis; heat-shock gene expression is generic to all cells and important for intracellular homeostasis.

Acute-Phase Proteins↗
PubMed1990

The sequence of development of intestinal tissue injury after strangulation ischemia and reperfusion.

Tissue injury at reperfusion has been reported after partial ischemia. However, previous attempts to demonstrate a component of injury caused by reperfusion after total ischemia have failed. This study was performed to evaluate the hypothesis that in such situations the extent of the tissue injury caused by ischemia itself prevented detection of a reperfusion component. Rats were subjected to near-total intestinal ischemia by means of a hydrostatic pressure clamp that produced preferential venous occlusion (strangulation) for periods from 1 to 90 minutes. Tissue injury was evaluated microscopically by a blinded examiner. Ischemic periods of 20 minutes or less did not induce detectable tissue injury. Longer durations of ischemia caused villous injury: the longer the period of ischemia, the more extensive the tissue injury. However, there was no exacerbation of injury seen after reperfusion, regardless of the duration of ischemia. In a separate series of rats, total arterial occlusion was employed without concomitant venous congestion. Such isolation arterial occlusion of 40 to 60 minutes' duration was followed by a statistically significant exacerbation of tissue injury at reperfusion. Thus total intestinal ischemia may be followed by reperfusion injury if there is no concomitant congestion and if ischemic injury is not too extensive.

Animals↗
PubMed1990

Effect of superoxide dismutase in cats with cold-induced edema.

We evaluated the potential role of SOD, an oxygen free radical scavenger, as a probe to cover the trigger period of injury and the prolonged period of development of edema in vasogenic brain edema. Vasogenic brain edema was produced in 34 cats by a standardized cortical freezing lesion. Brain edema and the disruption in the BBB were assessed by SG measurement and spread of Evans blue by planimetry. Detection of superoxide radicals was studied by topical application of NBT within the cranial window. Animals were separated into two groups: (a) controls; and (b) two SOD-treated groups--A was pretreated with 10,000 U/kg PEG-SOD intraperitoneally and sacrificed at 24 and 48 hr after lesions, and B received both a bolus injection of free SOD (4 mg/kg) and then 1 mg/kg/min for 20 min after the lesion and was sacrificed 6 hr later. Our preliminary data indicate that superoxide radicals were detected in the brain after cold-induced injury, but free and PEG-SOD had no beneficial effect on vasogenic brain edema produced by cold-induced injury. It is concluded that intracellular uptake of SOD might be necessary for an effect in the treatment of cold-induced brain edema.

Animals↗
PubMed1990

Inhibition of the compartment syndrome by the ablation of free radical-mediated reperfusion injury.

Skeletal muscle edema secondary to an increase in capillary permeability after reflow is an important cause of the compartment syndrome after acute arterial revascularization. The purpose of this study was to investigate the possible role of oxygen free radicals, generated at reperfusion, in the pathogenesis of the compartment syndrome secondary to acute arterial ischemia/reperfusion. A reproducible model of this syndrome was produced in anesthetized rabbits by femoral artery occlusion after surgical devascularization of collateral branches from the aorta to the popliteal artery. Increasing periods of ischemia from 6 to 12 hours, followed by 2 hours of reperfusion, were associated with corresponding increases in the anterior muscle compartment hydrostatic pressure and inversely proportional decreases in tibialis anterior muscle blood flow within that compartment as assessed by xenon 133 washout (n = 46) (r = -0.62, p less than 0.001). Anterior compartment pressure increased from 5 +/- 1 to 48 +/- 5 mm Hg (n = 46) (p less than 0.001) after 7 hours of total arterial ischemia and 2 hours of reperfusion. Ablation of free radicals generated from xanthine oxidase with either allopurinol (n = 8) or oxypurinol (n = 8), by scavenging the superoxide radical at reperfusion with superoxide dismutase (n = 8), or by blocking secondary hydroxyl radical formation with deferoxamine (n = 8) significantly ameliorated the rise in compartment pressure (p less than 0.05) in each case; it also significantly improved muscle perfusion in the superoxide dismutase-, allopurinol-, and deferoxamine-treated animals (p less than 0.05). These findings indicate that development of the compartment syndrome after acute arterial revascularization may be due, at least in part, to microvascular injury mediated by oxygen-derived free radicals generated from xanthine oxidase at reperfusion.

Allopurinol↗
PubMed1989

Xanthine:acceptor oxidoreductase activities in ischemic rat skin flaps.

Xanthine:acceptor oxidoreductase activities were assayed in free skin flaps following prolonged preservation. In normal rat skin, xanthine dehydrogenase transfers electrons to NAD+ and accounts for 73% of total oxidoreductase activity, and xanthine oxidase transfers electrons to molecular oxygen and accounts for the remaining 27%. Xanthine oxidase activity increased significantly in skin flaps during ischemia: approximately 30 and 100% increases after 6 and 24 hr of ischemia, respectively. Allopurinol inhibited xanthine oxidoreductase activity: free skin flaps obtained from allopurinol-treated animals exhibited a low level of xanthine oxidoreductase activity throughout the period of preservation. Systemic allopurinol significantly improved the survival rate from 32 to 75% of free flaps transferred after 24 hr of preservation at room temperature. These observations suggest that the xanthine oxidase system is a major source of oxygen free radicals following ischemia/reperfusion in skin. The increase in xanthine oxidase is attributable to the conversion of xanthine dehydrogenase to oxidase, a conversion which involves sulfhydryl oxidation in skin flaps.

Allopurinol↗
PubMed1989

The role of metal ions in ischemia/reperfusion injury in skin flaps.

The role of hydroxyl radical generation by the metal-catalyzed Haber-Weiss reaction in producing injury to postischemic skin flaps in rats was evaluated. The venous drainage from groin island flaps was occluded for 7 hr and then reperfused. The flaps were infused with either deferoxamine, CaNa2EDTA, histidine, salicylate, or vehicle (saline) at the time of reperfusion. In another experimental group, the role of hydrogen peroxide was evaluated by the infusion of catalase at the time of reperfusion. Treatment with a single dose of deferoxamine (40 mg/kg), CaNa2EDTA (50 mg/kg), or histidine (50 mg/kg), significantly increased the flap survival rate from 24 to 63, 75, and 63%, respectively. A large dose of salicylate (80 mg/kg) improved the flap survival rate (to 63%): a smaller dose (40 mg/kg) offered no improvement. A large dose of catalase ameliorated the survival rate (to 88%). The results suggest that the presence of metal ions is required for the expression of free radical-induced tissue damage. Hydrogen peroxide appears to be essential for the production of this injury.

Animals↗
PubMed1989

Role of prostacyclin in the splanchnic hyperemia contributing to portal hypertension.

To determine the possible role of prostacyclin (PGI2) as a mediator of the splanchnic hyperemia seen with portal hypertension, the portal and mesenteric hemodynamics in normal and portal hypertensive rabbits were studied before and after cyclo-oxygenase blockade. Three weeks after partial portal vein ligation, splenic pulp pressure was elevated from 4.3 +/- 0.9 to 9.8 +/- 0.8 mmHg (p less than 0.01). Mesenteric blood flow increased from 77.0 +/- 4.7 ml.min-1.100 g-1 to 99.1 +/- 5.19 ml/min-1/100 g-1. Mesenteric vascular resistance fell from 0.82 +/- 0.6 mmHg/ml-1/min-1 to 0.49 +/- 0.07 mmHg/ml-1/min-1 (p less than 0.01). These hemodynamic changes were associated with a 27.3 +/- 0.2% rise in systemic arterial levels of PGI2 (p less than 0.01) and were substantially ameliorated by cyclo-oxygenase blockade with indomethacin. The effects of indomethacin blockade were reversed by exogenous PGI2. Moreover, in normotensive rabbits, infusion of PGI2 reproduced the splanchnic hyperemia and caused a very small but significant increase in portosystemic shunting. These findings support the previously proposed concept that splanchnic hyperemia may contribute to the maintenance of chronic portal hypertension. Furthermore, they suggest that this effect may be partially mediated by splanchnic PGI2 production.

Animals↗
PubMed1989

Morphologic characterization of acute injury to vascular endothelium of skin after frostbite.

Cyclo-oxygenase inhibitors and free-radical scavengers protect the skin against necrosis induced by frostbite. However, the tissue component(s) that determine the evolution of skin necrosis and the mechanism of this pharmacologic protection are not precisely defined. We have studied freezing injury to rabbit ears by serial biopsies examined by light and electron microscopy. The morphologic evidence of skin injury due to freezing was localized exclusively in the endothelial cells, particularly in the arterioles. Within 1 hour, the entire microvasculature demonstrated endothelial damage. Intravascular platelet aggregation occurred just after thawing and closely paralleled the endothelial cell injury. Very few neutrophils were seen initially (at 10 minutes). By 1 hour, leukocyte aggregates were present, and they further increased at 6 hours. Swelling of the interstitium started 10 minutes after thawing, while extravasation of erythrocytes began to appear by 6 hours. Parenchymal elements of skin were relatively free of damage. In the ear cartilage, the chondrocytes showed evidence of damage immediately after freezing. The administration of superoxide dismutase (SOD) during thawing (reperfusion) did not qualitatively alter any of the initial morphologic changes induced by freezing. We conclude that the endothelial cell is the initial target of injury induced by freezing, an initial injury that is mediated by a non-free-radical-mediated mechanism. It is likely that this acute injury ultimately compromises blood flow and leads to skin necrosis.

Animals↗
PubMed1989

Change in hepatic gene expression after shock/resuscitation.

In response to specific stresses, such as a heat pulse or the sequence of hypoxia-reoxygenation, each isolated cell (prokaryotic and eukaryotic) that has been studied characteristically alters gene expression to synthesize a set of proteins (heat-shock proteins) that are important for intracellular homeostasis. To determine whether a corresponding response occurs within parenchymal cells in vivo when subjected to the complex stress of circulatory shock, liver biopsy specimens were obtained from a swine model of cardiogenic shock before and after shock/resuscitation. With use of complementary DNA prepared from post-shock/resuscitation messenger RNA, a library was constructed and screened for differential gene expression. Of 32/4000 clones initially screened as positive for induction after shock/resuscitation, six were confirmed positive by Northern blot analysis. The nucleotide sequences of two of these six have been determined, and one has been unambiguously identified as metallothionein.

Animals↗