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G B Bulkley

Publications and source records attributed to G B Bulkley.

At least 109 records · Page 6Linked to original sources
PubMed1986

Free-radical-mediated postischemic reperfusion injury in the kidney.

Acute tubular necrosis is a frequent occurrence following hypovolemic shock and human renal transplantation. Although this postischemic injury was originally thought to result from ischemia alone, it has recently been recognized that significant tissue injury can occur during the period of reperfusion. The demonstration of the oxygen free-radical-mediated postischemic reperfusion injury by Granger, Rutili, and McCord in ischemic cat intestine suggested that this mechanism might also be operative following renal ischemia. In the kidney, postischemic injury results in necrosis of the proximal renal tubule and accumulation of erythrocytes in the outer renal medulla. It has been proposed that the primary event leading to these pathologic changes is a free-radical-mediated injury to the endothelial cells in the inner stripe of the outer medulla. Experimental evidence in animals subjected to warm and cold ischemia supports a free-radical-mediated mechanism. The clinical significance of these findings is demonstrated in preclinical animal studies of renal transplantation in which approximately two-thirds of the injury following cold ischemia could be ablated by superoxide dismutase administered just prior to reperfusion or by allopurinol when administered both at the time of preservation and reperfusion or at the time of preservation alone.

Acute Kidney Injury↗
PubMed1986

Pathogenesis of nonocclusive ischemic colitis.

The nonocclusive component of ischemic colitis in anesthetized pigs was mimicked using cardiogenic shock produced by pericardial tamponade. Increases in pericardial pressure produced decreases in arterial pressure (PA) and cardiac output (CO), with corresponding rises in total peripheral resistance (i.e., cardiogenic shock). This was associated with marked reductions in blood flow through the inferior mesenteric artery (IMA), due primarily to disproportionate increases in IMA vascular resistance. Levels of plasma renin activity correlated closely with these changes in mesenteric hemodynamics. Confirmed, total alpha adrenergic blockade with phenoxybenzamine failed to block this selective mesenteric vasoconstriction, while ablation of the renin-angiotensin axis with captopril completely abolished it, thereby ameliorating the colonic ischemia. Central intravenous infusions of pathophysiologic levels of angiotensin II, without tamponade, mimicked the response to shock seen with tamponade alone. In an additional group of pigs, 4 hours of sustained shock (tamponade) followed by 2 hours of normotension (release of tamponade and resuscitation) produced lesions characteristic of ischemic colitis, including full-thickness mucosal ulceration. Such lesions were ameliorated significantly in pigs in which the renin-angiotensin system had been ablated by bilateral nephrectomy. Nonocclusive ischemic colitis appears to be mediated primarily by a remarkable sensitivity of the colonic vasculature to the renin-angiotensin axis.

Animals↗
PubMed1986

Improved survival in free skin flap transfers in rats.

We have demonstrated previously that oxygen-derived free radicals are important mediators of tissue injury in experimental island skin flaps that have been subjected to prolonged ischemia (vascular occlusion) followed by reperfusion. In this study the role of oxygen free radicals in ischemia/reperfusion injury has been investigated in free flap transfers. Groin skin flaps were harvested, stored at room temperature for 21 to 24 hours, and transplanted to the contralateral groin. These free flap transfers normally exhibit a high incidence of complete necrosis. Treatment before the onset of reperfusion with a single dose of superoxide dismutase (SOD), a scavenger of superoxide radicals, increased the survival rate of these skin flaps from 38% in the control group to 76% (p less than 0.025). Tissue levels of SOD were measured before ischemia, after ischemia but before reperfusion, and 30 minutes after reperfusion: untreated flap tissues, which were destined to undergo necrosis, exhibited a significant decrease in SOD activity after reperfusion, whereas SOD-treated flap tissues, destined to survive, demonstrated increased enzyme activity. High levels of tissue SOD activity thus appeared to be associated with improved flap survival. The results have significant clinical implications with regard to organ preservation and transplantation.

Animals↗
PubMed1986

Oxygen-derived free radicals and acute pancreatitis: a review.

The role of oxygen-derived free radicals in the pathogenesis of acute pancreatitis has been investigated in a series of studies using an ex vivo, perfused canine pancreas preparation. Three models of experimental acute pancreatitis have been developed in this preparation: ischemic pancreatitis, gallstone pancreatitis, and alcohol-induced pancreatitis. In each model, the pancreas becomes edematous, gains weight, and the perfusate develops hyperamylasemia during the 4 hour period of perfusion. Pretreatment with the free radical scavengers superoxide dismutase and catalase significantly ameliorates these manifestations of pancreatic injury in each of the three models. The source of the free radical generation was investigated by pretreating the preparation with allopurinol, a quite specific inhibitor of xanthine oxidase. In each of the three models, this also significantly ameliorated the injury process. These experiments demonstrate that oxygen-derived free radicals, generated by activated xanthine oxidase, appear to play a central role in the pathogenesis of acute pancreatitis in these models. These findings shed light on the fundamental pathophysiology of this disease and may provide the basis for more effective therapy in the future.

Acute Disease↗
PubMed1986

Collateral blood flow in segmental intestinal ischemia: effects of vasoactive agents.

We evaluated the effects of common vasoactive agents on collateral blood flow to an ischemic segment of small intestine and on the hemodynamic determinants of that flow. Two adjacent canine jejunal segments were isolated together, and the artery to each was cannulated for autoperfusion from a femoral and a carotid artery, respectively. Arterial pressure, arterial blood flow into, and venous outflow from each segment was measured separately. Venous pressure was zero. Vascular resistances were calculated. After clamping the arterial circuit to one segment, designated "ischemic," its steady-state venous outflow was taken as the collateral blood flow from the nonischemic into the ischemic segment. Without drugs, collateral blood flow was equal to 29 +/- 4 ml/min X 100 gm or, 56% +/- 8% of normal, well above the level needed to sustain oxygen consumption and thereby prevent ischemic injury. Local intra-arterial infusion of the vasodilators isoproterenol and papaverine not only failed to increase collateral flow but actually caused a small but (with isoproterenol) significant reduction, caused by vasodilation in the nonischemic bed, and a resulting drop in arterial pressure distal to the occlusion in the ischemic segment (i.e., a steal phenomenon). The vasoconstrictors levarterenol and vasopressin also reduced collateral flow but by direct and preferential vasoconstriction of the dilated ischemic bed. These findings suggest that collateral blood flow may be optimal without drugs and is decreased only by vasoactive agents, including vasodilators. This contradicts the rationale for vasodilator therapy for the direct augmentation of collateral blood flow in acute occlusive intestinal ischemia.

Animals↗
PubMed1986

Effect of collateral circulation on intestinal viability following segmental devascularization in the rat.

The collateral circulation in the rat small intestine was studied by evaluating the viability of an intestinal segment after its primary mesenteric vascular supply had been interrupted. After ligation of the main mesenteric branches of a 30-cm segment of either jejunum or ileum, viability was assessed immediately by the fluorescence pattern observed under ultraviolet illumination after the peripheral intravenous injection of sodium fluorescein. Viability was assessed again at 48 hours by the fluorescein technique and by gross and histologic examination. With the marginal vessels intact, the collateral circulation was able to sustain 10 per cent of the entire length of small intestine beyond the point of devascularization. On the other hand, when the marginal vessels had been ligated, this length of sustained intestine proved to be negligible. With respect to the above findings, there was no difference in the extent or pattern of collateral circulation at different levels along the small intestine, from proximal jejunum to jejuno-ileal junction to terminal ileum. Systemic infusion of a vasodilator, isoproterenol, was found to substantially decrease the length of small intestine maintained viable by collateral flow. This was associated with a greater decrease in systemic vascular resistance than in mesenteric vascular resistance, which resulted in a drop in mesenteric blood flow. In each of the above studies, the ultimate viability of the intestine by histologic section at 48 hours correlated closely with the fluorescein pattern immediately after devascularization. These studies demonstrate that the collateral circulation of the small intestine is extensive and sufficient to maintain viability in a substantial proportion of the length of the entire intestine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Hemophilus aphrophilus meningitis followed by vertebral osteomyelitis and suppurative psoas abscess.

Hemophilus aphrophilus is an uncommon pathogen in man. It has rarely been reported as a cause of meningitis, exclusively in boys three years or younger. Osteomyelitis due to this organism is also rare. H. aphrophilus was responsible for meningitis, probable thoracic empyema, and ultimately vertebral osteomyelitis and suppurative psoas abscess formation in a woman following metrizamide myelography. The patient responded well to antibiotic treatment and surgical drainage. The organism was sensitive not only to chloramphenicol but also to newer cephalosporin antibiotics.

Abscess↗
PubMed1985

Relationship of blood flow and oxygen consumption to ischemic injury in the canine small intestine.

The relationship of blood flow and oxygen uptake to ischemic intestinal injury was investigated by measuring the clearance of 131I-albumin from the blood to the lumen of isolated, perfused segments of canine jejunum. Reductions in blood flow for 2 h to various levels confirmed the previously demonstrated relationship of oxygen uptake to blood flow, i.e., oxygen uptake was flow-independent at blood flows above 30 ml/min X 100 g, and flow-dependent at levels below this. Blood flows above this threshold did not change the level of albumin clearance seen under control conditions (0.022 +/- 0.003 ml/min X 100 g). However, increases in the mucosal permeability to albumin were seen after blood flow was reduced to levels where oxygen uptake was decreased by more than 50%. These findings indicate that the ability of the small intestine to maintain oxygen consumption during low flow states may be an important factor in providing protection from ischemic injury, even during prolonged periods of hypoperfusion.

Animals↗
PubMed1985

Soybean trypsin inhibitor attenuates ischemic injury to the feline small intestine.

Recent evidence suggests that oxygen free radicals are largely responsible for the increased vascular permeability and early mucosal lesions associated with partial intestinal ischemia. It is postulated that oxygen radicals are produced by the reaction of the enzyme xanthine oxidase with hypoxanthine and molecular oxygen. In normal healthy cells, xanthine oxidase exists as a nicotinamide adenine dinucleotide-reducing dehydrogenase and not the oxygen radical-producing oxidase. In the intestine, dehydrogenase-to-oxidase conversion is nearly complete with less than 1 min of ischemia. Biochemical evidence from the intestine and liver indicate that ischemia-induced conversion of xanthine dehydrogenase to xanthine oxidase can be prevented by administration of protease inhibitors such as soybean trypsin inhibitor. In order to assess the role of proteases in oxygen radical-mediated ischemic injury to the small bowel, quantitative analyses of mucosal lesion development and vascular permeability were performed in autoperfused segments of cat ileum subjected to 1 or 3 h of ischemia and pretreated with 15 mg/kg (i.v.) soybean trypsin inhibitor. One hour of ischemia produced a significant increase in intestinal vascular permeability. The ischemia-induced increase in vascular permeability was significantly attenuated by soybean trypsin inhibitor pretreatment. Three hours of ischemia led to the development of mucosal lesions in untreated animals. Pretreatment with soybean trypsin inhibitor largely prevented the development of the mucosal lesions. The findings of our study are consistent with biochemical evidence that, during ischemia, proteases trigger the conversion of xanthine dehydrogenase to xanthine oxidase and thereby lead to oxygen radical production and subsequent tissue injury.

Animals↗
PubMed1985

Effects of superoxide dismutase and allopurinol on the survival of acute island skin flaps.

We have demonstrated previously that oxygen-derived free radicals are important mediators of tissue injury following ischemia (total venous occlusion) and reperfusion in small (3 cm X 6 cm) island skin flaps in rats. In this study, we evaluated extension of this concept to regional ischemia in large (8 cm X 8 cm) acute island skin flaps which were constructed to exceed their sole blood supply via unilateral inferior epigastric vessels. Under normal (control) circumstances, a significant portion of the flap would undergo necrosis at the periphery, mimicking the corresponding clinical situation. Blocking the generation of superoxide radicals from xanthine oxidase with a single dose of allopurinol prior to flap elevation significantly improved the area of flap viability from 34 +/- 12% to 57 +/- 6% (p less than 0.01) in the random portion of the flap, contralateral to the source of blood supply. Similarly, the detoxification of superoxide radicals with a single dose of superoxide dismutase improved viability from 41 +/- 6% to 58 +/- 7% (p less than 0.01). Similar results were obtained when either of these agents were administered 60 minutes after flap elevation. These findings suggest that oxygen-derived free radicals play an important role in the development of tissue necrosis in the critical transition zone between well-vascularized and devascularized skin.

Allopurinol↗
PubMed1985

The pathogenesis of acute pancreatitis. The source and role of oxygen-derived free radicals in three different experimental models.

Recent experimental work has suggested that oxygen-derived free radicals may play an important role in initiating the early capillary injury in acute pancreatitis. Data from models of ischemic injury in other organs have suggested the enzyme xanthine oxidase is important in generating oxygen-derived free radicals. The present study was performed to determine whether xanthine oxidase is the source of free radical production in experimental pancreatitis. Utilizing the isolated, perfused, ex vivo canine pancreas preparation, three models of pancreatitis were initiated with (1) free fatty acid infusion (FFA), (2) partial duct obstruction and secretin stimulation (POSS), and (3) ischemia (ISCH). In each model, during a 4-hour perfusion, edema developed, weight gain occurred (FFA 120.6 +/- 21.1 gm; POSS 44.5 +/- 6.9 gm; ISCH 63.3 +/- 14.0 gm), and the serum amylase became elevated (FFA 1827 +/- 397 u/dl; POSS 10,171 +/- 1487 u/dl; ISCH 1860 +/- 365 u/dl). When the xanthine oxidase enzyme inhibitor allopurinol was added to the perfusate prior to the 4-hour perfusion, edema formation was absent or minimal, weight gain was significantly less (FFA 15.2 +/- 2.5 gm p less than 0.05; POSS 8.8 +/- 2.7 gm p less than 0.001; ISCH 12.3 +/- 2.8 gm p less than 0.01), and the amylase remained normal or the elevation was significantly decreased (FFA 996 +/- 189 u/dl p less than 0.05; POSS 3021 +/- 1074 u/dl p less than 0.001; ISCH 993 +/- 214 u/dl p less than 0.002). These data confirm that oxygen-derived free radicals play an important role in the pathogenesis of experimental acute pancreatitis, and suggest that the enzyme xanthine oxidase may well be the source of their production.

Acute Disease↗
PubMed1985

The role of oxygen free radicals in mediating the reperfusion injury of cold-preserved ischemic kidneys.

We evaluated the hypothesis that postischemic renal failure is caused primarily at reperfusion by oxygen-derived free radicals in a swine model designed to realistically mimick human cadaveric renal transplantation. Both kidneys were removed, flushed with Euro-Collins solution, stored 24 hr at 4 degrees C, and then transplanted to a second pig. Experiments were paired, each pig receiving one treated and one control kidney. All pigs received the optimal conventional regimen of hydration, phenoxybenzamine, furosemide, and mannitol to allow assessment of free radical treatment superimposed thereupon. Two days later creatinine clearance (CCR) was measured from each kidney via separate ureterostomies. Untreated kidneys developed severe functional impairment, CCR falling from a normal level of 25.5 +/- 6.3 ml/min (n = 8) to 7.7 +/- 0.9 ml/min (n = 14, P less than .05 vs. control). The infusion of 20 mg of the free radical scavenger superoxide dismutase (SOD) into the renal artery at reperfusion substantially ameliorated this injury (CCR = 15.9 +/- 1.7 ml/min, n = 18, P less than 0.05 vs. control). A dose-response curve to SOD showed no effect of doses of 0.2 mg (CCR = 8.0 +/- 1.1 ml/min, n = 4) or 2 mg (CCR = 7.7 +/- 0.9, n = 5), and no greater benefit from 100 mg (CCR = 16.1 +/- 2.1 ml/min, n = 3, P less than 0.05 vs. control). Blocking the generation of superoxide radicals from xanthine oxidase with allopurinol (50 mg/kg) afforded similar protection (CCR = 18.2 +/- 1.8; n = 11, P less than 0.01 vs. control). On the other hand, following an 18-hr period of cold ischemia, little damage was sustained by the untreated (control) kidneys (CCR = 22.1 +/- 0.6 ml/min). Consequently, under these conditions the ablation of free radical generation with allopurinol provided no significant benefit. These findings suggest that after a critical period of cold ischemic preservation, metabolic changes take place within the kidney that lead to free radical generation and consequent tissue injury upon reperfusion, despite optimal preservation by conventional methods. This damage can be prevented by simple nontoxic measures--which, therefore, show great promise for use in the prevention of early renal failure following cadaveric renal transplantation.

Allopurinol↗
PubMed1985

Characterization of segmental collateral blood flow in the small intestine.

Collateral blood flow and the pressures and resistances determining that flow were measured between two adjacent segments of canine jejunum following acute occlusion of the arterial branch perfusing one of the segments (the "recipient" segment). Collateral flow was approximately 55% of control flow in the recipient segment. This flow was provided by an equal increment in arterial flow to the nonischemic ("donor") segment, such that pressures, resistances, and flows in the donor segment were not affected. Virtually all of the total collateral flow was derived from precapillary channels and was therefore available to the capillary bed of the recipient segment. Collateral flow was adequate to maintain the recipient segment in a nonischemic state, as indicated by the absence of a reactive hyperemia following release of the arterial occlusion. Selective occlusions of intramural or extramural collateral channels indicate that about two-thirds of the total collateral flow is derived from the extramural (marginal) vessels, while the remainder is supplied by intramural collaterals. For the most part collateral flow between adjacent segments is determined simply by the pressure gradient between connecting collateral channels.

Animals↗
PubMed1985

Control of gastric vascular resistance in cardiogenic shock.

That local splanchnic ischemia is associated with the acute gastric "stress" erosions seen in shock is well established. The hemodynamic mechanism mediating that ischemia is unknown. Pericardial tamponade was produced in anesthetized pigs while hemodynamic parameters were monitored in the systemic circulation as a whole and in the vascular beds of the celiac and left gastric arteries, respectively. Stepwise increases in pericardial pressure produced progressive decreases in arterial pressure and cardiac output (i.e., reproducible, quantitable, and rapidly reversible levels of cardiogenic shock). This produced a profound reduction in blood flow in the celiac and gastric beds that was significantly disproportionate to the reduction in cardiac output. This was due to significant increases in celiac and gastric vascular resistance that were more than twice as great as those seen in the systemic circulation as a whole (i.e., selective splanchnic vasoconstriction). This response was abolished by ablation of the renin-angiotensin axis, whether by bilateral nephrectomy, captopril, or saralasin, and mimicked, without tamponade, by the infusion of angiotensin II. Levels of celiac artery blood flow and resistance correlated significantly with endogenous levels of plasma renin activity. On the other hand, this response was not abolished by confirmed alpha-adrenergic blockade (phenoxybenzamine) or by sympathectomy. In this model, cardiogenic shock produces regional splanchnic ischemia in the celiac and gastric vascular beds by inducing a severe and disproportionate vasospasm that is mediated primarily by the renin-angiotensin axis.

Animals↗
PubMed1984

The role of oxygen-derived free radicals in the pathogenesis of acute pancreatitis.

Acute pancreatitis may be initiated in the ex vivo, perfused canine pancreas preparation by a variety of stimuli. These include oleic acid infusion (FFA), partial duct obstruction with secretin stimulation (POSS), and a 2-hour period of ischemia (ISCH). In each model, pancreatitis is characterized by weight gain, edema, and hyperamylasemia. Oxygen-derived free radicals such as superoxide, hydrogen peroxide, and the hydroxyl radical are highly reactive toxic substances that are normally produced in small amounts during oxidative metabolism. Ordinarily, these substances are detoxified by endogenous intracellular enzymes called free radical scavengers (FRS), such as superoxide dismutase (SOD) and catalase (CAT). These studies were undertaken to evaluate the possible role of oxygen-derived free radicals in the initiation of acute pancreatitis in the isolated canine model. All preparations were perfused for 4 hours with autologous blood. Controls (N = 6): these glands remained normal in appearance, gained minimal weight (6 +/- 1 g), and serum amylase remained normal (less than 1000 u/dl). FFA pancreatitis, FFA alone (N = 6): these glands became edematous, gained weight (113.5 +/- 27.0 g), and developed hyperamylasemia (2087 +/- 387 u/dl). FFA + FRS (N = 6), SOD (50 mg) and CAT (50 mg) were added to the perfusate at time zero: these glands became only minimally edematous, gained less weight (31.8 +/- 10.1 g, p less than 0.05), and amylase remained normal (p less than 0.05). POSS pancreatitis, POSS alone (N = 8): these glands became edematous, gained weight (38.6 +/- 4.6 g), and developed marked hyperamylasemia (9522 +/- 3226 u/dl). POSS + FRS (N = 6): these glands did not develop edema, gained less weight (15.1 +/- 2.6 g, p less than 0.05), and serum amylase only increased to 1815 +/- 343 u/dl, (p less than 0.05). ISCH pancreatitis, ISCH alone (N = 6): these glands became edematous, gained weight (75.8 +/- 25 g), and developed hyperamylasemia (1679 +/- 439 u/dl). ISCH + FRS (N = 6): these glands did not develop edema, gained only 18.3 +/- 9.0 g (p less than 0.005), and serum amylase remained normal (p less than 0.05). These studies demonstrate that, in this canine preparation, acute pancreatitis is significantly ameliorated by oxygen-free radical scavengers. Since this was true whether the pancreatitis was produced by FFA infusion, POSS, or ischemia, it suggests that oxygen-derived free radicals may mediate a common essential step in the pathogenesis of all forms of pancreatitis.

Acute Disease↗
PubMed1984

Effect of allopurinol on the survival of hyperemic island skin flaps.

Allopurinol was investigated in 3 x 6 cm congested island skin flaps in rats. Eight hours of venous occlusion produced total flap necrosis. Pretreatment with systemic allopurinol, an inhibitor of xanthine oxidase, enhanced the survival rate of hyperemic skin flaps. Xanthine oxidase activities were demonstrated in skin, and these enzyme activities were noted to increase in skin flaps during ischemia and reperfusion. Much of this increase in enzyme activity was prevented by allopurinol treatment. The xanthine oxidase system appears to be one of the sources of the superoxide radical, which may be involved in ischemic and reperfusion injury in skin.

Allopurinol↗