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Biomedical subjects

J C Stanley

Publications and source records attributed to J C Stanley.

At least 127 records · Page 7Linked to original sources
PubMed1989

Decreased oxygen consumption as a toxic manifestation of protamine sulfate reversal of heparin anticoagulation.

Protamine sulfate has been observed to interfere with the control of isolated mitochondrial respiration in vitro. This study was designed to determine if oxygen consumption changes in intact animals occur in vivo during protamine administration. Oxygen consumption was assessed in seven dogs anticoagulated with heparin (150 IU/kg) and reversed 30 minutes later with protamine sulfate (1.5 mg/kg). Oxygen saturations measured included arterial (SaO2 arterial), mixed venous (SvO2 systemic), jugular (SvO2 jugular), portal (SvO2 portal), and coronary (SvO2 coronary). Cardiac output (CO) and carotid artery flow determinations allowed calculation of systemic oxygen consumption (VO2 systemic) and cerebral oxygen consumption VO2 cerebral. Hemodynamic measurements included arterial blood pressure (BP), pulmonary artery systolic and diastolic pressures (PAS, PAD), and heart rate (HR). Protamine sulfate administration resulted in hypotension (delta BP -64 mm Hg), pulmonary hypertension (delta PAS + 13 mm Hg, delta PAD + 11 mm Hg), and bradycardia (delta HR -30). Shortly after protamine administration, CO fell 54% and carotid artery flow fell more than 50%, yet declines in SvO2 systemic and SvO2 jugular were not observed. In fact these parameters increased 3% and 2%, respectively. VO2 systemic fell 55% and VO2 cerebral fell 57%. Similarly, SvO2 portal and SvO2 coronary increased 6% and 9%, respectively. Significant correlations existed between changes in VO2 systemic and BP (r = 0.05, p less than 0.001), HR (r = 0.3, p less than 0.01, PAD (r = -0.3, p less than 0.05, and CO (r = 0.8, p less than 0.001). Impaired oxygen utilization was most evident during the first 5 minutes after protamine administration. This investigation, for the first time, establishes that protamine sulfate decreases in vivo oxygen consumption, a finding that may account for certain of the drug's adverse side effects.

Animals↗
PubMed1989

Protamine-induced reductions of endothelial cell ATP.

Protamine, a polycationic protein used to reverse heparin anticoagulation, is frequently associated with decreased oxygen consumption, systemic hypotension, pulmonary artery hypertension, and bradycardia. This investigation examines the hypothesis that these events reflect toxic effects of protamine on endothelial cells. Cultured bovine pulmonary artery endothelium was exposed to protamine (12.5 to 500 micrograms/ml, corresponding to clinical doses 0.75 to 30 mg/kg), either alone (n = 6) or 3 minutes after exposure to heparin, 0.1 IU/microgram protamine (n = 6). ATP was measured 1 to 180 minutes after protamine by a luciferase-luciferin assay and cell viability determined by trypan blue exclusion. Ultrastructure was assessed by transmission electron microscopy. Polylysine, 25 micrograms/ml, a cytotoxic polycationic agent, was also studied. Dose-dependent reductions in ATP (range, -11% to -51%) and ATP per viable cell (up to -41%) occurred. Decreases in ATP did not occur until after 30 minutes with protamine alone, compared with differences as early as 1 minute after protamine with prior heparin. Progressive mitochondrial injury was noted evident by swollen cristae, vacuolization, and eventual disruption. Polylysine caused similar changes. Protamine decreases endothelial cell ATP and prior heparin exposure accelerates this effect. The toxicity may reside in the positive charges on these molecules and mitochondrial damage may account for reductions in cellular ATP and systemic oxygen consumption.

Adenosine Triphosphate↗
PubMed1989

A prospective study of clinically and endoscopically documented colonic ischemia in 100 patients undergoing aortic reconstructive surgery with aggressive colonic and direct pelvic revascularization, compared with historic controls.

Clinically and endoscopically proved ischemia of the colon complicates elective aortic reconstruction in 1% to 2% and 6% to 7% of cases, respectively. Operative mortality exceeds 60% when transmural infarction occurs. A prospective study of colonic ischemia was undertaken in 100 male patients (mean age, 62.4 +/- 7.9 years) undergoing operation for aortic aneurysms (58) or aortoiliac occlusive disease (42). Conventional aortic surgery was undertaken in 88 patients, and in 12 patients adjunctive procedures to enhance colonic perfusion were performed 14 times, including IMA reimplantation (8), direct bypass to the internal iliac artery (4), and anastomosis of an aortofemoral bypass limb to adjacent common iliac artery (2). Colonoscopy was performed within 24 to 48 hours of aortic reconstruction. Three patients had endoscopic evidence of colonic ischemia. Transmural infarction did not develop in any patient, and bowel resections or diverting colostomies were not necessary. Three patients died, none manifesting colonic ischemia. The 12% utilization of adjunctive procedures to enhance blood flow in the colon was substantially greater than the 4% frequency of an earlier experience from our institution in which nearly half of the 5.7% operative mortality was attributed to colonic infarction. Attention to factors contributing to ischemia of the colon, and more frequent adjunctive revascularization of the colon, may lessen this complication of aortic reconstructive surgery.

Angiography↗
PubMed1988

Lack of effect of dihydroergotamine on endothelial and smooth muscle cell proliferation and endothelial cell prostanoid production.

The most important effect of dihydroergotamine is venoconstriction, but certain metabolic effects and changes in vessel prostanoid activity have also been suggested. In this study endothelial cell production of 6-keto PGF1 alpha and TxB2 was quantitated in vitro. No evidence of altered prostanoid production was noted after incubation with dihydroergotamine (exposure ranging from 5 x 10(-3) to 5 x 10(-7) g/l). Similarly, no effect of dihydroergotamine on the growth rates of endothelial cells or smooth muscle cells in vitro was documented.

6-Ketoprostaglandin F1 alpha↗
PubMed1988

Comparison of static incubation versus physiologic perfusion techniques for quantitation of luminal release of prostacyclin and thromboxane in canine arteries and veins.

Intraluminal release of 6-keto-PGF1 alpha and TxB2 in ex vivo canine arteries and veins was assessed during five consecutive 15-min periods using static incubation and physiologic perfusion techniques. Arterial segments were perfused with 90 ml/min pulsatile flow at 100 mm Hg and vein segments with 90 ml/min nonpulsatile flow at 7 mm Hg. During the final 15-min period vessels were stimulated with arachidonic acid (AAS). Perfusion of vein segments caused a higher release of 6-keto-PGF1 alpha during the first 30 min (P less than 0.05) and following AAS (P less than 0.05) than did static incubation. Perfused arterial segments exhibited a higher release than did incubated segments of 6-keto-PGF1 alpha for 45 min (P less than 0.01) as well as following AAS (P less than 0.01). TxB2 release was higher during the entire observation period in perfused arteries and veins compared to incubated vessels (P less than 0.01 and less than 0.05, respectively). There was no correlation between the amounts of 6-keto-PGF1 alpha or TxB2 released when comparing values obtained by one technique to values obtained by the other (P greater than 0.1). These data suggest that flow related shear stress alters vascular prostanoid production, and that such should be accounted for when interpreting results of studies on prostacyclin and thromboxane release from intact vessels.

6-Ketoprostaglandin F1 alpha↗
PubMed1988

Anticoagulant effects of protamine sulfate in a canine model.

Protamine sulfate is considered a weak anticoagulant, yet little is known concerning the mechanism of this effect or its relation to prior heparin exposure. This investigation defined the influence of increasing doses of protamine, with and without prior heparin anticoagulation, on the activated clotting time (ACT), thrombin clotting time (TCT), prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen level, platelet count, and platelet aggregation to ADP in dogs (n = 8). Four doses of intravenous protamine sulfate (1.5, 3.0, 6.0, and 15.0 mg/kg) were studied in each animal, with at least 5 days between individual studies. Four dogs received heparin, 150 IU/kg 10 min prior to protamine sulfate administration, and four dogs received protamine sulfate alone. Protamine sulfate caused anticoagulation, both in the presence and absence of heparin, with significant changes occurring in the ACT, PTT, platelet count, and platelet aggregation. Relevant changes did not occur in the TCT, PT, or fibrinogen levels. Platelet effects were capable of causing bleeding with standard or excess use of protamine sulfate, especially if platelet numbers were already decreased, as might occur in surgical procedures where thrombocytopenia commonly accompanies major blood loss and replacement. The ACT, reflecting both the coagulation cascade and platelet function, was the test most profoundly affected by protamine overdosage, and therefore may be misleading as a measure of protamine reversal of heparin. The TCT, which is sensitive to heparin anticoagulation but not protamine-induced anticoagulation, should be more accurate in differentiating inadequate heparin reversal from the effects of excess protamine.

Animals↗
PubMed1988

Complement depletion and persistent hemodynamic-hematologic responses in protamine-heparin reactions.

Hypotension, bradycardia, pulmonary artery hypertension, neutropenia, and thrombocytopenia have been suspected to be due to complement activation following protamine reversal of heparin. This investigation examined these phenomena in complement-depleted animals. Eight dogs received intraperitoneal naja n. naja cobra venom factor (CVF), 20 U/kg, 48 and 24 hr prior to anticoagulation with sodium heparin, 150 IU/kg, and reversal 30 min later with protamine sulfate, 1.5 mg/kg. Decomplementation was confirmed in all dogs. Systemic blood pressure (BP), pulse (HR), pulmonary artery systolic and diastolic pressures, (PAS, PAD), cardiac output (CO), platelet count (PTC), and white blood count (WBC) with differential were monitored. The maximal mean changes for the entire group were BP, -43 mm Hg; HR, -16; PAS, +6 mm Hg; PAD, +3 mm Hg; CO, -27%; PTC, -49%; and WBC, -48%. These hemodynamic and hematologic responses, occurring in the face of CVF-induced decomplementation, support the conclusion that complement components C3 and C5-C9 are not influential factors contributing to these protamine-heparin-induced events.

Animals↗
PubMed1988

Influence of pressure, flow rate, and pulsatility on release of 6-keto-PGF1 alpha and thromboxane B2 in ex vivo-perfused canine veins.

The influence of pressure, flow, and pulsatility on the release of prostacyclin (measured as 6-keto-PGF1 alpha) and thromboxane (measured as TxB2) was assessed in canine jugular veins perfused ex vivo with Hanks' balanced salt solution for five consecutive 15-minute periods. Control segments were perfused at 7 mm Hg with nonpulsatile flow at a rate of 90 ml/min, whereas experimental segments were perfused with pulsatile flow as well as nonpulsatile flow at pressures of 50 or 100 mm Hg and flow rates of 60 or 130 ml/min. Prostacyclin release from control segments during the first 15-minute period was 49.5 +/- 7.4 pg/mm2/15 min, which declined to 13.9 +/- 2.5 pg/mm2/15 min after 60 minutes (p less than 0.002). Arachidonic acid stimulation during the last 15-minute perfusion period increased the release to 56.1 +/- 9.4 pg/mm2/15 min (p less than 0.002). Thromboxane release from control segments was initially 4.4 +/- 1.2 pg/mm2/15 min, which declined to 0.8 +/- 0.2 pg/mm2/15 min after 60 minutes (p less than 0.002), and subsequently increased with arachidonic acid stimulation to 1.3 +/- 0.1 pg/mm2/15 min (p less than 0.01). In contrast to control perfusion conditions, changes in nonpulsatile flow rates did not affect prostacyclin release, whereas thromboxane release was lower when perfused at 60 ml/min. Pressures of 50 and 100 mm Hg increased the initial release of prostacyclin. Similarly, pulsatile flow enhanced prostacyclin release at both low and high pressures, being more pronounced with the latter.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗
PubMed1988

The effect of protamine sulfate on platelet function.

The adverse effects of protamine sulfate, used to neutralize the anticoagulant action of heparin, include systemic hypotension, pulmonary artery hypertension, thrombocytopenia and leukopenia. For further evaluation of protamine's mechanism of action, a three-part investigation was performed. In part I platelet-rich plasma (PRP) was prepared from canine blood samples (n = 6) taken before and 2 minutes after injection of protamine. In part II human PRP (n = 5) was preincubated with protamine or distilled water. Adenosine diphosphate-induced aggregation of protamine-treated platelets was unchanged, but thrombin-induced aggregation was inhibited in both canine and human preparations (p less than 0.05). In part III thrombocytopenia was produced in splenectomized dogs (n = 5), using microporous filters, to 4.5-8.4% of the initial platelet count. Protamine reversal of the heparinization caused hypotension (maximally -29 mmHg 90 s after protamine), but not pulmonary arterial hypertension. Leukopenia developed before additional thrombocytopenia appeared. Protamine-platelet interaction inhibits thrombin-induced platelet aggregation. Platelets may play an important role in the pulmonary pressure rise during protamine reversal, but do not mediate the systemic hypotension.

Animals↗
PubMed1988

Endothelial cell proliferation in vitro after incubation with anticoagulant and antiplatelet drugs.

An in vitro tissue culture model was used in the evaluation of various anticoagulant and antiplatelet drugs on endothelial cell proliferation and eicosanoid production. Low concentrations, less than normally achieved plasma concentrations of various heparins (beef lung, porcine intestinal and low molecular weight heparin from porcine intestine), increased endothelial cell growth. Higher concentrations showed a decrease for regular heparins, most marked for beef lung heparin -45%, compared to -21% for porcine intestinal heparin, but still an increase, +22%, was noted for low molecular weight heparin. Of the antiplatelet drugs, ibuprofen and dazoxiben reduced plating efficiency and endothelial cell proliferation. Of the antiplatelet drugs, all but dipyridamole reduced prostacyclin metabolite production. The difference in endothelial cell proliferation between heparins is of great interest and warrants further investigation.

Animals↗
PubMed1988

Endothelial cell seeding of expanded polytetrafluoroethylene vena cava conduits: effects on luminal production of prostacyclin, platelet adherence, and fibrinogen accumulation.

The blood-surface interface of 12 mm ID x 5 cm ePTFE vena cava conduits, unseeded (n = 8) and seeded (n = 8) with enzymatically derived autologous endothelial cells, was studied in a canine model at 4 and 12 weeks after graft implantation. Acetylsalicylic acid (325 mg each day) and Coumadin (prothrombin time 1.4 to 1.7 times the control value) were administered preoperatively and continued 4 weeks postoperatively. Platelets labeled with 111In and 125I-labeled fibrinogen were administered 24 hours before graft removal. Luminal platelet adherence, expressed as 10(6) platelets/cm2 of graft surface, was 8.9 +/- 5.6 vs. 56.4 +/- 8.0 (p less than 0.008) and 4.0 +/- 0.9 vs. 12.4 +/- 2.3 (p less than 0.005) in seeded vs. unseeded grafts at 4 and 12 weeks, respectively. Luminal fibrinogen deposition, expressed in micrograms per square centimeter of graft surface, was 11.8 +/- 2.2 vs. 32.0 +/- 2.0 (p less than 0.06) and 6.1 +/- 2.4 vs. 12.4 +/- 6.3 (p less than 0.005) in seeded vs. unseeded grafts at 4 and 12 weeks, respectively. Cumulative 4- and 12-week luminal production of 6-keto-PGF1 alpha from seeded and unseeded grafts represented 11% and 5%, respectively, of that produced from the native iliac vein. Luminal endothelial cell coverage was 71% +/- 22% vs. 33% +/- 9% and 79% +/- 8% vs. 55% +/- 8% (p less than 0.05) in seeded and unseeded grafts at 4 and 12 weeks, respectively. Although endothelialization was not complete in seeded vena cava grafts, it is clear that seeded prostheses exhibited improved thromboresistance compared with unseeded conduits.

Animals↗
PubMed1988

Effect of anticoagulant and antiplatelet drugs on in vitro smooth muscle cell proliferation.

Effects of anticoagulant and antiplatelet drugs on vascular smooth muscle cell plating efficiency and proliferation were assessed using in vitro tissue culture techniques. Canine carotid artery smooth muscle cells were derived, pooled and plated into tissue culture cluster wells to which various drugs were added. Regular beef lung and porcine intestinal and low molecular weight porcine intestinal heparins reduced smooth muscle cell counts. Among antiplatelet drugs, reduced smooth muscle cell counts were seen with dipyridamole and ibuprofen, as well as with the combinations of ASA and dipyridamole, and ASA and dazoxiben. Although in vitro results cannot necessarily be extrapolated to in vivo settings, especially in regard to antiplatelet drugs, results of this study indicate direct effects of certain commonly used clinical agents in reducing smooth muscle cell growth.

Animals↗
PubMed1987

Stimulation of glycogenolysis in isolated hepatocytes by adenosine and one of its analogues is inhibited by caffeine.

The adenosine analogues 5'-(N-ethyl)carboxamidoadenosine (NECA) and N6-(phenylisopropyl)adenosine (PIA) activate glycogen phosphorylase 5-fold and 4.2-fold respectively in rat hepatocytes incubated in the absence of endogenous adenosine. Half-maximally effective concentrations are 0.5 microM for NECA and 20 microM for PIA, demonstrating the presence of A2-adenosine receptors. Exogenous adenosine activates phosphorylase 4.6-fold, but high rates of adenosine disappearance from the medium render estimates of its half-maximally effective concentration unreliable. These effects of NECA and adenosine are inhibited by 0.1 mM-caffeine. Activation of phosphorylase by a physiological concentration of adenosine (3.3 microM) was 50% inhibited by a physiological concentration of caffeine (35 microM).

Adenosine↗
PubMed1987

Protamine reversal of anticoagulation achieved with a low molecular weight heparin. The effects on eicosanoids, clotting and complement factors.

Hemodynamic and hematologic effects of protamine reversal of low molecular weight heparin (LMWH) anticoagulation with and without protamine pretreatment, as well as reversal of anticoagulation with unfractionated standard heparin (SH), were studied in canine subjects. Protamine reversal caused less severe thrombocytopenia in the two LMWH groups compared to SH animals, while neutropenia occurred equally in all groups. Cl-esterase inhibitor levels were minimally increased, whereas C3 levels and leucotriene levels were unaltered. TxB2 and 6-keto-PGF1 alpha increased during protamine reversal of LMWH anticoagulation. TCT and APTT were affected less with LMWH than SH anticoagulation. Anti-Xa levels increased with anticoagulation in all animals, but protamine did not reverse the elevated anti-Xa levels in LMWH anticoagulated dogs to the same degree as occurred with SH anticoagulation. TCT, APTT and bleeding times were normalized by protamine in all animals. Protamine reversal of LMWH anticoagulation with or without protamine pretreatment did not reveal any clear differences in eicosanoids or complement factors compared to SH anticoagulation, although differences in anti-Xa activity clearly separated these two heparins.

Animals↗
PubMed1987

Alternative techniques of seeding cultured endothelial cells to ePTFE grafts of different diameters, porosities, and surfaces.

Attachment of 111Indium-oxine labeled cultured canine venous endothelial cells to expanded polytetrafluorethylene (ePTFE) grafts was evaluated in vitro. Three alternative seeding techniques were studied in grafts having different diameters, porosities, and surfaces, including: (I) manual milking of blood containing endothelial cells within the graft; (II) a two-step procedure of incubating grafts initially with blood and then with an endothelial cell suspension; and (III) mechanical spinning of grafts filled with blood containing endothelium. Method II had significantly higher cell attachment to the graft (11.6%) than did Method I (1.5%) or III (4.7%). A somewhat higher seeding efficiency was noted in 10-mm-I.D. grafts (11.6%) compared to 6-mm-I.D. grafts (6.3%). Different graft porosity, created by altering internodal distances, did not cause significant changes in cell attachment (10 microns, 13.4%; 30 microns, 6.3%; 90 microns, 16.0%). Fibronectin-coated surfaces, which should have enhanced cell adhesion, demonstrated a 6.0% cell attachment, a lower efficiency than the 11.6% observed with a blood coating alone. Acetone-soaked surfaces, which should have predictably exhibited less hydrophobicity, produced quite variable attachments (range 3.4 to 59.7%, mean 23.4%). In the present investigation the best seeding technique was method II, the two-step incubation procedure. Consistent differences were not noted with various ePTFE graft configurations or surfaces.

Animals↗
PubMed1987

Haemodynamic and haematologic alterations with protamine reversal of anticoagulation: comparison of standard heparin and a low molecular weight heparin fragment.

Reversal of anticoagulation with protamine sulfate causes many adverse haemodynamic and haematologic effects which could be due to differences in the mechanism of action of standard and low molecular weight heparin. Three groups of dogs were investigated: one group received normal saline pretreatment followed by heparinisation with standard heparin 150 IU/kg followed by protamine sulfate reversal 1.5 mg/kg after aortic interposition grafting: the second group were given normal saline pretreatment followed by heparinisation with low molecular weight heparin 150 U antiXa/kg and after grafting protamine sulfate reversal 1.5 mg/kg. The third group were given protamine sulfate pretreatment 2.25 mg/kg followed by low molecular weight heparin 150 U antiXa/kg and later protamine sulfate reversal 1.5 mg/kg after grafting. The same haemodynamic changes were seen regardless of the type of heparin or pretreatment with protamine given along with low molecular weight heparin. There was a suggestion that regular heparin cause a more pronounced increase in pulmonary artery pressure and a decrease in heart rate. On the other hand the systemic hypotension and reduction of cardiac output seemed more pronounced in the low molecular weight heparin group. Platelet count decreased less in the low molecular weight heparin group, but white blood cell count was equally reduced. Pretreatment with protamine did not abolish the adverse effects of protamine when reversing anticoagulation achieved with low molecular weight heparin, a finding not shared with standard heparin-protamine interactions.

Animals↗