The toxicity of erythrocytic stroma.
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Animals↗
Biomedical subjects
M Feola
Publications and source records attributed to M Feola.
Mechanisms of toxicity of hemoglobin solutions.
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Animals↗
Effects of hemoglobin perfusion on contractile function of the isolated ventricular septa.
Effects of three unmodified hemoglobin solutions on myocardial contractile function was evaluated using isolated perfused rabbit interventricular septa. The hemoglobin solutions tested were: a human hemoglobin solution (SFHS-A), a bovine hemoglobin prepared by a column chromatography (SFHS-B), and a bovine hemoglobin obtained by a ultrafiltration method (SFHS-C). Myocardial effects were assessed by comparing contractile parameters; developed tension (DT), resting tension (RT), and perfusion pressure (PP), measured before (control perfusion with Tyrode buffer) and during hemoglobin perfusion. Further, to examine the effects of hemoglobin solutions on myocardial contractility following a period of impaired flow, septal responses to a 10-minute period of ischemia (stopflow) were also studied. After a 10-minute perfusion with hemoglobin solution, SFHS-C increased DT to 124 +/- 12% (paired t-test, p less than 0.05) without causing a significant increase in RT or PP while SFHS-A and SFHS-B decreased DT to 96 +/- 20% (p greater than 0.05) and to 77 +/- 7% (p less than 0.05), respectively. A significant rise in PP (40-50% above baseline) was also noted with these solutions (p less than 0.05). Similarly, after a 30-minute reperfusion following a 10-minute ischemia, SFHS-C allowed significantly better percentage recovery (95 +/- 3%) than septa perfused with SFHS-A (81 +/- 2%) or SFHS-B (63 +/- 6%) (Student's t-test, p less than 0.05). These results indicate that hemoglobin solution, if properly prepared, does not seem to have acute deleterious effects on contractile function of the isolated heart.
Animals↗
Complement activation and the toxicity of stroma-free hemoglobin solutions in primates.
The toxicity of hemoglobin solutions was studied in the context of their ability to activate serum complement (C). Three bovine polymerized hemoglobin solutions (BPHSs) with different degrees of purity were used for experiments in vitro and in vivo. BPHS-1 contained bacterial endotoxins (E) (5 EU/ml) and stromal phospholipids (PLs) (1.2 mg/dl), BPHS-2 contained only PLs (2.0 mg/dl), while BPHS-3 was completely free of both contaminants. C-activation was studied by the direct measurement of C3a, C4a, and C5a des Arg fragments, using commercially available RIA kits. During 1 hour of incubation with fresh monkey plasma, BPHS-1 and -2 activated both pathways of C, while BPHS-3 caused no activation of any factor. In vivo, Hb solutions were used to replace one-third of blood volume in three groups of six Coebus monkeys each, while fresh homologous plasma was used in a control group of four animals. Impure solutions activated the alternative pathway of C and caused significant reactions of the circulating blood (thrombocytopenia, leukopenia, and disseminated intravascular coagulation) associated with multiorgan dysfunction (cardiac arrhythmias, hypoxemia, reduction of renal clearance of endogenous creatinine, and elevation of liver enzyme SGPT). The pure solution neither activated C nor caused any reaction in the circulating blood. However, it caused a moderate degree of direct tissue injury, evidenced by transient reduction of creatinine clearance and elevation of SGPT. These observations suggest that impure and pure Hb solutions carry separate mechanisms of toxicity. Complement, activated by toxic impurities, plays an active role in the toxicity of impure solutions. C-activation in vitro could be used as a screening test of biocompatibility.
Animals↗
Toxicity of polymerized hemoglobin solutions.
Four solutions of bovine polymerized hemoglobin (BPHS) and rabbit plasma were used to replace one-third of the blood volume in five groups of rabbits. The first three solutions were "impure" because of the presence of stromal phosphatidyl-ethanolamine and phosphatidyl-serine in BPHS-1, environmental endotoxins in BPHS-2, and a large amount of higher molecular weight hemoglobin-glutaraldehyde polymers in BPHS-3. These solutions caused a 33 per cent mortality rate and significant morbidity which was characterized by hemodynamic instability, respiratory and renal insufficiency, elevation of hepatic enzyme levels, thrombocytopenia, leukopenia, disseminated intravascular coagulation (DIC) and activation of the alternate pathway of complement. Histopathologic changes found in the heart, lungs, liver, spleen and kidney were characterized by a combination of ischemic and inflammatory lesions. Fibrin thrombi were visible by immunofluorescence in the microcirculation. In contrast, the fourth solution (BPHS-4) was free of the aforementioned impurities; caused no deaths and minimal morbidity, which was limited to elevated levels of serum glutamic pyruvic transaminase and reduction of creatinine clearance; no DIC or complement activation, and mild histopathologic changes which were exclusively ischemic in nature. The results of this study indicated that the toxicity of polymerized hemoglobin solutions is due principally to the presence of impurities. Pure hemoglobin does exhibit mild toxicity when compared with a control solution which is most likely due to a vasoconstrictor effect of oxyhemoglobin.
Animals↗
"Isolength" postextrasystolic potentiation as a predictor of functional restoration following surgical revascularization for myocardial ischemia.
A previously developed method of programmed postextrasystolic potentiation (PESP) was assessed in eight patients with medically refractory unstable angina, as a predictor of functional restoration resulting from surgical revascularization. Prior to coronary arteriography, left ventricular segmental wall motion was determined during ventricular pacing and the first postextrasystolic beat following an extrasystole. The postextrasystole was induced at an interval calculated to occur at a time where ventricular preload was identical to the regular paced beat (isolength interval). The left ventricular wall was divided into six segments, each subscribing one area of the ventriculogram, and correction for rotation during systole was made. Of 48 segments, 21 were considered "jeopardized," due to greater than 70% reduction in cross-sectional lumen of the serving coronary arteries. Fifteen of these 21 responded to PESP, increasing their segmental area ejection fraction from 44 +/- 5 (paced "normal" beat) to 56 +/- 6 (postextrasystolic beat) (p less than 0.05). Following surgical revascularization, these segments showed an improvement in their baseline area ejection fraction from 44 +/- 6 to 58 +/- 5 (p less than 0.05). Six jeopardized segments that failed to respond to PESP prior to revascularization showed functional deterioration after revascularization. The 27 non-jeopardized segments (which were not revascularized) also showed functional improvement, suggesting improved collateral flow. This study demonstrates that isolength postextrasystolic potentiation obtained with a standardized pacing protocol may be used to predict the potential for improvement in cardiac function following surgical revascularization. Our results also show that lack of PESP predicts loss of left ventricular myocardial function following revascularization.
Aged↗
Human lung post-proline endopeptidase: purification and action on vasoactive peptides.
Post-proline endopeptidase (PPE, EC 3.4.21.26) was purified 3,450 times from human lung. PPE was routinely assayed with the artificial substrate, carbobenzoxy-glycyl-L-prolyl-p-nitroanilide (Z-Gly-Pro-pNA). The pH optimum was 7.4, and the Mr was 77,000. Thiol blocking agents were strongly inhibitory but serine blocking agents were not inhibitory. No metal ions were required for activity, but heavy metal ions such as Hg2+, Cu2+, Cd2+, and Zn2+ completely inactivated the enzyme. Both dithiothreitol (DTT) and ethylenediaminetetraacetic acid (EDTA) were required to stabilize PPE activity. Michaelis constant values for Z-Gly-Pro-pNA and carbobenzoxy-glycyl-L-prolyl-2-naphthylamide were 0.36 and 0.10 mmol/l, respectively. PPE cleaved vasoactive peptides including bradykinin (BK) and des-(Arg9)-BK (Pro3-Gly4 and Pro7-Phe8 bonds), angiotensins I and II (Pro7-Phe8 bond), substance P (Pro4-Gln5 bond), and oxytocin (Pro7-Leu8 bond). Each of these peptides inhibited PPE-catalyzed hydrolysis of Z-Gly-Pro-pNA competitively. BK had the lowest Ki value (2.35 mumol/l) and oxytocin had the highest Ki value (84.0 mumol/l). PPE was not inhibited by captopril, a potent inhibitor of angiotensin converting enzyme, which also cleaves the Pro7-Phe8 bond of BK.
Cations, Divalent↗
Nonthrombogenic small-caliber human umbilical vein vascular prosthesis.
The present investigation demonstrates covalent binding of heparin with carbodiimide to ammonium hydroxide-treated collagenous surfaces. Human umbilical vein grafts (HUVG) outperform carotid arteries of goat, porcine, and canine origin in both heparin loading and stability of the immobilized heparin preparation. The average heparin loading on the untreated carotid arteries and HUVGs and ammonium hydroxide-treated HUVGs were 18, 27, and 31.5 micrograms/cm2, respectively. There was negligible loss of heparin activity under in vitro and in vivo conditions. In vitro studies demonstrate that heparin-bound HUVGs discourage platelet adhesion and subsequent fibrin clot formation. In vivo studies with heparin-bound HUVGs show a significant increase in thrombus-free surface compared with control grafts. Heparin-bound HUVGs also show an enhanced patency rate in the two sets of protocols tested--one lasting for 3 in vivo days (seven grafts) and the other lasting for 7 (15 grafts) in vivo days. The studies conducted so far demonstrate the promise of developing a nonthrombogenic small-caliber HUVG prosthesis.
Ammonium Hydroxide↗
Parathyroid hormone reduces acute ischemic injury of the myocardium.
Synthetic parathyroid hormone (PTH), particularly the molecular fragment containing amino acids one to 34 (1-34), has been shown to produce coronary vasodilation and systemic vasodilation without tachycardia. On this basis, we tested the hypothesis that PTH(1-34) would favorably affect oxygen balance in acutely ischemic myocardium and reduce the extent of injury after coronary occlusion. Experiments were done upon the left anterior descending coronary artery which was ligated through a thoracotomy in anesthetized dogs subjected to ligation of the left anterior descending coronary artery. After 30 minutes of ischemia, the dogs were randomly assigned to either a group which received an intracoronary infusion of 0.008 nanomoles per kilogram of body weight per minute of PTH (1-34) for ten minutes at intervals of 30 minutes or a control group which received intracoronary saline solution. PTH(1-34) increased circumflex artery blood flow 290 +/- 62 per cent (p less than 0.005) and coronary venous return from the ischemic area 190 +/- 12 per cent (p less than 0.005) while reducing mean arterial pressure 12.5 +/- 1.7 per cent (p less than 0.05) without a change in the heart rate. These hemodynamic changes resulted in a 54.3 +/- 3.7 per cent (p less than 0.005) decrease in ischemic myocardial oxygen extraction and a reduction of infarct size (25 +/- 5 per cent of myocardium at risk in treated versus 75 +/- 10 per cent in the control group). It is concluded that PTH given after coronary artery occlusion increases collateral blood flow and oxygen supply to the ischemic myocardium while reducing oxygen requirements. Thus, PTH may offer significant protection for the acutely ischemic myocardium.
Animals↗
Studies on heparin immobilization to collagen.
After activation of carboxyl groups with carbodiimide, heparin binds to collagen by a stable covalent linkage. Covalent binding of heparin to collagen results in enhanced stability of the preparation. Also, heparin bound collagen retains its anticoagulative activity.
Anticoagulants↗
Nonthrombogenic arterial reconstruction.
Carboxyl groups of heparin were activated by carbodiimide (EDC) to allow stable covalent binding of heparin to various arterial reconstructions. Ammonium hydroxide treated Human Umbilical Veins Grafts (HUVG) outperform carotid arteries of goat, porcine and canine origin in both heparin loading and stability. In-vitro studies reveal that heparin bound HUVG retains its anticoagulative activity, showing promise towards the development of a nonthrombogenic small-caliber vascular prosthesis.
Ammonium Hydroxide↗
Vasoactive parathyroid hormone in the treatment of acute ischemic left ventricular failure and the prevention of cardiogenic shock.
Molecular fragment 1-34 of synthetic bovine parathyroid hormone (bPTH[1-34]) has been found to be a potent coronary vasodilator, a moderate systemic vasodilator, and a positive inotropic agent for the myocardium. On that basis, the hypothesis was tested that "vasoactive" PTH might be effective in the treatment of acute ischemic left ventricular failure (LVF) and the prevention of cardiogenic shock. Dogs whose sympathetic nerve activity was blocked by a combination of reserpine, propranolol, and chlorpromazine were anesthetized and subjected to open-chest occlusion of the left anterior descending coronary artery (LAD) plus sequential ligation of three diagonal branches. In ten untreated animals (control group), acute myocardial ischemia led to LVF and, within 4 hours, to cardiogenic shock (50% or greater reduction in cardiac output; 30% or greater reduction in mean aortic pressure; elevation of left atrial pressure above 20 mm Hg; and significant elevation of arterial blood lactate concentration). At the end of 4 hours, myocardial infarction measured by the incubation of transverse slices of the left ventricle in TTC solution represented 96 +/- 3% of the myocardium "at risk." In ten treated animals (experimental group), PTH(1-34) was administered intravenously, 1 U/kg/min, starting 30 minutes after coronary occlusion. Treatment improved left coronary blood flow from 55 +/- 5 to 120 +/- 11 ml/100 g LV/min, increased cardiac index from 72.5 +/- 7 to 117.5 +/- 12 ml/kg/min, reduced left atrial pressure from 27.5 +/- 2.5 to 15 +/- 2.5 mm Hg (all changes, P less than 0.005), sustained aortic pressure, and prevented the elevation of arterial blood lactate. At the end of 4 hours, myocardial infarction represented 30 +/- 1.2% of the myocardium at risk (difference between the two groups significant, P less than 0.005). Thus, PTH(1-34) exerted a tissue-sparing effect on the myocardium, restored LV function, and prevented the development of shock.
Animals↗
Development of a bovine stroma-free hemoglobin solution as a blood substitute.
A glutaraldehyde-polymerized or "stabilized" B-SFHS has been developed and tested in rabbits. This solution has been found to be nontoxic in terms of animal survival, nonantigenic when administered in single large volume infusions and capable of remaining in the circulation for a prolonged period of time while retaining the ability to transport and offload oxygen. Additionally, replacement of up to two-thirds of the blood volume with SB-SFHS was found to be advantageous over replacement with plasma protein fraction in terms of survival. By virtue of its unlimited supply, this bovine hemoglobin solution represents a new option for a "blood substitute."
Animals↗
Hemodilution with stroma-free hemoglobin solution.
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Hemodilution↗
Improved oxygenation of ischemic myocardium by hemodilution with stroma-free hemoglobin solution.
Experiments were conducted in anesthetized open-chest dogs subjected to occlusion of the left anterior descending coronary artery for three hours. The oxygenation of myocardial tissue was monitored by a polarographic technique capable of recording simultaneously the oxygen tension (Po2) of myocardial tissue and electrograms. Ischemic injury was monitored by means of ST-segment elevations on myocardial and epicardial electrograms. The volume of the myocardial infarct was measured at the end of each experiment by incubation of transverse slices of left ventricle in a solution of nitroblue tetrazolium and by separation of the unstained (ischemic) from the stained (normal) portions. In one group of dogs, hemodilution was performed after 15 minutes of ischemia by exchanging blood with a stroma-free hemoglobin solution (from a hematocrit reading of 45 +/- 3 percent to 23 +/- 2 percent). Changes occurring in this group were compared with those occurring in dogs that did not undergo hemodilution, underwent hemodilution with dextran 75, or were transfused with whole blood. Hemodilution with hemoglobin reduced aortic and left ventricular filling pressures while increasing coronary blood flow, increased myocardial Po2 from 2 +/- 2 mm Hg to 8 +/- 2 mm Hg (P less than 0.005), lowered the ST-segment elevation of both myocardial and epicardial electrograms, and reduced the volume of the myocardial infarct. These effects were unmatched by hemodilution with dextran or infusion of whole blood.
Animals↗
Alterations in cardiac lymph dynamics in acute myocardial ischemia in dogs.
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Acute Disease↗
Attenuation of cardiac sympathetic drive in experimental myocardial ischemia in dogs.
Sympathetic discharges to the heart were recorded from the left inferior cardiac nerve of 16 dogs. Inferior cardiac nerve activity (ICNA) under normal conditions consisted of grouped discharges, synchronous with the cardiac cycle and modulated by respiration. After ligation of the circumflex branch of the left coronary artery, ICNA declined concomitant with a decline in heart rate and mean aortic pressure. After 30 minutes, when arterial pressure tended to recover toward control values (six dogs), ICNA remained low; in contrast, when arterial pressure dropped to shock levels (three dogs), ICNA increaed. When aortic pressure fell precipitously as a result of ventricular fibrillation, even during the first 30 minutes of ischemia (seven dogs), ICNA immediately increased greatly. The results of this study suggest that acute coronary occlusion produces a cardiocardiac depressor reflex with attenuation of sympathetic discharge to the heart. This reflex, under the experimental conditions studied, gives way to the baroreceptor reflex when aortic pressure drops to critically low levels.
Animals↗
Improved survival after coronary bypass surgery in patients with poor left ventricular function: role of intraaortic balloon counterpulsation.
The operative mortality rate of aortocoronary bypass surgery in 23 patients with poor left ventricular function (ejection fraction 0.30 or less) operated on in 1973-74 was 34.7 percent. The incidence rate of operative myocardial infarction was 30.4 percent. In an attempt to improve survival, intraaortic balloon counterpulsation was used therafter in 25 similar patients. Counterpulsation was instituted preoperatively and continued intra- and postoperatively for 2 to 5 days. Preoperative studies revealed an "unloading" effect of the left ventricle, with significant reductions of systolic arterial blood pressure, end-diastolic pulmonary arterial pressure and end-diastolic left ventricular volume and pressure. Metabolic improvement was demonstrated by the lesser production of myocardial lactate after pacing-induced tachycardia when the ventricle was balloon-assisted. Intraoperatively, blood flow through the vein graft was found to increase with counterpulsation. The rate of operative myocardial infarction was reduced to 4 percent and the mortality rate to 8 percent. In patients who have sustained a significant loss of functioning myocardium, the beneficial hemodynamic and metabolic effects of intraaortic balloon counterpulsation appear to prevent furhter, possibly critical, myocardial damage in the perioperative period.
Assisted Circulation↗