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Biomedical subjects

B Weksler

Publications and source records attributed to B Weksler.

At least 37 records · Page 2Linked to original sources
PubMed1995

Isolated lung perfusion with FUDR is an effective treatment for colorectal adenocarcinoma lung metastases in rats.

Currently, the only treatment capable of significantly prolonging survival in patients with isolated pulmonary metastases from colorectal adenocarcinoma is complete resection. Systemic chemotherapy has been shown to provide little benefit. We evaluated the efficacy of highdose, organ-specific 2'-deoxy-5-fluorouridine (FUDR) using a model of isolated single-lung perfusion (ILP) in the rat. On day 0, 28 BDIX rats were inoculated intravenously with 10(6) viable Sp-5 colorectal adenocarcinoma cells. On day 10 after-tumor inoculation, animals were randomized into five treatment groups. Group I received a continuous intravenous infusion of FUDR (1 mg.kg-1.d-1) for 7 days administered by an osmotic minipump. Group II underwent isolated left lung perfusion with a buffered Hespan solution, groups III to V underwent ILP with 3.5, 7, and 14 mg of FUDR per milliliter of the buffered Hespan solution, respectively. Animals undergoing ILP were anesthetized with pentobarbital, intubated, and ventilated, and then underwent left thoracotomy with cannulation of the pulmonary artery; the pulmonary artery and vein were clamped proximally. Groups II to V were perfused for 20 minutes at a rate of 1 mL/min, followed by a 5-minute washout with FUDR-free buffered Hespan solution. On day 26 after tumor inoculation, the animals in all groups were sacrificed and their lungs were stained and counted. Animals that underwent ILP with 14 mg of FUDR per milliliter of the buffered Hespan solution showed a significant decrease in the number of tumor nodules on the treated side versus the number on the untreated side (455.2 +/- 87.3 versus 11 +/- 6.4; p < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Adenocarcinoma↗
PubMed1995

Isolated single-lung perfusion: a study of the optimal perfusate and other pharmacokinetic factors.

BACKGROUND: Isolated single-lung perfusion with doxorubicin hydrochloride was shown to be effective in clearing experimental sarcoma lung metastases in the rat. The best perfusate to be used for isolated lung perfusion and factors affecting the final lung concentration of doxorubicin are the subject of the present study. METHODS: In experiment 1, 60 animals were randomized to undergo isolated left lung perfusion with doxorubicin with six different perfusates (n = 10 per group): saline, low-potassium-dextran, 5% albumin, 6% hetastarch, 5% buffered albumin, and 6% buffered hetastarch. Five animals served as negative controls. After perfusion, the lung wet to dry ratio and final lung doxorubicin concentration were determined. In experiment 2, 60 animals underwent isolated left lung perfusion with either 80 micrograms/mL or 320 micrograms/mL of doxorubicin. Animals were perfused at either 0.5 mL/min or 1 mL/min and for 2, 6, or 10 minutes. At the end of the perfusion period, the left lung doxorubicin concentration was measured. Statistical analysis included analysis of variance, the Duncan test for multiple comparisons, and multiple linear regression analysis. Significance was defined as a p value of less than 0.05. RESULTS: In experiment 1, perfusion with 6% buffered hetastarch resulted in the lowest lung wet to dry ratio, significantly different from all groups except the controls. Perfusion with low-potassium-dextran solution led to the highest final lung concentration of doxorubicin. In experiment 2, a model to predict final lung doxorubicin concentration was constructed: Log (final lung concentration) = 1.9 + 0.0071.P + 0.186.T, where P is the measured perfusate concentration of doxorubicin, and T is the time of perfusion in minutes. The R2 was 0.91 and p, less than 0.001. The dose of doxorubicin per kilogram of animal body weight, the dose of doxorubicin per square meter of body surface area, the total amount of doxorubicin delivered, and the rate of perfusion did not meet the criteria to enter the equation. CONCLUSIONS: Isolated lung perfusion experiments should use 6% buffered hetastarch as the perfusate. The perfusate doxorubicin concentration and the duration of perfusion are the only factors determining the final lung concentration of doxorubicin. In lung perfusion experiments, the dose of chemotherapy is not as important as the perfusate concentration and the duration of the perfusion. Animals should be perfused at a lower rate so the lungs are exposed to less doxorubicin without changing the final lung concentration.

Albumins↗
PubMed1995

Thymoma: a multivariate analysis of factors predicting survival.

BACKGROUND: Despite complete surgical excision, malignant thymomas often recur with resultant death. We reviewed our series to determine which factors independently predict survival after surgical resection. METHODS: A retrospective analysis of patients operated on for thymoma between 1949 and 1993 at Memorial Sloan-Kettering Cancer Center was performed. Clinical data were collected from chart review. Only patients with a pathology report confirming the diagnosis of thymoma were included in this analysis. Kaplan-Meier survival curves were generated and comparisons of survival analyzed by log rank test. Multivariate analysis was performed by the Cox proportional hazard model. RESULTS: One hundred eighteen patients with thymoma underwent operation. There were 86 complete resections (73%), 18 partial resections (15%), and 14 biopsies (12%). By Masaoka staging, 25 patients were stage I (21%), 41 stage II (35%), 43 stage III (36%), and 9 stage IVa (8%). Overall survival was 77% at 5 years and 55% at 10 years. Tumor recurred in 25 (29%) of 86 completely resected thymomas. Stage of disease (p = 0.03) was the only independent prognostic factor affecting recurrence. By multivariate analysis, stage (p = 0.003), tumor size (p = 0.0001), histology (p = 0.004), and extent of surgical resection (p = 0.0006) were independent predictors of long-term survival. CONCLUSIONS: Patients with stage I disease require no further therapy after complete surgical resection. Neoadjuvant therapy should be considered for patients with large tumors and invasive disease.

Combined Modality Therapy↗
PubMed1994

Isolation and characterization of human bone marrow microvascular endothelial cells: hematopoietic progenitor cell adhesion.

To examine potential mechanisms by which hematopoiesis may be regulated by endothelial cells within the bone marrow (BM) microenvironment, we have devised a technique for the in vitro study of the interaction of human BM microvascular endothelial cells (BMEC) with hematopoietic cells. Microvessels isolated by collagenase digestion of spicules obtained from filtered BM aspirate were plated on gelatin-coated plastic dishes, and colonies of endothelial cells grown from microvessel explants were further purified by Ulex europaeus lectin affinity separation. BMEC monolayers isolated by this technique grew in typical cobblestone fashion, stained positively with antibody to factor VIII/von Willebrand factor, and incorporated acetylated LDL. Immunohistochemical studies showed that BM microvessels and BMEC monolayers express CD34, PECAM, and thrombospondin. Incubation of resting BMEC with BM mononuclear hematopoietic cells resulted in the selective adhesion of relatively large numbers of CD34+ progenitor cells and megakaryocytes. The binding of purified BM-derived CD34+ progenitor cells to BMEC was dependent on divalent cations and was partially blocked by antibodies to CD34. IL-1 beta treatment of BMEC monolayers resulted in an increase of CD34+ progenitor cell adhesion by mechanisms independent of CD34 or divalent cations. BMEC exhibit specific affinity for CD34+ progenitor cells and megakaryocytes, suggesting that the BM microvasculature may play a role in regulating the trafficking, proliferation, and differentiation of lineage specific hematopoietic elements, and possibly of pluripotent stem cells within the CD34+ population.

Antigens, CD↗
PubMed1994

Effect of growth hormone on tumor and host in an animal model.

BACKGROUND: The relative effects of growth hormone on tumor versus host growth and protein metabolism are not known. This study examines the influence of recombinant rat growth hormone (r-rGH) on host and tumor growth, host body composition, and protein synthesis of tumor and host in tumor-bearing rats. METHODS: After left flank implantation of methylcholanthrene-induced sarcoma, 28 Fischer rats with palpable tumor were treated with s.c. saline or 1 mg/kg/day r-rGH for 11 days. At death, fractional protein synthetic rates (FSRs) of tumor, liver, and gastrocnemius muscle were determined. In a separate experiment, 27 tumor-bearing rats received saline or 1 mg/kg/day r-rGH for 2 weeks. Tumor and host growth and host body composition were analyzed. RESULTS: Animals treated with r-rGH had significantly higher liver FSR than did controls (233 +/- 27%/day vs. 110 +/- 4%/day, respectively). No significant differences were associated with growth hormone administration with respect to tumor growth, host composition, or FSR of tumor or muscle. CONCLUSIONS: Growth hormone stimulates liver protein synthesis, without changing tumor growth, protein synthesis, or host composition in this rat sarcoma model. Further investigation of growth hormone as an anticachectic agent is warranted.

Animals↗
PubMed1994

Isolated single-lung perfusion with TNF-alpha in a rat sarcoma lung metastases model.

We conducted a trial of isolated lung perfusion using tumor necrosis factor (TNF) in an experimental sarcoma lung metastasis model. In an in vitro experiment, methylcholanthrene-induced sarcoma cells were incubated for 48 hours with 42 micrograms/mL of either human or murine TNF. Controls were incubated with Hank's balanced salt solution. In an in vivo experiment, 23 F344 rats were injected with 10(7) methylcholanthrene-induced sarcoma cells. On day 7, 4 animals were perfused with 210 micrograms of murine TNF, 5 animals were perfused with 420 micrograms of murine TNF, 10 animals underwent isolated lung perfusion with 420 micrograms of human TNF, and 4 animals were injected systemically with 420 micrograms of human TNF. Animals were sacrificed on day 14 and the lung nodules counted. The cells incubated with murine TNF exhibited a 21% decrease in growth (p = 0.07); cells incubated with human TNF showed a 37% decrease in growth (p < 0.05). Animals perfused with 210 micrograms/mL of murine TNF and animals treated by systemically administered human TNF showed no tumor response. Animals perfused with 420 micrograms/mL of murine TNF had 7.8 +/- 14.2 nodules on the left lung and 58.5 +/- 66.0 nodules on the right lung (p = 0.07). Animals perfused with 420 micrograms/mL of human TNF had 21.7 +/- 18.3 nodules on the left lung and 91.7 +/- 66.2 nodules on the right lung (p < 0.01). On the basis of these findings, we conclude that isolated lung perfusion with TNF can be done safely in the rat and is effective in decreasing the growth of sarcoma lung metastases.

Animals↗
PubMed1994

A simplified method for endotracheal intubation in the rat.

Endotracheal intubation in small laboratory animals is often necessary for survival experiments. Methods of airway control have included tracheostomy, blind intubation, and intubation under direct vision. Most of these methods are unsatisfactory and associated with high failure and complication rate. We developed an easy method of endotracheal intubation in the rat that requires simple material that is easily available to any research facility. The animals were anesthetized with pentobarbital sodium, the tongue was pulled out, and an otoscope was introduced into the oropharynx. By direct vision, a guide wire was inserted into the trachea and a 16-gauge intravenous catheter was glided over the wire. The first group of 70 rats underwent left thoracotomy with endotracheal intubation and mechanical ventilation at our laboratory as part of a study on isolated lung perfusion. The second group of five rats was anesthetized with pentobarbital, and a left carotid catheter and an endotracheal tube were inserted. Animals were ventilated with 100% O2. Arterial blood gases were sampled before intubation, 30 min after ventilation, and 60 min after extubation. In the first group, 94.3% (66 of 70) of the animals survived surgery and mortality was not directly related to the intubation and/or ventilation. All five animals of the second group survived the procedure to be extubated. Arterial PO2 before intubation, 30 min after intubation and ventilation, and 60 min after extubation was 77.1 +/- 8.5, 465.0 +/- 55.6, and 98.9 +/- 12.8 Torr, respectively. PCO2 at the same time points was 42.5 +/- 10.1, 35.1 +/- 6.3, and 32.7 +/- 6.5 Torr, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia↗
PubMed1994

Isolated single lung perfusion with doxorubicin is effective in eradicating soft tissue sarcoma lung metastases in a rat model.

The only effective therapy for patients with metastatic soft tissue sarcoma in the lung is surgical resection, with a 5-year survival of approximately 25%. Because systemic chemotherapy has not significantly affected survival in these patients, we began to investigate locoregional chemotherapy. We have previously shown that isolated single lung perfusion with doxorubicin in the rat results in higher lung tissue levels and lower systemic toxicity than does high-dose intravenous therapy. In the present study, we examined the safety of isolated lung perfusion with doxorubicin and its efficacy in the treatment of experimental pulmonary metastases from soft tissue sarcoma. In experiment 1, 15 F344 rats were randomized into three groups (n = 5): group I had isolated left lung perfusion with doxorubicin 320 micrograms/ml in saline solution; group II had left isolated lung perfusion with doxorubicin 480 micrograms/ml and group III with doxorubicin 640 micrograms/ml. All perfusions with doxorubicin were at 0.5 ml/min for 10 minutes followed by perfusion of saline solution for 5 minutes. On day 21, all animals underwent right (contralateral) pneumonectomy and were observed for over 10 days. In experiment 2, two groups of F344 rats were injected intravenously with 10(7) viable methylcholanthrene-induced sarcoma cells on day 0. On day 7, group I (n = 12) had left isolated lung perfusion with saline solution only and group II (n = 15) had isolated lung perfusion with doxorubicin 320 micrograms/ml. On day 21, all animals were killed, and their lungs were stained for metastases. Routine histologic sections from three animals from group II were examined. In experiment 1, 80% of the animals in group I survived contralateral pneumonectomy. There were no survivors in groups II and III. In experiment 2, three animals died after isolated lung perfusion (one from group I and two from group II), and one animal (group I) was excluded because of mediastinal tumor. All animals in both groups had massive tumor replacement of the right (untreated) lung. Group I animals had massive tumor replacement of the left (treated) lung, whereas animals in group II had eradication of metastases in nine of ten cases; no microscopic evidence of tumor was detected in all three animals evaluated for microscopic disease. Isolated lung perfusion with doxorubicin 320 micrograms/ml is safe and effective in eradicating experimental pulmonary sarcoma metastases in this model.

Animals↗
PubMed1993

Biochemical and functional properties of recombinant human sickle hemoglobin expressed in yeast.

Previous studies had indicated that recombinant and natural human sickle hemoglobin had similar chemical properties (Martin de Llano, J. J., Schneewind, O., Stetler, G., and Manning, J. M. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 918-922). In the present study, additional biochemical and physiological characterization of some primary through quaternary structural features of recombinant sickle hemoglobin are described. The molecular weight of the purified recombinant sickle hemoglobin was identical to natural sickle hemoglobin as determined by mass spectrometry, thus excluding extensive post-translational modification in the yeast system. Carboxypeptidases A and B together catalyzed the release of COOH-terminal amino acids at the same rate for recombinant and natural hemoglobin S, consistent with identity in their primary and secondary structures in this region of the molecule. The tryptic peptide maps of natural and recombinant hemoglobins were practically indistinguishable, indicating the same internal protein sequences for recombinant and natural hemoglobins. As a probe of the secondary structure of recombinant sickle Hb, the reactivity of the SH group of Cys-93(beta) was investigated for the glutathione sickle hemoglobin adduct, which has significant anti-gelling and anti-sickling properties. The position of glutathione at Cys-93(beta) was established by direct mass spectrometric analysis of enzyme digests; reduction of this derivative to the unmodified chains was also observed by mass spectrometry and by isoelectric focusing. The oxygen equilibrium curves of recombinant and natural sickle hemoglobin at high protein concentration were superimposable with identical Hill coefficients of 3.3. The response of recombinant sickle hemoglobin to chloride with respect to a lowered oxygen affinity was identical to that of natural sickle hemoglobin. The gelation properties of recombinant and natural sickle hemoglobins were identical at the high hemoglobin concentrations that occur in the red cell. Therefore, the yeast expression system synthesizes a completely functional recombinant sickle hemoglobin with the same biochemical and physiological properties as natural sickle hemoglobin with respect to features characteristic of its primary through quaternary structures.

Amino Acids↗
PubMed1993

Growth hormone administration preserves lean body mass in sarcoma-bearing rats treated with doxorubicin.

Cachexia and malnutrition play a significant role in the morbidity associated with antineoplastic chemotherapy regimens. Conventional nutritional support during cancer therapy has shown little benefit in terms of reducing morbidity and mortality. We examined the anabolic properties of growth hormone (GH) that preserve normal body composition in sarcoma-bearing animals treated with doxorubicin. On day 0, 40 male Fischer 344 rats were inoculated with 10(6) methylcholanthrene-induced sarcoma cells s.c. in the left flank. On day 9, animals were randomized into 3 groups: control (CTL, n = 13); doxorubicin (DOX, n = 13); and doxorubicin plus GH (DOX-GH, n = 14). Two CTL animals were excluded due to tumor invasion into the peritoneal cavity. From day 9 to day 23, the DOX-GH group received daily s.c. recombinant rat GH injection (1 mg/kg). On day 13, DOX and DOX-GH groups received 7 mg/kg of DOX i.v. while the CTL group received sham i.v. sterile saline injection. Body weight and tumor dimensions were measured daily. On day 23, all animals were weighed and sacrificed. Tumors were resected and weighed. Body composition analysis was performed. Plasma GH levels were measured by radioimmunoassay and insulin growth factor 1 levels were measured by chondrocyte proliferation bioassay. The DOX-GH group had a significantly higher mean body weight, carcass weight, total fat free body mass, insulin growth factor 1, and GH plasma levels as compared to the DOX group. No difference in total food intake was observed between the DOX and DOX-GH groups. There was no difference in final tumor weight and tumor growth rate between DOX and DOX-GH groups. Exogenous growth hormone can attenuate weight loss and preserve host body composition in tumor-bearing rats treated with doxorubicin without stimulating tumor growth.

Animals↗
PubMed1993

Isolated single-lung perfusion with doxorubicin is pharmacokinetically superior to intravenous injection.

To investigate new modalities in the treatment of pulmonary metastases we developed a model of isolated single-lung perfusion in the rat. In this study we compare the pharmacokinetics of isolated lung perfusion and intravenous doxorubicin. In the first experiment, designed to evaluate lung tissue levels of doxorubicin, 35 rats were randomized into seven groups (n = 5). The first five groups underwent isolated lung perfusion with 72.1 +/- 6.9, 118.4 +/- 12.1, 255.2 +/- 12.8, 384.1 +/- 46.2, and 457.6 +/- 32.5 micrograms/mL of doxorubicin, respectively, for 10 minutes. Groups 6 and 7 received 5 mg/kg and 7 mg/kg of intravenous doxorubicin, respectively. A second study was designed to measure heart tissue level of doxorubicin in 3 groups of 5 rats each. Two groups received 5 or 7 mg/kg of intravenous doxorubicin and a third group underwent isolated lung perfusion with 255.2 +/- 12.8 micrograms/mL of doxorubicin for 10 minutes. A third study, designed to evaluate toxicity in vivo, had a similar design, and the animals were followed up for 21 days after treatment. Lung doxorubicin concentration after isolated lung perfusion was significantly higher than after intravenous doxorubicin (p < 0.01). Tissue doxorubicin concentration was 25 and 20 times higher after isolated lung perfusion with 255.2 +/- 12.8 micrograms/mL than after 5 or 7 mg/kg of intravenous doxorubicin, respectively. Heart concentration of doxorubicin was significantly lower after isolated lung perfusion with 255.2 +/- 12.8 micrograms/mL of doxorubicin as compared with 5 or 7 mg/kg of intravenous doxorubicin (p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Isolated single lung perfusion in the rat: an experimental model.

To evaluate isolated single lung perfusion with chemotherapy in a rat lung metastasis model, we developed a model of in vivo isolated single lung perfusion. Twenty male rats were anesthetized with pentobarbital sodium (50 mg/kg) and intubated endotracheally. A left thoracotomy was performed with an operating microscope (x16 magnification), the left pulmonary artery was cannulated, and a left pulmonary venotomy was performed. Isolated left lung perfusion was performed for 10 min at 0.5 ml/min with heparinized whole blood (n = 10) or 0.9% normal saline (n = 10). Pulmonary vein effluent was collected by suction. Nineteen of the 20 (95%) animals survived isolated left single lung perfusion. Twenty-one days after isolated left lung perfusion right pneumonectomy was performed. Fifteen of the 19 animals (78%) survived right pneumonectomy. Postoperatively, animals that survived surgery recovered preoperative body weight. In vivo isolated single lung perfusion in rats is feasible with low mortality and morbidity and may be useful in the study of isolated perfusion with chemotherapy and in diverse physiological and pharmacological experiments.

Anesthesia↗
PubMed1992

Laparoscopy in the evaluation of the intrathoracic abdomen after penetrating injury.

Penetrating trauma to the intrathoracic abdomen is a difficult clinical problem, especially with reference to the detection of diaphragmatic injuries. A retrospective analysis of 657 laparotomies for penetrating abdominal trauma at our institution revealed 78 laparotomies with negative results. The majority (44.8%) were for wounds in the lower chest and upper abdomen. The role of laparoscopy in evaluating these difficult areas was studied in 40 (34 stab wounds and 6 gunshot injuries) patients. Fifteen stab wounds and five gunshot wounds were nonpenetrating. Laparoscopy revealed eight clinically unsuspected diaphragmatic lacerations in seven patients. Twenty patients had hemoperitoneum. Five patients with omental bleeding and abdominal wall bleeding and four with nonbleeding liver lacerations underwent nontherapeutic laparotomies. One patient with a nonbleeding liver laceration was observed successfully without laparotomy. Ten of the 20 patients with hemoperitoneum had therapeutic laparotomies. The incidence of diaphragmatic lesions discovered by laparoscopy in this series was comparable with that reported after a mandatory laparotomy for thoracoabdominal wounds. It is concluded that laparoscopy is an excellent modality for the evaluation of the intrathoracic abdomen and the diaphragm.

Abdominal Injuries↗
PubMed1990

Vascular prostacyclin is increased in patients ingesting omega-3 polyunsaturated fatty acids before coronary artery bypass graft surgery.

Interest in the antithrombotic potential of diets enriched with fish oil-derived polyunsaturated fatty acids (omega-3 PUFAs) prompted us to examine how these fatty acids, when taken preoperatively, affect hemostasis, plasma lipid levels, and production of prostacyclin (PGI2) by vascular tissues in atherosclerotic patients undergoing coronary artery bypass graft surgery. Fifteen patients with angiographically proven coronary artery disease received 3 g/day eicosapentaenoic acid and 1.3 g/day docosahexaenoic acid as capsules of purified fish oil for 28 days before surgery. Platelet aggregation induced by low concentrations of ADP, collagen, and epinephrine decreased (p less than 0.05) and serum thromboxane B2 decreased 36% (p less than 0.01) from baseline values. Bleeding times increased 40% (p less than 0.01) from baseline. Serum triglycerides decreased 50% (p less than 0.05) without a change in total serum cholesterol. Spontaneous production of PGI2 measured as 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha), its stable hydrolytic product, by saphenous vein and aortic and atrial tissues obtained at surgery was greater in tissues from patients receiving omega-3 PUFA supplements than in tissues from matched controls (13.8 +/- 2.2 versus 8.6, 21.0 +/- 3.1 versus 11.5 +/- 2.1, and 166 +/- 13 versus 102 +/- 15 ng/g, respectively, all p less than 0.05). Arachidonate-stimulated production of PGI2, as indicated by increased levels of 6-keto-PGF1 alpha, was increased. Despite changes in platelet function, bleeding time, and vascular PGI2, the perioperative blood loss was not increased in subjects receiving fish oil supplements. Thus, omega-3 PUFAs at moderate dosages may exert antithrombotic effects by increasing prostacyclin production by vessel walls as well as by direct inhibition of platelet activity.

Aged↗
PubMed1983

Purification of human platelet calcium-activated protease. Effect on platelet and endothelial function.

Calcium-activated protease (CAP) was purified from the cytosol fraction of homogenized human platelet concentrates using a combination of gel filtration chromatography and affinity chromatography on antipain aminohexyl-Sepharose and activated thiol-Sepharose 4B. Purified CAP is composed of two different polypeptides of Mr = 80,000 and 27,000. Half-maximal protease activity was observed at 0.52 mM Ca2+, and all activity was inhibited by antipain, leupeptin, and N-ethylmaleimide. Activated CAP showed a time-dependent inactivation in the presence of 1 mM Ca2+ with only 5% of the control protease activity remaining after a 1-h exposure to calcium. Preincubation of washed platelets with varying amounts of CAP (0.2-0.4 units) significantly interfered with thrombin-induced platelet aggregation. In addition, ristocetin-induced platelet agglutination in the presence of von Willebrand factor was completely inhibited by 0.4 units of CAP. Concomitant with these protease-induced changes in platelet function, a decrease was observed in a major glycoprotein band of Mr = 150,000 present in platelet membranes and presumed to be glycoprotein Ib. In addition to these effects on platelets, CAP inhibited thrombin-induced production of prostacyclin by cultured human endothelial cells in a dose-dependent manner when the cells were pretreated with CAP. Thus platelet CAP can modulate membrane functions in both platelets and endothelial cells and may thus contribute to the regulation of hemostasis.

Blood Platelets↗
PubMed1981

The effects of crystalloid potassium cardioplegic solution on arterialized canine vein grafts. Assessment of chronic prostacyclin production and histopathologic alterations.

Efforts to improve myocardial preservation during aortocoronary bypass procedures have led to the perfusion of saphenous vein segments with potassium cardioplegic (KCP) solutions after completion of the distal anastomosis. Recent reports show that the procurement of veins leads to varying degrees of damage, particularly to the endothelial surface, as a result of the dissection itself, the hydrostatic pressure required to distend the veins in obtaining hemostasis and the composition of the solutions used to irrigate the harvested segments. The biologic activity of arterialized vein segments is largely unknown. We tested the hypothesis that the degree of venous injury inherent in vein harvesting may be compounded by perfusion with a potassium-rich solution, a known vascular irritant. The external jugular vein was removed from 18 dogs. Half of the vein was perfused with 300 ml of a KCP solution at 4 degrees C (40 mEq/l KCl, 10 ml sodium bicarbonate, pH 7.6, osmolarity 340 mosmol) and the other half with lactated Ringer's solution (LR). The treated vein was reversed and interposed into the excluded internal carotid circulation. A sham dissection was done on the opposite jugular vein. The veins were harvested after 6 weeks and assayed for spontaneous and arachidonate-stimulated (AS) prostacyclin activity as well as light microscopic analysis of morphologic changes. Spontaneous and AS production of prostacyclin did not differ significantly in the sham, LR and KCP groups: 1539 +/- 709 and 4166 +/- 1802, 1569 +/- 763 and 3767 +/- 2706, 1860 +/- 1233 and 3947 +/- 3347 pg/ml). Light microscopic analysis revealed an intense adventitial fibrotic reaction in the KCP group and the appearance of fibroblast-like cells in the outer layer of the vein wall. The intima was intact in all three groups. We conclude that intimal damage sustained during harvesting is repaired within 6 weeks, and there is no impairment to surface production of prostacyclin. The intense adventitial fibrotic reaction observed in the KCP-treated group has not been previously reported, and its significance remains unexplained.

6-Ketoprostaglandin F1 alpha↗
PubMed1978

Collagen-induced platelet aggregation and release. I Effects of side-chain modifications and role of arginyl residues.

To investigate the mechanisms governing collagen interaction with blood platelets, the effects of side-chain modifications on collagen-induced platelet aggregation and release of serotonin were studied. Since many chemical modifications alter the ability of collagen to form fibers that, according to current theory, may complicate interpretation of data, we eliminated this possibility by using collagen stabilized in a native-type fibrillar structure by treatment with either glutaraldehyde or ultraviolet irradiation. Acetylation, methylation, succinylation, treatment with 2,4-dinitrofluorobenzene, 2,4,6-trinitrobenzene sulfonic acid or 1,2-cyclohexanedione, and deguanidination with hypobromite were used to modify collagen side-chain reactive groups: amino, carboxyl, hydroxyl and guanidino. Both unmodified monomeric dispersed and fibrillar collagen preparations initiated platelet aggregation and release, although the kinetics and magnitude of the response were different. Monomeric collagen which had been modified by deguanidination, methylation or succinylation, failed to polymerize in physiological conditions and did not induce platelet aggregation and release. However, none of the chemical modifications of stabilized native-type collagen fibers, except treatment with hypobromite or cyclohexanedione, had an effect on collagen-induced platelet aggregation and release. Both hypobromite and cyclohexanedione modified guanidino groups of arginyl residues. Results showed that the ability of a collagen sample to induce platelet aggregation and release of serotonin is dependent on the arginine content of fibrillar collagen. These data demonstrate that manipulation of amino, carboxyl and hydroxyl groups is unimportant as long as the native-type fibrillar structure is maintained, and that arginyl residues are directly involved in collagen-platelet interaction. Moreover, the data suggest that only the arginyl residues in the Y position of the tripeptide unit Gly-X-Y of collagen are responsible.

Amino Acid Sequence↗