Biomedical subjects

A K Chaudhary

Publications and source records attributed to A K Chaudhary.

At least 19 recordsLinked to original sources

PubMed2000

1,3-butadiene: cancer, mutations, and adducts. Part IV: Molecular dosimetry of 1,3-butadiene.

Analysis of N7-guanine adducts derived from 1,3-butadiene (BD) was conducted with use of liquid chromatography-mass spectrometry (LC-MS) in combination with stable isotope methods. The N7-guanine adducts were shown to undergo spontaneous depurination from DNA in vitro in both calf-thymus DNA and TK6-cell DNA. A comparison was made between BD-derived N7-guanine adduct concentrations both in liver DNA and urine of rats and mice exposed to BD. This has provided insight into the exposure of the animals to 1,2-epoxy-3-butene (BDO), 1,2,3,4-diepoxybutane (BDO2), and 1,2-dihydroxy-3,4-epoxybutane (BDO-diol), the three oxidative metabolites of BD thought to be responsible for BD-mediated carcinogenesis. The liver DNA of mice contained more of the two N7-guanine adducts of BDO--N7-2-hydroxy-3-butenyl-1-guanine (2HB1G) and N7-1-hydroxy-3-butenyl-2-guanine (1HB2G)--than the amounts in rats during the 10-day BD exposure and the 6 days after exposure that were monitored. An excess of 1HB2G over 2HB1G by a factor of approximately 10 in the rat liver and a factor of approximately 5 in the mouse liver was also observed. This regioselective difference was apparent during both the 10-day exposure and the 6 days after exposure. The half-lives of 2HB1G and 1HB2G were estimated as 4.3 days and 3.5 days, respectively, in the DNA of BD-exposed mice and rats. Higher amounts of 2HB1G and 1HB2G appeared in rat urine compared with mouse urine after the 10-day exposure to 1,250 ppm BD. Analysis of liver DNA for N7-guanine adducts derived from BDO2 revealed the presence of two diastereomeric forms of N7-(2,3,4-trihydroxybutyl)-1-guanine (THBG). One of the diastereomers [(+/-)-THBG] was formed by reaction of DNA with (+/-)-BDO2 or BDO-diol, and the other diastereomer (meso-THBG) was formed by reaction of DNA with meso-BDO2 or BDO-diol. There was more (+/-)-THBG and meso-THBG in liver DNA of mice compared with amounts in rats during the 10 days of BD exposure and the 6 days after exposure. A twofold excess of (+/-)-THBG over meso-THBG in rat liver was found at all of the time points monitored. After 10 days of exposure to BD, (+/-)-THBG in mouse liver was also present in an almost twofold excess over meso-THBG. At 6 days after exposure to BD, however, (+/-)-THBG and meso-THBG were present in almost equal amounts in mouse liver. Furthermore, amounts of the two THBG diastereomers in mouse liver 6 days after exposure to BD were almost fivefold greater than amounts in rat liver. The half-lives of (+/-)-THBG and meso-THBG appeared to be longer in mouse liver (4.1 days and 5.5 days, respectively) than in rat liver (3.6 days and 4.0 days, respectively). Higher amounts of (+/-)-THBG were excreted in rat urine compared with mouse urine. It is noteworthy that each of the N7-guanine adducts derived from BD was present in higher concentrations in the liver DNA of mice exposed to 1,250 ppm BD than in the liver DNA of rats exposed to the same dose. Conversely, each of the adducts was present in higher concentrations in the urine of rats compared with the urine of mice after exposure to 1,250 ppm BD.

Animals↗

PubMed1999

Quantitative analysis of cimetidine in human plasma using LC/APCI/SRM/MS.

A quantitative method was developed and validated for rapid and sensitive analysis of cimetidine in human plasma. The method involved the use of liquid chromatography (LC) coupled with atmospheric pressure chemical ionization (APCI) and selected reaction monitoring (SRM) mass spectrometry (MS). A cimetidine analog, SKF92374, was used as the internal standard. Separation of cimetidine and the internal standard was accomplished using a reverse-phase HPLC column (C18). The eluted components were ionized by the APCI source and subsequently detected by a highly selective triple quadrupole mass spectrometer in the SRM mode. Linear standard curves were obtained from 5 ng/mL (lower limit of quantitation) to 10,000 ng/mL. The results demonstrated excellent precision (%RSD 1. 1-8.9%) and accuracy (94.7-108.0%) over this range. In addition, the amount of plasma sample needed for analysis was small (50 muL), and the plasma pretreatment (analyte recovery >94%) was simple and time saving. This assay was used to evaluate cimetidine levels in premature infants following intravenous infusion of cimetidine.

Child↗

PubMed1999

Persistence of N7-(2,3,4-trihydroxybutyl)guanine adducts in the livers of mice and rats exposed to 1,3-butadiene.

Liquid chromatography (LC) in combination with tandem mass spectrometry (MS/MS) and stable isotope methodology was employed for the analysis of the N7-guanine (Gua) adducts derived from 1,2:3, 4-diepoxybutane (BDO2) a reactive metabolite of 1,3-butadiene (BD). Two diastereomeric forms of N7-(2,3,4-trihydroxybutyl)guanine (THBG) were identified in the livers of both mice and rats. One of the diastereomers [(+/-)-THBG] was formed by reaction of DNA with (+/-)-BDO2, and the other diastereomer (meso-THBG) was formed by reaction of DNA with meso-BDO2. There was significantly more (+/-)-THBG and meso-THBG in the liver DNA of the mice when compared with those of the rats during the 10 days of exposure to BD and the 6 days of postexposure that were monitored. There was a 2-fold excess of (+/-)-THBG over meso-THBG in the rat liver at all the time points. In the mouse liver after 10 days of exposure to BD, the (+/-)-THBG (3.9 adducts/10(6) normal bases) was also present in an almost 2-fold excess over meso-THBG (2.2 adducts/10(6) normal bases). However, 6-days after exposure to BD, (+/-)-THBG (1.2 adducts/10(6) normal bases) and meso-THBG (1.0 adduct/10(6) normal bases) were present in almost equal amounts in the mouse liver. Furthermore, there was an almost 5-fold excess of the two THBG diastereomers in the mouse liver DNA 6 days after exposure to BD when compared with rat liver DNA. The half-lives of (+/-)-THBG and meso-THBG appeared to be slightly longer in mouse liver (4.1 and 5.5 days, respectively) than in rat liver (3.6 and 4.0 days, respectively). The apparent persistence of these adducts in the mouse may contribute to the increased susceptibility of this species to BD-induced carcinogenesis. It is possible that (+/-)-THBG and meso-THBG could have also been derived from the reaction of DNA with the hydrolysis product of BDO2, 1,2-dihydroxy-3,4-epoxybutane (DHEB). Surprisingly, a vast majority of the studies in which the mutagenic and carcinogenic potential of BDO2 have been examined have only employed the commercially available (+/-)-BDO2. In light of the present findings, additional studies will be required to determine the potency of meso-BDO2 and the DHEB that is the precursor to meso-THBG as mutagens and carcinogens.

Animals↗

PubMed1999

Interrelationship between substrates and inhibitors of human CYP3A and P-glycoprotein.

PURPOSE: CYP3A and P-gp both function to reduce the intracellular concentration of drug substrates, one by metabolism and the other by transmembrane efflux. Moreover, it has been serendipitously noted that the two proteins have many common substrates and inhibitors. In order to test this notion more fully, systematic studies were undertaken to determine the P-gp-mediated transport and inhibitory characteristics of prototypical CYP substrates. METHODS: L-MDR1, LLC-PK1, and Caco-2 cells were used to evaluate established CYP substrates as potential P-gp substrates and inhibitors in vitro, and mdr1a deficient mice were used to assess the in vivo relevance of P-gp-mediated transport. RESULTS: Some (terfenadine, erythromycin and lovastatin) but not all (nifedipine and midazolam) CYP3A substrates were found to be P-gp substrates. Except for debrisoquine, none of the prototypical substrates of other common human CYP isoforms were transported by P-gp. Studies in mdr1a disrupted mice confirmed that erythromycin was a P-gp substrate but the CYP3A-inhibitor ketoconazole was not. In addition, CYP3A substrates and inhibitors varied widely in their ability to inhibit the P-gp-mediated transport of digoxin. CONCLUSIONS: These results indicate that the overlap in substrate specificities of CYP3A and P-gp appears to be fortuitous rather than indicative of a more fundamental relationship.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1997

Cellular retinoic acid-binding protein(II) presence in rat uterine epithelial cells correlates with their synthesis of retinoic acid.

Vitamin A (retinol) and retinoic acid are necessary for the maintenance of the female reproductive system of higher animals. Our previous work has demonstrated cell specific expression of cellular retinoic acid-binding protein (CRABP) and cellular retinoic-acid binding protein(II) [CRABP(II)] in the uterus of the rat. CRABP(II) expression was shown to be induced in the uterine surface epithelial cells by treatment of prepubertal rats with pregnant mare serum gonadotropin (PMSG). Here we report that, after PMSG treatment, collected uteri had markedly higher levels of retinoic acid than did the uteri of prepubertal rats treated with the control vehicle. Smooth muscle, stromal, and epithelial cells were then cultured from uteri from such animals and provided with retinol or with the retinol/retinol-binding protein complex. Retinoic acid production, analyzed by high-performance liquid chromatography, was observed for the epithelial cells from the uteri of prepubertal animals treated with PMSG, cells previously shown to express CRABP(II) and confirmed here to continue to express it in culture. Little or no retinoic acid was produced by cultured epithelial cells from the prepubertal uteri [shown previously to be negative for CRABP(II)] or by smooth muscle and stromal cells taken from uteri of prepubertal or PMSG-treated rats (shown previously to express CRABP). Retinoic acid production by uterine epithelial cells [and CRABP(II) expression] was also observed if the prepubertal rat was treated with estrogen before cell collection. At no time did cells expressing CRABP exhibit significant retinoic acid synthesis. Thus, this system revealed an important difference in retinoid metabolism between cells expressing CRABP and CRABP(II) and suggests CRABP(II) may participate in retinoic acid production and/or secretion.

Animals↗

PubMed1997

Analysis of the malondialdehyde-2'-deoxyguanosine adduct pyrimidopurinone in human leukocyte DNA by gas chromatography/electron capture/negative chemical ionization/mass spectrometry.

A method is described for the assay of the major malondialdehyde-deoxyguanosine adduct (M1G) based on immunoaffinity purification and gas chromatography/electron capture/negative chemical ionization/mass spectrometry. A stable isotope of M1G-deoxyribose ([2H2]M1G-dR) was used as an internal standard. Recovery of internal standard throughout the entire assay procedure was approximately 40%. The assay showed a linear response over a range of 10-1000 pg of M1G-dR and was verified by analysis of a synthetic. M1G-containing oligomer. The limit of detection in biological samples was 100 fmol/sample, corresponding to 3 adducts/10(8) bases for 1 mg of DNA. DNA was isolated from the blood of 10 healthy human donors, and M1G levels were measured. A mean value of 6.2 +/- 1.2 adducts/10(8) bases was obtained, with no obvious differences bases on age or cigarette smoking. A small, but statistically significant difference was observed between the levels in females (5.1 +/- 0.4 adducts/10(8) bases) and males 6.7 +/- 1.1 adducts/10(8) bases). The presence of M1G in leukocyte DNA was further verified by analysis using liquid chromatography/electrospray ionization mass spectrometry.

Adult↗

PubMed1997

Temperature-dependent formation of a conjugate between tris(hydroxymethyl)aminomethane buffer and the malondialdehyde-DNA adduct pyrimidopurinone.

The stability of the major adduct formed between the endogenous product malondialdehyde (MDA) and deoxyguanosine, a pyrimidopurinone termed M1G-dR, was tested under a variety of conditions required for nucleic acid manipulation. M1G-dR was found to be stable at neutral pH and 37 degrees C but to be unstable when stored at -20 degrees C in the presence of Tris buffers. A new product with a characteristic absorption band at 350 nm was identified by 1H-NMR as an enamino-imine comprised of one molecule of Tris, one molecule of MDA, and deoxyguanosine. The formation of the conjugate was observed on reaction of Tris with M1G-dR or its ring-opened derivative N2-(3-oxo-1-propenyl)deoxyguanosine. The Tris-M1G-dR conjugate was unstable in aqueous solutions at room temperature, undergoing hydrolysis. However, the Tris conjugate of M1G base remained stable at room temperature in organic solvent. The isolation and properties of a conjugate between M1G-dR and Tris suggest that cross-links may form by reaction of MDA with DNA but they are likely to be unstable to hydrolysis.

Cross-Linking Reagents↗

PubMed1996

Liquid chromatography/electrospray ionization tandem mass spectroscopy (LC/ESI MS/MS) analysis of 1,2-epoxybutene adducts of purine deoxynucleosides.

Calf thymus DNA was reacted with 1,2-epoxybutene (BDO) in phosphate buffered saline at 37 degrees C for 12 h. DNA was ethanol precipitated and hydrolyzed with 1 M HCl to release DNA bases. Adenine (A)-BDO and guanine (Gua)-BDO adducts were analyzed in the ethanol supernatant and DNA hydrolysate using LC/ESI MS/MS. Reaction of BDO with A resulted in the formation of seven A-BDO adducts with MH+ ions at m/z 206. Two of these adducts were observed in the ethanol supernatant. In addition, two formaidopyrimidine (FAPY)-adducts were detected with MH+ ions at m/z 224 in DNA hydrolysate. These data are consistent with formation of regioisomeric N-7 or N-9 adducts which can be released by spontaneous depurination or ring opening. Four other A-BDO adducts were detected in DNA hydrolysate. Similar adducts were observed for Gua. This new methodology permits simultaneous determination of initially formed adducts as well as those arising as a consequence of depurination. The latter adducts provide the opportunity for monitoring exposure to BDO through analysis of N-7 or N-3 adducts excreted in the urine.

Adenine↗

PubMed1996

Characterization of an N6-oxopropenyl-2'-deoxyadenosine adduct in malondialdehyde-modified DNA using liquid chromatography/electrospray ionization tandem mass spectrometry.

Animals↗

PubMed1994

Detection of endogenous malondialdehyde-deoxyguanosine adducts in human liver.

Endogenous DNA adducts may contribute to the etiology of human genetic disease and cancer. One potential source of endogenous DNA adducts is lipid peroxidation, which generates mutagenic carbonyl compounds such as malondialdehyde. A sensitive mass spectrometric method permitted detection and quantitation of the major malondialdehyde-DNA adduct, a pyrimidopurinone derived from deoxyguanosine. DNA from disease-free human liver was found to contain 5400 adducts per cell, a frequency comparable to that of adducts formed by exogenous carcinogens.

Adolescent↗

PubMed1994

Analysis of the malondialdehyde-2'-deoxyguanosine adduct in rat liver DNA by gas chromatography/electron capture negative chemical ionization mass spectrometry.

Malondialdehyde (MDA), a product of lipid peroxidation, causes mutations in bacterial and mammalian cells and cancer in rats. MDA reacts with deoxynucleosides in vitro and the monomeric adduct of MDA with deoxyguanosine (M1G-dR) is the major adduct formed. We have developed a sensitive analytical method to characterize and quantify M1G-dR from biological matrices using gas chromatography/electron capture negative chemical ionization mass spectrometry (GC/ECNCI MS). Reduction of M1G-dR with sodium borohydride produced a dihydro derivative (H2-M1G-dR). This more stable analog had improved high-performance liquid chromatographic characteristics which facilitated its isolation from biological fluids. H2-M1G-dR was converted to a monopentafluorobenzyl derivative with simultaneous depurination; it was then converted to the corresponding t-butyldimethylsilyl derivative and analyzed by GC/ECNCI MS. (2H2)H2-M1G was used as internal standard. Quantitative analysis was carried out using selected ion monitoring of m/z 302 and m/z 304 where the limit of detection was 10 pg (30 fmol) injected on-column. The level of M1G-dR in normal rat liver was 5.2 +/- 0.2 modified bases per 10(7) bases (n = 6 rats).

Animals↗

PubMed1993

Cranio-metaphyseal dysplasia.

Cranio-metaphyseal dysplasia in two brothers, aged fourteen and twelve, is reported. Both brothers presented with deafness, repeated episodes of cold and cough and mouth breathing. Striking craniofacial configuration consisted of hypertelorism, prominent glabella and zygomatic arches, mandibular prognathism and overgrowth of middle third of face. Both patients had genu valgum deformity. Low intelligence and poor scholastic performance present in both brothers were attributed to deafness. Radiographic features consisted of obtuse mandibular angle, defective dentition, sclerotic frontal sinuses, sclerotic mastoids and temporal bones. Splaying of metaphyses of long bones was associated with mild sclerosis. Mild degree of widening of ribs was also present. One brother also had hallux valgus deformity. The radiographic and clinical differentiation of cranio-metaphyseal dysplasia and metaphyseal dysplasia (Pyle's disease) is highlighted.

Adolescent↗

PubMed1992

Oxygen free radical producing activity of polymorphonuclear leukocytes in patients with Parkinson's disease.

Oxygen free radicals (OFRs) have been suggested in the pathogenesis of Parkinson's disease (PD). These free radicals exert their cytotoxic effect by peroxidation of lipid membrane resulting in the formation of malondialdehyde (MDA). Polymorphonuclear (PMN) leukocyte is one of the major sources of OFR. However, the oxygen free radical producing activity of PMN leukocytes in patients with PD is not known. We therefore studied the oxygen free radical producing activity of polymorphonuclear leukocytes and MDA levels in the serum of healthy subjects and in patients with Parkinson's disease. The oxygen free radical producing activity of PMN leukocytes in blood and the MDA content in serum were significantly higher in patients with Parkinson's disease than in healthy subjects. These results indicate a possible role of oxygen free radicals in the pathogenesis of Parkinson's disease.

Aged↗

PubMed1992

Increased oxygen free radical activity in patients on cardiopulmonary bypass undergoing aortocoronary bypass surgery.

Cardiac dysfunction after cardiopulmonary bypass (CPB) has been reported by various investigators. Oxygen free radicals have been shown to depress cardiac function and contractility. To evaluate the possible role of oxygen free radicals (OFR) in post-pump cardiac dysfunction, measurements of cardiac function, OFR producing activity of polymorphonuclear (PMN) leukocytes (PMN chemiluminescence) and malondialdehyde (MDA), a lipid peroxidation product, in blood were made at induction of anesthesia (T1), before cross clamping of the aorta (T2), after closure of the chest (T3), and 24 hours postoperatively (T4) in 21 patients undergoing aortocoronary bypass surgery. The total OFR-derived chemiluminescence at T1, T2, T3, and T4 was 1590 +/- 156, 3169 +/- 338, 1972 +/- 214, and 2614 +/- 366 mv.min.10(6) PMN-1, respectively. Superoxide dismutase (SOD)-inhibitable chemiluminescence at T1, T2, T3, and T4 was 1214 +/- 129, 2674 +/- 328, 1752 +/- 215, and 2139 +/- 292 mv.min.10(6) PMN-1, respectively. Superoxide anion at T1, T2, T3, and T4 was 0.99 +/- 0.14, 1.30 +/- 0.17, 1.07 +/- 0.14, and 1.19 +/- 0.12 nmol.10(6) PMN-1.30 min-1, respectively. Blood MDA at T1, T2, T3, and T4 was 0.17 +/- 0.02, 0.25 +/- 0.03, 0.20 +/- 0.03, and 0.23 +/- 0.02 nmol/ml, respectively. OFR-derived and SOD inhibitable chemiluminescence, superoxide anion, and blood MDA increased significantly during CPB and postoperatively. There were decreases in the blood pressure and stroke volume, and increases in the central venous pressure, capillary wedge pressure, and heart rate during CPB and postoperatively. Cardiac output remained unchanged during this procedure. There was leukopenia during CPB.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1991

Oxygen-derived free radicals producing activity and survival of activated polymorphonuclear leukocytes.

Activation of polymorphonuclear (PMN) leukocytes is known to generate oxygen free radicals (OFR). However the fate of activated PMN leukocytes is not known. We investigated the OFR producing (chemiluminescence) activity and the survival of the activated PMN leukocytes. The study was divided into two groups. Group I, In vivo study (n = 7): zymosan (8.4 mg/kg) was administered intravenously in the anesthetized dogs and the blood samples were collected before and after 5, 15, 30, 60 and 120 min of zymosan administration. This group represents the in vivo pre-stimulated PMN leukocytes; Group II, In vitro study (n = 7): the blood were collected from dogs and further divided into two groups. Group A (n = 7): non-stimulated, without any added zymosan and group B (n = 7): zymosan was added to stimulate PMN leukocytes. Blood samples from group A and B were also collected at various time intervals similar to in vivo studies. Oxygen free radical producing activity of PMN leukocytes was monitored by measuring luminol-dependent chemiluminescence (CL). Opsonized zymosan was used to activate PMN leukocytes. The studies in which the PMN leukocytes were stimulated in in vivo, both oxygen derived free radicals and superoxide dismutase (SOD) inhibitable oxygen free radical CL decreased significantly for 60 min and tended to reach thereafter to the pre-stimulated values. The resting chemiluminescence (chemiluminescence without zymosan stimulation in the assay medium) increased significantly for 15 min reaching to pre-stimulated values at 30 min and thereafter. In in vitro studies, oxygen derived free radicals CL of pre-stimulated PMN leukocytes (Group B) was depressed for the whole duration of investigation while SOD inhibitable CL was depressed for only 60 min. There was approximately a two-fold increase in the resting CL within 5 min of PMN leukocyte activation and it remained high for the whole duration of study. The chemiluminescence of non-stimulated PMN leukocytes in vitro (group A) remained practically normal throughout the period of observation. In in vivo studies, total white blood cells (WBC) and PMN leukocyte counts decreased initially and tended to approach towards pre-stimulated values at the end of the protocol. There were no changes in these counts in in vitro studies. These results indicate that the capacity to generate OFR is decreased in the in vivo and in vitro pre-stimulated PMN leukocytes. However this activity recovers with time. This study also suggests that the activated PMN leukocytes are not destroyed.

Animals↗

PubMed1991

Increased production of oxygen free radicals in cigarette smokers.

Oxygen free radicals are known to produce damage in many biological tissues. Cigarette smoking is a major risk factor for various diseases. It is possible that oxygen free radical producing activity of polymorphonuclear (PMN) leucocytes is increased by cigarette smoking. We studied the oxygen free radical producing (luminol-dependent chemiluminescent) activity of PMN leucocytes in blood and the malondialdehyde (lipid peroxidation product) content of blood and serum in nonsmokers and smokers. The zymosan-induced chemiluminescent activity was measured on a LKB 1251 luminometer. The malondialdehyde (MDA) was measured as thiobarbituric acid (TBA) reactive substances. The chemiluminescent activity due to oxygen-derived free radicals (superoxide anion, hydrogen peroxide, hydroxyl radical) and superoxide dismutase (SOD)-inhibitable (superoxide anion) in nonsmokers were 1215.1 +/- 91.1 and 849.3 +/- 72.3 mV min/10(6) PMN leucocytes respectively. There was a significant increase in the oxygen-derived free radicals and SOD-inhibitable chemiluminescence in smokers. The values of blood and serum MDA were 171.7 +/- 6.1 and 222.2 +/- 5.6 nmoles/l respectively in nonsmokers. There was an increase in both blood and serum MDA in smokers. These results suggest that the increased generation of oxygen free radicals by PMN leucocytes might be responsible for an enhanced risk of various diseases related to cigarette smoking.

Adult↗

PubMed1990

Effect of oxygen free radicals, hypoxia and pH on the release of liver lysosomal enzymes.

We investigated the effect of acidic environment, hypoxia and oxygen free radicals on the release of beta-glucuronidase from rat liver lysosomes. A lysosomal enriched fraction from the homogenate of rat liver was prepared, using differential centrifugation technique. Exogenous oxygen free radicals were generated using xanthine-xanthine oxidase system. The release of beta-glucuronidase activity was measured from the lysosomes. The lysosomal fraction was exposed to various pH (8.0, 7.4, 6.5, 6.0, 5.5) and pO2 (454, 172, 96, 57,34 mm Hg) separately or to a combination of low pH (5.5, 6.5) and low pO2 (34, 57 mm Hg). The changes in pH or pO2 separately did not cause any increase in the release of beta-glucuronidase activity. The presence of oxygen free radicals at each pH or pO2 resulted in about a 3-fold increase in the release of beta-glucuronidase. A combination of very low pO2 and pH (pO2 (mm Hg)/pH; 34/5.5, 34/6.5) resulted in an increased release of beta-glucuronidase from lysosomes. Oxygen free radicals in the presence of both low pO2 and pH resulted in a further increase in the release of beta-glucuronidase. These data indicate that oxygen free radicals and not the alterations in pH and/or pO2 are primarily responsible for the disruption of lysosomes.

Animals↗

PubMed1990

Effect of polymorphonuclear leukocyte-derived oxygen free radicals and hypochlorous acid on cardiac function and some biochemical parameters.

Polymorphonuclear (PMN) leukocyte activation is known to result in the production and release of oxygen free radicals and hypochlorous acid. Various clinical conditions are associated with PMN leukocyte stimulation. The present investigation deals with the effects of stimulated PMN leukocytes in the absence and in the presence of scavengers of oxygen free radicals (superoxide dismutase, catalase), hypochlorous acid quencher (methionine), and myeloperoxidase inhibitor (azide) on cardiac function and contractility; blood lactate, gases, and pH levels, blood and cardiac tissue malondialdehyde; and PMN leukocyte chemiluminescence activity in anesthetized dogs. Opsonised zymosan was used for stimulation of PMN leukocytes, and the effects were observed for 2 hours. The dogs were divided into four groups: group I, zymosan; group II, superoxide dismutase + catalase + zymosan; group III, methionine + zymosan; group IV, azide + methionine + zymosan. Zymosan produced a decrease in cardiac function and in indices of myocardial contractility and an increase in systemic and pulmonary vascular resistance. There was a decrease in blood pH and in PMN leukocyte chemiluminescense and an increase in the blood lactate and malondialdehyde. Superoxide dismutase plus catalase and methionine reduced the effect of zymosan on cardiac function and contractility and on blood malondialdehyde, lactate, and pH. The combination of azide and methionine did not prevent the deleterious effects of zymosan on cardiac function and contractility. Cardiac tissue malondialdehyde levels were lower in groups III and IV than in groups I and II which had values similar to each other. Methionine was superior to superoxide dismutase plus catalase in the prevention of the deleterious effects of PMN leukocyte stimulation on the various measured parameters. These results suggest that oxygen free radicals and hypochlorous acid are cardiac depressants and increase systemic and pulmonary vascular resistance in addition to causing tissue damage. Clinical situations with PMN stimulation may result in cardiac depression. The oxygen free radical scavenger and hypochlorous acid quencher may be beneficial in the counteraction of the deleterious effects of PMN leukocyte stimulation on the hemodynamic parameters and cellular integrity.

Animals↗