Biomedical subjects

B J Buckley

Publications and source records attributed to B J Buckley.

At least 19 recordsLinked to original sources

PubMed2000

Adaptive responses to peroxynitrite: increased glutathione levels and cystine uptake in vascular cells.

We and others recently demonstrated increased glutathione levels, stimulated cystine uptake, and induced gamma-glutamylcysteinyl synthase (gamma-GCS) in vascular cells exposed to nitric oxide donors. Here we report the effects of peroxynitrite on glutathione levels and cystine uptake. Treatment of bovine aortic endothelial and smooth muscle cells with 3-morpholinosydnonimine (SIN-1), a peroxynitrite donor, resulted in transient depletion of glutathione followed by a prolonged increase beginning at 8-9 h. Concentration-dependent increases in glutathione of up to sixfold occurred 16-18 h after 0.05-2.5 mM SIN-1. Responses to SIN-1 were inhibited by copper-zinc superoxide dismutases and manganese(III)tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride, providing evidence for peroxynitrite involvement. Because glutathione synthesis is regulated by amino acid availability, we also studied cystine uptake. SIN-1 treatment resulted in a prolonged increase in cystine uptake beginning at 6-9 h. Increases in cystine uptake after SIN-1 were blocked by inhibitors of protein and RNA synthesis, by extracellular glutamate but not by extracellular sodium. These studies suggest induction of the x(c)(-) pathway of amino acid uptake. A close correlation over time was observed for increases in cystine uptake and glutathione levels. In summary, vascular cells respond to chronic peroxynitrite exposure with adaptive increases in cellular glutathione and cystine transport.

Adaptation, Physiological↗

PubMed1998

The use of controlled-release oxycodone for the treatment of chronic cancer pain: a randomized, double-blind study.

To compare the effectiveness and safety of controlled-release (CR) oxycodone tablets with immediate-release (IR) oxycodone in patients with chronic cancer pain, a multicenter, randomized, double-blind, parallel-group study was performed in 111 patients with cancer pain. Patients were treated with 6 to 12 tablets or capsules of fixed-combination opioid/nonopioid analgesics per day at study entry. Patients received 30 mg of CR oxycodone tablets every 12 hr or 15 mg of IR oxycodone four times daily for 5 days. No titration or supplemental analgesic medications were permitted. The mean (+/- SE) baseline pain intensity (0 = none, 1 = slight, 2 = moderate, 3 = severe) was 1.5 +/- 0.1 for the CR oxycodone-treated group and 1.3 +/- 0.1 for the group given IR oxycodone (P > 0.05). The 5-day mean pain intensity was 1.4 +/- 0.1 and 1.1 +/- 0.1 for the CR and IR groups, respectively (P > 0.05). Discontinuation rates were equivalent (33%). There was no significant difference between treatment groups in the incidence of adverse events. This study demonstrates that cancer pain patients given 6 to 12 tablets or capsules of fixed-dose combination analgesics can be equally well treated with CR oxycodone administered every 12 hr or IR oxycodone four times daily at the same total daily dose. CR oxycodone offers the benefits of twice daily dosing.

Adult↗

PubMed1998

Controlled-release oxycodone compared with controlled-release morphine in the treatment of cancer pain: a randomized, double-blind, parallel-group study.

Controlled-release oral formulations of oxycodone and morphine are both suitable analgesics for moderate to severe pain. They were compared in cancer-pain patients randomized to double-blind treatment with controlled-release oxycodone (n = 48) or controlled-release morphine (n = 52) every 12 h for up to 12 days. Stable analgesia was achieved by 83% of controlled-release oxycodone and 81% of controlled-release morphine patients in 2 days (median). Following titration to stable analgesia, pain intensity (0=none to 3=severe) decreased from baseline within each group (p </= 0.005), from 1.9 (0.1) to 1.3 (0.1), mean (SE), with controlled-release oxycodone, and from 1.6 (0.1) to 1.0 (0.1) with controlled-release morphine (no significant between-group differences). Typical opioid adverse experiences were reported in both groups. Hallucinations were reported only with controlled-release morphine (n = 2). Visual analog scores (VAS) for 'itchy' and 'scratchin' were lower with controlled-release oxycodone (p </= 0.044), as was peak-to-trough fluctuation in steady-state plasma concentration (p = 0.004). The correlation between plasma concentration and dose was stronger (p = 0.026) for oxycodone (0.7) than morphine (0.3). The relationship between pain intensity (VAS) and plasma concentration was more positive for oxycodone (p = 0.046). There was a positive relationship between morphine-6-glucuronide concentrations and urea nitrogen and creatinine levels (p = 0.001). Controlled-release oxycodone was as effective as controlled-release morphine in relieving chronic cancer-related pain, and as easily titrated to the individual's need for pain control. While adverse experiences were similar, controlled-release oxycodone was associated with less itching and no hallucinations. Controlled-release oxycodone provides a rational alternative to controlled-release morphine for the management of moderate to severe cancer-related pain.

Clinical Trial↗

PubMed1998

Comparison of controlled-release and immediate-release oxycodone tablets in patients with cancer pain.

PURPOSE: This study compared the clinical efficacy of oxycodone hydrochloride controlled-release (CR) tablets administered every 12 hours with immediate-release (IR) oxycodone tablets administered four times daily in patients with cancer-related pain. PATIENTS AND METHODS: Cancer patients who required therapy for moderate to severe pain were randomized to CR oxycodone every 12 hours (n=81) or IR oxycodone four times daily (n=83) for 5 days in a multicenter, double-blind study. Pain intensity was assessed four times daily (categorical scale of none, slight, moderate, and severe); acceptability of therapy was assessed twice daily (categorical scale of very poor, poor, fair, good, and excellent). RESULTS: Pain intensity remained slight during the study, with mean oxycodone doses of 114 mg/d (range, 20 to 400 mg/d) for CR and 127 mg/d (range, 40 to 640 mg/d) for IR. Acceptability of therapy was fair to good with both treatments. While standard conversion ratios provided an acceptable dose for many patients, a protocol amendment that allowed initial titration and use of rescue medication reduced the discontinuation rate for lack of acceptable pain control (from 34% to 4% with CR and from 31% to 19% with IR before and after amendment, respectively) without increasing the discontinuation rate for adverse events (from 8% to 7% with CR and from 13% to 11% with IR). Fewer adverse events were reported with CR (109) than with IR (186) oxycodone (P=.006). CONCLUSION: CR oxycodone every 12 hours was as effective as IR oxycodone four times daily in managing moderate to severe cancer-related pain and was associated with fewer reports of adverse events.

Analgesics, Opioid↗

PubMed1998

Long-term administration of controlled-release oxycodone tablets for the treatment of cancer pain.

We conducted a study of the safety of controlled-release (CR) oxycodone tablets (OxyContin Tablets) administered chronically to patients with cancer-related pain in a usual clinical setting. These patients had participated in 1 of 2 double-blind, active-control studies. Our study was an open, 3-month treatment study that included 87 patients. Patients received CR oxycodone tablets every 12 hr in a manner that reflected typical clinical practice. Supplemental immediate-release (IR) oxycodone was available PRN for breakthrough pain. Patients recorded medication use, adverse events, and evaluations of pain intensity and acceptability of therapy in a daily diary. Forty-four patients (51%) completed all 12 weeks of study; 43 patients (49%) discontinued participation. At baseline and throughout the study period, the overall mean pain-intensity score was slight to moderate. A comparison of initial and final doses showed a significant but modest increase in total daily CR oxycodone dose. An increase or decrease in titration of the oxycodone dose occurred for 66 patients (84%) at least once during the 12-week study period, primarily for increased pain. Forty-four patients (56%) did not undergo dose titration when the latter was indicated. Half of the patients used IR oxycodone rescue almost daily; the mean number of rescue doses per day was 1.5. Despite stable pain control and an increasing total daily CR oxycodone dose, the percentage of patients reporting common opioid-related adverse events decreased over the course of the study. CR oxycodone tablets administered every 12 hr were successfully used to manage cancer pain over a 12-week period. Importantly, side effects diminished over time without a concomitant change in efficacy.

Administration, Oral↗

PubMed1997

Tunicamycin increases intracellular calcium levels in bovine aortic endothelial cells.

Tunicamycin is a nucleoside antibiotic that inhibits protein glycosylation and palmitoylation. The therapeutic use of tunicamycin is limited in animals because of its toxic effects, particularly in cerebral vasculature. Tunicamycin decreases palmitoylation of the endothelial isoform of nitric oxide synthase, stimulates nitric oxide synthesis, and increases the concentration of intracellular calcium ([Ca2+]i) in bovine aortic endothelial cells (B. J. Buckley and A. R. Whorton. FASEB J. 11: A110, 1997). In the present study, we investigated the mechanism by which tunicamycin alters [Ca2+]i using the Ca2+-sensitive dye fura 2. We found that tunicamycin increased [Ca2+]i without increasing levels of inositol phosphates. When cells were incubated in the absence of extracellular Ca2+, [Ca2+]i rapidly rose in response to tunicamycin, although a full response was not achieved. The pool of intracellular Ca2+ mobilized by tunicamycin overlapped with that mobilized by thapsigargin. Extracellular nickel blocked a full response to tunicamycin when cells were incubated in the presence of extracellular Ca2+. The effects of tunicamycin on [Ca2+]i were partially reversed by washing out the drug, and the remainder of the response was inhibited by removing extracellular Ca2+. These results indicate that tunicamycin mobilizes Ca2+ from intracellular stores in a manner independent of phospholipase C activation and increases the influx of Ca2+ across the plasma membrane.

Animals↗

PubMed1996

Ca(2+)-dependent nitric oxide release in endothelial but not R3230Ac rat mammary adenocarcinoma cells.

We have characterized the ability of several cell types associated with the microvasculature of solid tumors to release nitric oxide (NO.) in response to increases in cytosolic Ca2+ concentration ([Ca2+]c). EA.hy926 immortalized human umbilical vein endothelial cells (EC), rat fibroblasts (RFL), and tumorigenic cells isolated from R3230Ac rat mammary adenocarcinoma (MaC) were treated with thapsigargin (TG), an inhibitor of Ca(2+)-ATPase. NO. output was measured via a chemiluminescence detection system. Baseline NO. output was detectable only for EC. TG caused a significant increase in EC NO. output that could be blocked with NG-monomethyl-L-arginine and restored with L-arginine. TG did not stimulate NO. release from RFL or MaC cells, despite elevating [Ca2+]c in all cells. A Ca(2+)-dependent isoform of NO synthase (eNOS) was detected by immunoblot only in EC. These data indicate that EC, but not RFL or MaC, are capable of Ca(2+)-dependent NO. release and suggest that any Ca(2+)-dependent NO. release within this tumor is primarily of endothelial (and not tumorigenic cell) origin.

Adenocarcinoma↗

PubMed1995

Regulation of Ca(2+)-dependent nitric oxide synthase in bovine aortic endothelial cells.

Vascular endothelium responds to Ca(2+)-mobilizing agonists by producing nitric oxide (NO), a potent vasodilator and inhibitor of platelet aggregation. Regulation of constitutively expressed endothelial NO synthase (eNOS) in intact cells is not well understood. We investigated the kinetics of NO formation in response to Ca(2+)-mobilizing agonists, the requirement for extracellular L-arginine, and the role of NO in regulating eNOS activity. When endothelial cells were stimulated with bradykinin and ATP in the presence of 100 microM L-arginine, we observed a rapid and transient rise in intracellular Ca2+ concentration ([Ca2+]i) from 50 +/- 8 nM to 698 +/- 74 and 637 +/- 53 nM, respectively, and a rapid and transient rise in NO production from a basal level of 37 pmol.min-1.mg protein-1 to 256 and 275 pmol.min-1.mg protein-1, respectively. When cells were stimulated with A-23187 or thapsigargin in the presence of 100 microM L-arginine, we observed a sustained increase in [Ca2+]i and a sustained increase in NO production. The rate of NO synthesis was linear over 30 min, rising above control levels of 7 pmol/min to 53 pmol/min for A-23187 and 62 pmol/min for thapsigargin. Thapsigargin stimulated NO production and [Ca2+]i with 50% effective concentration values of 0.01 and 0.05 microM, respectively. Ca(2+)-stimulated NO production was attenuated by the NO synthase inhibitor NG-monomethyl-L-arginine, the removal of extracellular L-arginine, and the Ca(2+)-chelator ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid. When we exposed cells to NO gas (3.1 mM for 15 min) and S-nitrosoglutathione (10 mM for 1 h) thapsigargin-stimulated NO production was decreased by 50%.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Arachidonic acid stimulates protein tyrosine phosphorylation in vascular cells.

Arachidonic acid and its metabolites are important cellular mediators. In this study, we report a novel role for arachidonic acid in vascular cell signaling. We tested the effects of exogenous arachidonic acid on protein tyrosine phosphorylation in cultured vascular endothelial and smooth muscle cells. Arachidonic acid stimulated the phosphorylation of tyrosine-containing proteins of approximately 58, 93, and 120 kDa in the three cell types studied. This response was dose dependent, with a maximum effect observed with 40 microM arachidonic acid. Phosphorylation was rapid and transient, reaching a peak 0.5 min after the addition of arachidonic acid and returning to baseline by 8 min. A common set of protein substrates was phosphorylated in smooth muscle cells treated with the Ca(2+)-mobilizing agonist endothelin, concomitant with an increase in endogenous unesterified arachidonic acid. To determine whether the protein tyrosine phosphorylation was due to arachidonic acid or to a metabolite, we used inhibitors of cyclooxygenase, lipoxygenase, and epoxygenase pathways. Ibuprofen, nordihydroguaiaretic acid, eicosatriynoic and eicosatetraynoic acids, and 8-methoxypsoralen failed to inhibit the arachidonic acid-mediated response. We also found increased protein tyrosine phosphorylation after treatment with oleic, linolenic and gamma-linoleic acid. These results suggest a mechanism of protein tyrosine phosphorylation that is directly stimulated by unmetabolized unsaturated fatty acids.

Animals↗

PubMed1994

Ca(2+)-independent arachidonic acid release by vascular endothelium requires protein synthesis de novo.

We investigated the mechanism by which the G-protein activators aluminium fluoride and vanadate stimulate arachidonic acid release in pig aortic endothelial cells. Our previous study demonstrated a novel Ca(2+)-independent pathway of phospholipase A2 (PLA2) activation stimulated by aluminium fluoride in this model. In the present study, we found that sodium metavanadate stimulated a rapid concentration-dependent release of [3H]arachidonic acid from prelabelled cells. A more than 3-fold enhancement of arachidonic acid release was achieved in cells treated with 1 mM vanadate for 20 min. Synthesis of prostaglandin products was similarly enhanced. The release of arachidonic acid was not dependent on the presence of extracellular Ca2+, but did require protein synthesis de novo. Both cycloheximide and actinomycin D completely blocked aluminium fluoride- and vanadate-stimulated arachidonic acid release. Because fluoride and vanadate are known protein tyrosine phosphatase inhibitors, it is possible that PLA2 activation occurred secondarily to changes in protein tyrosine phosphorylation. Both aluminium fluoride and vanadate stimulated the rapid phosphorylation of 58, 93 and 120 kDa tyrosine-containing protein substrates. However, in contrast with arachidonic acid release, this response was found to be sensitive to the presence of extracellular Ca2+ and insensitive to blockers of protein synthesis de novo. Furthermore H2O2 treatment resulted in rapid tyrosine phosphorylation of the same substrates without a concomitant increase in arachidonic acid release. These results suggest that the effects of aluminium fluoride and vanadate on PLA2 are not due to changes in protein tyrosine phosphorylation, but do require rapid protein synthesis de novo.

Aluminum Compounds↗

PubMed1993

Oxidant injury to the alveolar epithelium: biochemical and pharmacologic studies.

This multifaceted study involved a combined biochemical and cellular analysis of oxidant metabolism by a lung cell at risk from injury by endogenous and environmental oxidants, the pulmonary alveolar type II epithelial cell. Within the framework of this study, a method was developed for effectively delivering antioxidant enzymes and alpha-tocopherol to the intracellular compartment of alveolar epithelial cells. Alveolar type II cells are key sources of pulmonary surfactant phospholipids and apoproteins and serve as progenitors of type I alveolar epithelium, thus playing an important role in the re-epithelialization of the lung alveolus after exposure to pulmonary oxidants. The type I and II pulmonary epithelium also play an essential collaborative role in maintaining the integrity of the air-blood barrier of the lung. Because of these critical properties of the alveolar epithelium and their recognized sensitivity to oxidant stress derived from diverse sources, such as activated inflammatory cells, hyperoxia, the environmental oxidants and nitrogen dioxide, and surgical procedures, such as cardiopulmonary bypass and lung transplantation, we endeavored to understand more about the oxidant metabolism and antioxidant pharmacology of these cells. In our experiments, we made the observation that loss of differentiated oxidant generation and antioxidant properties of type II cells occurs very rapidly in vitro. For example, we observed a 50% to 75% reduction in the specific activities of type II cell superoxide dismutase, catalase, and glutathione peroxidase, all critical scavengers of cell superoxide and hydrogen peroxide and key enzymes in the attenuation of hydroxyl radical formation. Although the differentiated characteristics of the type II cell antioxidant defenses changed in vitro, they may have become more reflective of type I alveolar epithelial cells. The type I cell is the most vulnerable for oxidant damage in the alveolus because of its large surface area and the possibility of a reduced antioxidant capacity compared to type II alveolar epithelium. In spite of this limitation, we were able to culture type II cells and study their adaptive and toxic responses to exogenously administered oxidant stress. We also observed that a significant source of self-generated oxidants in type II cells was the enzyme xanthine oxidase. Normal rates of oxidant production by this enzyme had an inhibitory effect on incorporation of biosynthetic precursors into surfactant phospholipids; these effects were eliminated by the xanthine oxidase inhibitor, allopurinol.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1992

Cardiac responses elicited by stimulation of loci within stellate ganglia of developing swine.

Stimulation with bipolar electrodes of specific loci in stellate ganglia elicited in anesthetized piglets, 1-4 weeks of age, alterations in cardiac function and aortic pressure. Responses were also elicited by chemical stimulation in specific loci of these ganglia. The probability of eliciting a cardiovascular response by stimulating loci in a stellate ganglion increased with increasing postnatal age. For instance, no responses were elicited when loci in the left stellate ganglia of 1-week-old piglets were stimulated. Significant heart rate responses were obtained only when loci in right stellate ganglia were stimulated. The number of ganglionic loci from which cardiovascular responses were obtained increased with increasing postnatal age. It is concluded that the capacity of stellate ganglion neurons to modulate the cardiovascular system matures during the first four weeks of life, heart rate being modulated primarily by neurons in the right stellate ganglion and inotropism by neurons in both stellate ganglia.

Aging↗

PubMed1991

Regulation of arachidonic acid release in vascular endothelium. Ca(2+)-dependent and -independent pathways.

Ca2+ metabolism and its relationship to arachidonic acid release were studied in cultured pig aortic endothelial cells. When cells were treated with bradykinin, a rapid rise in intracellular Ca2+ concentration ([Ca2+]i) occurred. Arachidonic acid release from cells prelabelled with [3H]arachidonic acid and subjected to flow-through conditions closely followed the changes in [Ca2+]i. Attenuation of the Ca2+ response by chelating extracellular and intracellular Ca2+ or by desensitization of receptors led to comparable attenuation of arachidonate release. Activation of protein kinase C inhibited Ca2+ mobilization in response to bradykinin and stimulated arachidonic acid release. Inhibition of protein kinase C had no effect on bradykinin-stimulated arachidonic acid release, suggesting that protein kinase C does not mediate the bradykinin response. The role of GTP-binding regulatory proteins (G-proteins) in mediating the bradykinin response was also investigated. Bradykinin-stimulated arachidonic acid release was not diminished by preincubation with pertussis toxin. Treatment with the G-protein activator AlF4- resulted in the release of a large pool of arachidonic acid and the formation of lysophospholipids. Combined treatment with AlF4- and bradykinin resulted in a greater than additive effect on arachidonic acid release. In contrast with bradykinin, AlF(4-)-stimulated arachidonic acid release was not dependent on the presence of extracellular Ca2+ or the mobilization of intracellular Ca2+. These results demonstrate Ca(2+)-dependent (bradykinin) and Ca(2+)-independent (AlF4-) pathways of phospholipase A2 activation.

Alkaloids↗

PubMed1991

Regulation of endothelial cell prostaglandin synthesis by glutathione.

Prostaglandin synthesis in in vitro systems is dependent on glutathione and peroxide concentrations. We tested the effects of glutathione depletion and H2O2 exposure on prostaglandin synthesis in cultured porcine aortic endothelial cells. Depletion of glutathione using buthionine sulfoximine (BSO), diethylmaleate, and 2,4-chlorodinitrobenzene increased prostaglandin synthetic capacity. Production of prostacyclin, but not prostaglandin E2, from exogenous arachidonic acid was significantly greater than in controls. Glutathione depletion also resulted in enhanced production of prostacyclin from exogenous prostaglandin H2. These responses were not due to direct effects of glutathione-depleting agents on prostaglandin synthetic enzymes. Exposure to H2O2 also altered prostaglandin synthetic capacity in endothelial cells. While 5 microM H2O2 stimulated prostaglandin production from exogenous arachidonate, 25 and 50 microM were found to be inhibitory. Prostaglandin synthetic capacity was greater in BSO-treated cells which were exposed to 5 and 10 microM H2O2 than in cells exposed to H2O2 alone. However, prostaglandin synthetic capacity was greatly reduced in BSO-treated cells exposed to 50 microM H2O2. Thus, normal levels of cellular glutathione exert an inhibitory influence on prostaglandin synthesis. However, glutathione depletion increases the sensitivity of prostaglandin synthesis to inhibition by 50 microM H2O2.

Animals↗

PubMed1991

Effects of acute hypoxemia on responses to dopamine and dobutamine in neonatal swine.

The effects of acute hypoxemia on cardiovascular responses to dopamine (DA) and dobutamine (DB) were studied in 2-4 day (n = 21) and 13-17 day (n = 27) old swine under sodium pentobarbital anesthesia. Sequential 10-min infusions of 2, 5 and 15 mu/kg/min of DA or DB or normal saline were administered under conditions of normoxemia and repeated during hypoxemia. Data are presented as mean percent of baseline value +/- SE. During normoxemia, DA increased aortic pressure, cardiac output, heart rate, LV dP/dt max and renal resistance and decreased mesenteric resistance in both ages, while DB increased heart rate, LV dP/dt max and cardiac output in both age groups and decreased total arterial resistance and renal resistance in the youngest. Increases in LV dP/dt max were larger with DA as compared to DB (p less than 0.05) with the highest dose in younger (152 +/- 5% vs. 124 +/- 4%) and older (201 +/- 29% vs. 157 +/- 9%) animals. Hypoxemia reduced heart rate responses to DA and DB in older piglets, contractility responses to DB in older animals, aortic pressure responses to DA in all animals and renal resistance responses to DA in older animals. Hypoxemia had little or no effect on cardiac output and total arterial, mesenteric and carotid resistance responses to DA and DB. Thus, in the newborn: 1) DA is a stronger inotropic agent during normoxemia and hypoxemia while the chronotropic effects of the two drugs did not differ. 2) Changes in cardiac output with both drugs did not differ significantly during normoxemia and were not affected by hypoxemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗

PubMed1990

Increasing extracellular calcium concentration does not prevent hypotensive effects of verapamil in neonatal swine.

Effects of CaCl2 on cardiac function and regional circulatory responses to verapamil (V) infusion were studied in pentobarbital-anesthetized 2-week-old swine. V 100 micrograms/kg (n = 15) or 300 micrograms/kg (n = 15), given as a 2-min intravenous infusion, was repeated after 30 min. Only V was given to 15 of these. The other 15 were given CaCl2 (15 mg/kg) over 2 min, pre-V (protocol A), and over 4 min, 2 min pre-V and during V (protocol B). Positive chronotropic and negative inotropic responses to V were attenuated by CaCl2; hypotensive effects were unaltered. Renal, but not mesenteric and femoral, vasodilation was augmented by CaCl2, CaCl2 alone produced marked positive inotropic and renal vasodilatory effects which contributed to maintenance of the hypotensive effect of V.

Animals↗

PubMed1990

Comparative effects of bicarbonate and dichloroacetate in newborn swine with hypoxic lactic acidosis.

UNLABELLED: Sodium bicarbonate (BC) and dichloroacetate (DCA) were studied in 7- to 14-day-old (n = 25) anesthetized swine with hypoxic acidosis. BC (base deficit X kg X 0.3, n = 10), DCA (300 mg/kg, n = 7) or saline (n = 8) was infused for 1 h. Blood lactic acid, dP/dtmax, heart rate and cardiac output increased and base excess and total arterial and carotid resistances (R) decreased with acidosis; aortic pressure, renal and mesenteric R did not change. BC induced higher pH, base excess and lactic acid. Heart rate in all and dP/dtmax with BC and DCA were restored; renal and mesenteric R and aortic pressure decreased in all. Cardiovascular responses to DCA and BC did not differ except for renal R. CONCLUSION: BC is a more effective alkalizer than DCA, which induced a greater renal vasodilation; both restored contractility.

Acidosis, Lactic↗

PubMed1987

Pulmonary cadmium oxide toxicity in the rat.

Although occupational exposures to cadmium have usually involved inhalation of insoluble cadmium oxide (CdO) particles, experimental studies of pulmonary cadmium toxicity have relied on aerosol exposures to soluble cadmium chloride particles. The present study describes a model of acute lung injury based on single 3-h exposures of rats to 0.5 and 5.3 mg/m3 CdO. Biochemical changes were correlated with pathological observations for 15 d postexposure to CdO. Four days following CdO exposure, histopathological observations included focal areas of epithelial hyperplasia, a mononuclear interstitial infiltrate, and increased numbers of alveolar macrophages. In the high-dose group, these changes were correlated with increases in tissue protein and DNA contents of 217% and 195% of controls, respectively. While lungs from the low-dose exposures had returned to a normal appearance by 15 d postexposure, high-dose-exposed lungs exhibited an increase in noncellular thickening of the interstitium and a continued general hypercellularity at this time. In the high-dose exposure group, activities of the enzymes glutathione peroxidase, glutathione reductase, and the dehydrogenase of glucose 6-phosphate and 6-phosphogluconate were significantly elevated two- to fivefold at 2-4 d postexposure. When a correction was made for changes in lung cell number, significant increases were observed only in activities of the pentose-cycle dehydrogenases at 180-238% of controls. These increases suggested an enhanced ability of CdO-exposed lungs to generate the pentose-cycle products NADPH and ribose 5-phosphate, which would be needed for lipid and nucleic acid biosynthesis expected during the proliferative stages of epithelial repair. This study has demonstrated that the response to CdO exposure includes the induction of enzymatic activities that are related to antioxidant defense and lung repair.

Air Pollutants, Occupational↗