Showing papers by "University of Tennessee Health Science Center published in 1982"

Effect of AV3V lesions on development of DOCA-salt hypertension and vascular Na+-pump activity.

Abstract: We studied the effects of anteroventral third ventricle (AV3V) lesions on the vascular Na+-pump activity of deoxycorticosterone acetate-salt (DOCA-salt) treated rats. Blood pressures and Na+-pump activity of the isolated tail arteries, measured as ouabain-sensitive 86Rb-uptake, were determined in untreated control rats, DOCA-salt treated rats, rats with AV3V lesions, and rats with AV3V lesions which were treated with DOCA-salt. Control rats receiving DOCA treatment developed higher blood pressures than rats receiving no DOCA treatment. Placement of AV3V lesions prior to administration of DOCA prevented the increase in blood pressure. Vascular Na+-pump activity in the DOCA-treated group was reduced by 20% compared to all other groups. The AV3V lesions prevented the suppression of Na+-pump activity caused by DOCA treatment. Suppression of vascular Na+-pump activity was due to a humoral substance since Na+-pump activity of tail arteries from control rats incubated in plasma from DOCA-salt treated rats was suppressed by 25% when compared to those incubated in control plasma. Our findings support the hypothesis that a circulating pressor substance is at least partially responsible for the development of DOCA-salt hypertension and that the mechanism by which AV3V lesions prevent DOCA hypertension may be through the interruption of secretion, transport, or synthesis of this factor.

Myeloperoxidase-catalyzed incorporation of amines into proteins: role of hypochlorous acid and dichloramines.

Abstract: Myeloperoxidase-catalyzed oxidation of chloride (Cl-) to hypochlorous acid (HOCl) resulted in formation of mono- and dichloramine derivatives (RNHCl and RNCl2) of primary amines. The RNCl2 derivatives could undergo a reaction that resulted in incorporation of the R moiety into proteins. The probable mechanism was attack of RNCl2 or an intermediate formed in the decomposition of RNCl2 on histidine, tyrosine, and cystine residues and on lysine residues at high pH. Incorporation of radioactivity from labeled amines into stable, high molecular weight derivatives of proteins was measured by acid or acetone precipitation and by gel chromatography and electrophoresis. Whereas formation of RNCl2 was favored at low pH, the subsequent incorporation reaction was favored at high pH. Up to several hours were required for the maximum amount of incorporation, which was less than 10% of the label in RNCl2. For the amines tested, incorporation was in the order histamine greater than 1,2-diaminoethane greater than putrescine greater than taurine greater than lysine greater than glucosamine greater than leucine greater than methylamine. Initiation of the reaction required HOCl, and oxidized forms of bromide, iodide, or thiocyanate did not substitute. Inhibitors of incorporation fell into three classes. First, ammonia or amines competed with the labeled amine for reaction with HOCl, so that larger amounts of HOCl were required. Second, readily oxidized substances such as sulfhydryl or diketo compounds or thioethers (methionine) reduced RNCl2. Third, certain compounds competed with protein as the acceptor for the incorporation reaction. The amount required to block incorporation into protein depended on protein concentration. Among these inhibitors were imidazole compounds (histidine), phenols (tyrosine), and disulfides (glutathione disulfide, GSSG). Low yields of derivatives of histidine, tyrosine, and GSSG were detected by thin-layer chromatography. Acid-precipitable derivatives were obtained by reacting RNCl2 with polyhistidine or polytyrosine, and to a lesser extent with polylysine at high pH, but not with other poly(amino acids). Precipitable derivatives were also obtained by incubating MPO-containing extracts from leukocyte granules with hydrogen peroxide, Cl-, and labeled amines. The extracts were found to have a high content of substances with primary amino groups, which competed for incorporation. The results account for oxidative incorporation of amines into proteins in leukocytes and provide evidence that HOCl and nitrogen-chlorine (N-Cl) derivatives are formed in these cells. The characteristics of the incorporation reaction suggest that it would not contribute significantly to the antimicrobial activity of myeloperoxidase (MPO). Nevertheless, the reaction may provide a sensitive method for studying MPO action in vivo.

Protective antigenic determinant of streptococcal M protein shared with sarcolemmal membrane protein of human heart.

Abstract: We present definitive evidence that at least one protective antigenic determinant on type 5 M protein of group A streptococci evokes antibody that is cross-reactive with human heart tissue. One of nine rabbits immunized with a peptide fragment of type 5 M protein (pep M5) produced antibody that cross-reacted by immunofluorescence with sarcolemmal membranes of human heart. The cross-reactive antibody could be removed by absorbing the antiserum with sarcolemmal membranes, types 5 and 19 streptococci, or their pepsin-extracted M proteins, but with no other serotypes tested. Although each of the pep M5 immune sera was opsonic for type 5 streptococci, only the heart-reactive antiserum opsonized type 19 streptococci. The opsonization of type 19 streptococci was abolished by absorbing the antiserum with sarcolemmal membranes isolated from human heart tissue. Purified heart-reactive antibodies eluted from sarcolemmal membranes opsonized both types 5 and 19 streptococci, indicating that the heart cross-reactive determinant of type 5 M protein is cross-protective. The cross-reactive antigen was purified by affinity chromatography from detergent extracts of sarcolemmal membranes and determined to be a complex protein composed of four subunits apparently linked by disulfide bonds.

Brain tumor imaging by positron emission computed tomography using 11C-labeled amino acids

Abstract: We report our preliminary clinical results on positron emission tomography of human cerebral tumors with 11C-tagged amino acids. Carbon-11-DL-valine and 11C-DL-tryptophan were used for imaging the tumors. Some attempts at quantitation of the uptake were also carried out. The implications of

Epinephrine synthesis inhibitors block naloxone-induced LH release.

Abstract: Administration of the opiate receptor antagonist, naloxone, evoked rapid rises in plasma LH levels in estrogen, progesterone-primed ovariectomized rats. Pretreatment with a peripherally acting epinephrine (EPI) synthesis inhibitor, SK&F 29661, failed to influence the naloxone-induced LH release. However, two centrally acting EPI synthesis inhibitors, SK&F 64139 and LY 78335, which selectively suppressed hypothalamic EPI levels, blocked stimulation of LH release by naloxone. These results implicate brain EPI neurons in mediation of endogenous opioid peptide influence on LH release.

Saline Catharsis: Effect on Aspirin Bioavailability in Combination with Activated Charcoal

Abstract: The effect of a saline cathartic combined with activated charcoal or activated charcoal alone on aspirin bioavailability was characterized in six healthy volunteers. Using a random, Latin-square design, subjects were given 975 mg aspirin followed by either water alone, 15 Gm activated charcoal (AC), or 15 Gm activated charcoal plus 20 Gm sodium sulfate (AC + SS) separated by one week. Both AC (44.16 +/- 16.85 microgram/ml) and AC + SS (58.61 +/- 10.63 microgram/ml) decreased (P less than 0.001) the maximal plasma salicylate concentration (Cpmax) compared to control (86.61 +/- 12.69 microgram/ml). Urinary salicylate recovery was decreased (P less than 0.01) for AC (57.88 +/- 16.26 per cent) and AC + SS (61.00 +/- 11.49 per cent) as compared to control (93.73 +/- 6.83 per cent), while for area under the plasma concentration-time curve (AUC) only AC showed a decrease (P less than 0.01) compared to control. Neither AC nor AC + SS differed from each other for Cpmax, AUC, or cumulative urinary recovery. Our findings indicate that the addition of sodium sulfate to activated charcoal has no added effect on limiting aspirin adsorption relative to activated charcoal alone.

Regulation of episodic growth hormone secretion by the central epinephrine system. Studies in the chronically cannulated rat.

Abstract: Catecholamines are postulated to regulate growth hormone (GH) secretion by their influence on the release of two hypothalamic substances, somatostatin, which inhibits GH release, and GH-releasing factor, as yet unidentified. Extensive pharmacologic studies in man and animals indicate a stimulatory effect of central norepinephrine and dopamine on GH, but the function of epiphephrine (EPI) is uncertain. Furthermore, many of the agents used to study the role of catecholamines in GH regulation are not selective in that they affect adrenergic as well as nor-adrenergic and/or dopaminergic neurotransmission. In the present investigation, central nervous system (CNS) EPI biosynthesis was selectively interrupted with the specific norepinephrine N-methyltransferase inhibitors, SK & F 64139 (Smith, Kline & French Laboratories) and LY 78335, (Eli Lilly & Co. Research Laboratories) and the effects of central EPI depletion on episodic GH secretion in the chronically cannulated rat model were determined. Inhibition of CNS EPI synthesis with SK & F 64139 caused complete suppression of episodic GH secretion and concomitantly reduced the EPI level in the hypothalamus without affecting dopamine or norepinephrine. Administration of LY 78335 produced similar effects on pulsatile GH. Morphine-induced, but not clonidine-induced, GH release also was blocked by SK & F 64139. These results indicate that (a) the central EPI system has a major stimulatory function in episodic GH release, (b) morphine-induced GH release is mediated by the central EPI system, and (c) clonidine stimulates GH release by activation of postsynaptic α-adrenergic receptors. Drugs that affect CNS adrenergic systems have a potential role in the diagnosis and treatment of disorders of GH secretion.

The pes anserinus transfer. A long-term follow-up.

Abstract: We evaluated forty-eight patients (fifty knees) with pes anserinus transfer at an average of nine years after operation. There was a high incidence of anteromedial and anterolateral rotatory instability. The incidence (54 per cent) of significant roentgenographic changes at follow-up was also high. Although many patients were improved symptomatically after pes anserinus transfer, only nineteen patients (38 per cent) had no limitation of function.

Enhancement of prostaglandin output during activation of beta-1 adrenoceptors in the isolated rabbit heart.

Abstract: The purpose of this study was to elucidate the type of adrenoceptor that mediates the effect of adrenergic stimuli on prostaglandin (PG) synthesis in the isolated rabbit heart and to determine the relationship of the released PGs to the mechanical changes elicited by catecholamines and stimulation of the cardiac sympathetic nerves. The output of 6-keto PGF1 alpha, PGE2 and PGF2 alpha was increased by electrical stimulation of the sympathetic nerves, norepinephrine, isoproterenol, dobutamine and angiotensin II, but not by phenylephrine or isoetharine. Propranolol or atenolol, but not phentolamine or butoxamine, blocked the output of PGs elicited by adrenergic stimuli. Indomethacin prevented the increase in PG formation caused by all stimuli. Moreover, the adrenergically induced release of PGs was not related to changes in heart rate, systolic tension or vascular tone elicited by the adrenergic stimuli. These data indicate that the adrenergically induced release of PGs in the isolated rabbit heart is due to the activation of beta-1 adrenoceptors and is independent of the mechanical effects produced by the adrenergic stimuli.

Delayed rupture of renal pseudoaneurysm: complication of percutaneous nephrostomy

Abstract: Percutaneous nephrostomy has become an increasingly acceptable therapeutic alternative, both for high-risk patients and for patients in whom the technique offers delay on avoidance of major surgery. Lack of major morbidity or mortality, palliation of symptoms, and reduced convalescent period are major advantages [i -3]. However, the procedure is not without its risks. We report a case of traumatic renal artery pseudoaneurysm following percutaneous nephrostomy with delayed rupture into the collecting system. This case also exhibits many of the therapeutic options now available to the interventional radiologist.

Intramembrane changes in retinal pigment epithelial cell junctions of the dystrophic rat retina.

Abstract: A progressive failure in phagocytosis by the retinal pigment epithelium (RPE) occurs in the Royal College of Surgeons rat with inherited retinal degeneration. Another change that can be attributed to a defect in the RPE is a breakdown in the blood-retinal barrier. RPE cell junctions, which form a part of this barrier, become permeable to extracellular tracer during the dystrophic process. We have used the freeze-fracture technique to study the structure of RPE cell junctions in normal and dystrophic retinas. In normal retinas, tight junctions between RPE cells consisted of 8 to 16 anastomosing strands on the cytoplasmic membrane leaflet (P-face) and a complementary pattern of grooves on the external membrane leaflet (E-face). Gapjunctional aggregates of hexagonally packed P-face particles and complementary E-face pits were enclosed within the tight junctional strands. In dystrophic retinas changes were first seen at postnatal day 21. Subtle breaks in P-face tight-junctional strands became more pronounced with time. Eventually the tight junctions appeared to unravel from the gap junctional aggregates, which became isolated and appeared to break off into patches of particle aggregates. The increased density of background particles in the membranes adjacent to disassembling junctions suggested that junctional elements were being removed by dispersal. Endocytosis of junctional elements was observed in both dystrophic and control retinas but may be accelerated in the dystrophic retina. In the late stages of the dystrophy some RPE cell junctions appeared to have proliferated and occupied extensive areas of the RPE membrane. (INVEST OPHTHALMOL Vis SCI 23:305-318, 1982.)

Lithium prophylaxis of tricyclic-antidepressant-induced mania in bipolar patients.

Abstract: The authors reviewed the charts of3O bipolar patients taking lithium who were treated with tricvclic antidepressants; 12

Use of the carbon dioxide laser in the operative management of intracranial meningiomas: a report of twenty cases.

Abstract: This study presents 20 cases of meningioma of various intracranial locations, all of which were removed with the carbon dioxide surgical laser system. The carbon dioxide laser is contrasted with other means of meningioma removal to emphasize the advantages of this new technology. These advantages include: (a) the ability to operate with smaller exposures, (b)reduced brain retraction, (c) a reduced amount of mechanical manipulation by vaporizing the tumor mass, (d) vaporization of the dural attachment after the removal of tumor, (e) improved operative precision, and (f) decreased intraoperative significant advancement in the ability to remove meningiomas that might prove difficult to extirpate by conventional means.

Steroid therapy in septic shock. Survival studies in a laboratory model.

Abstract: The efficacy of pharmacologic doses of steroids in the treatment of septic shock was evaluated using a laboratory model. The model produced a septic insult of gradual onset followed by a rapid progression, allowing for the evaluation of postcontamination therapeutic regimens. In Sprague-Dawley rats, the cecum was ligated distal to the ileocecal valve and doubly punctured. Control animals (n = 41) received no postoperative therapy. Mortality was 37 per cent at 24 hours and 90 per cent at 48 hours. Approximately 25 animals were assigned to each of five experimental groups. Pharmacologic doses of methylprednisolone at four and eight hours postoperatively did not alter survival. Short-term gentamicin (STG) at four and eight hours improved early survival, which then declined to control values. Addition of steroid to STG had no effect. Long-term gentamicin (LTG) administered through the third postoperative day produced significant increased survival over controls throughout the study. Pharmacologic doses of steroid at four and eight hours added to LTG resulted in a significant increase (P less than 0.05) in survival rate over the treatment with LTG alone.

The effect of intracerebroventricular indomethacin on osmotically stimulated vasopressin release.

Abstract: Experiments were carried out to investigate the effect of intracerebroventricular administration of a prostaglandin synthesis inhibitor on the osmotic control of vasopressin (ADH) secretion. During ventriculocisternal perfusion with indomethacin (7.6 μg/min) or vehicle, dogs were infused intravenously with either 2.5 or 0.15 M NaCl. Hypertonic saline infusion elevated plasma osmolality approximately 60 mosm/kg H2O. In accordance, the plasma ADH concentration increased substantially in animals perfused ventriculocisternally with the vehicle (from 2.1 ± 0.7 to 7.3 ± 1.3 μU/ml); this response was markedly attenuated, however, in animals perfused with indomethacin (from 1.0 ± 0.2 to 2.2 ± 0.4 μU/ml). Isotonic saline infusion caused a decline in plasma ADH concentration which was similar in the indomethacin- and vehicle-perfused groups. Mean arterial blood pressure was unchanged during the experiments. In a companion study, ventriculocisternal perfusion with 152 ng PGE2/min was found to be as effective in stimulating ADH release in the presence of indomethacin as in its absence, indicating that the action of indomethacin in the first study was not nonspecific. The suppression of osmotically induced ADH release by intracerebroventricular indomethacin suggests that endogenous brain prostaglandins play a critical intermediary role in the osmotic control of ADH secretion.

Pulmonary artery occlusion due to histoplasmosis

Abstract: Histoplasma mediastinitis with complete or partial pulmonary artery obstruction due to compression and/or intraluminal granuloma was diagnosed in five patients and surgically verified in two. The patients, ages 12-27 years, had cough, dyspnea (four cases), and hemoptysis (two cases). Radionuclide imaging showed unilateral absence of pulmonary perfusion and minimal diminution of ventilation. Differentiation of this inflammatory process from other causes of ventilation-perfusion mismatch, for example, congenital hypoplasia and certain acquired causes of arterial obstruction, especially thromboembolism, may be possible by correlating radiographs, laminograms, and clinical history. Angiography can delineate the extent of perfusion impairment and may suggest its cause.

Adrenergic and cholinergic mechanisms in digitalis inotropy.

Abstract: In anesthetized dogs, the effects of peripheral cardiac nerves upon cardiotonic steroid-induced contractile force increases were determined by comparing the effects seen with cardiac nerves intact, cardiac denervation, stellate ganglia removed or vagi sectioned. Additionally, structure-activity relationships among four cardiotonic steroids were determined by comparing the contractile force effects of bolus i.v. injections of digitoxigenin (the genin), digitoxigenin-galactose (genin-neutral sugar combination), digitoxigenin-aminogalactose (ASI-222, genin-aminosugar combination) and digoxin. The effects of these drugs upon cardiac rate, mean blood pressure and cardiac contractile force were recorded. Cardiotonic steroids differ in their interaction with cardiac nerves. Digitoxigenin, in addition to its direct contractile force effect on the myocardium, modulates contractile force through adrenergic mechanisms. In contrast, both digoxin and ASI-222 influence their direct inotropic responses through cholinergic mechanisms. Neither adrenergic nor cholinergic mechanisms significantly affect the peak inotropic response of digitoxigenin-galactose. Our data indicate that alterations in both the aglycone and the sugar moieties can significantly alter the contribution of the autonomic nervous system to the contractile force response.

Effect of prostaglandins on pancreatic circulation in anesthetized dogs.

Abstract: To assess the contribution of prostaglandins (PGs) to the maintenance of vascular tone and exocrine secretion in the pancreas, the effects of several products of arachidonic acid metabolism on the blood flow and flow rate of exocrine secretion were examined in the isolated blood perfused pancreas of the pentobarbital-anesthetized dog with and without pretreatment with the cyclooxygenase inhibitors, indomethacin (2 mg/kg i.v.) or sodium meclofenamate (10 mg/kg i.v.). Intra-arterial administration of PGE2, PGI2 and thromboxane B2 at doses of 30 to 300 ng/kg produced vasodilation and increased flow of blood to the pancreas. Injections of either PGF2 alpha, 30 to 300 ng/kg, or PGD2, 10 to 100 ng/kg, produced a biphasic effect, viz., transient vasoconstriction followed by a prolonged vasodilation. Administration of either indomethacin or sodium meclofenamate significantly reduced pancreatic blood flow (P less than .01). In animals pretreated with either of the cyclooxygenase inhibitors, the effect of PGE2, PGI2 or PGD2 to increase blood flow to the pancreas was prolonged in duration. Administration of either PGs, thromboxane B2 or cyclooxygenase inhibitors did not markedly alter the flow rate of exocrine pancreatic secretion. These data indicate that one or more products of arachidonic acid formed through the cyclooxygenase pathway contribute to the maintenance of pancreatic vascular bed in a dilated state.

An Analysis of Federal Narcotic Detoxification Policy: Implications for Rehabilitation

Abstract: The current federal narcotic detoxification policy, limiting such treatment to 21 d, is analyzed with respect to its impact on the success rate for complete withdrawal. Data are drawn from an historical review of American Medical Association statements on narcotic addiction and a review of empirical data on short- and long-term detoxification. The 3-week limit is shown to interfere with achieving successful detoxification rates, although it continues to guide federal detoxification policy. Empirical evidence supports long-term detoxification that recognizes other factors as also having a therapeutic effect. It is time to revise the current federal policy to more accurately reflect the progress made in long-term care.

Alterations in reserve bilirubin binding capacity of albumin by free fatty acids. II. In Vitro and In Vivo studies using difference spectroscopy

Abstract: The effects of free fatty acids (FFA) on reserve bilirubin binding capacity of solutions of human serum albumin (Alb) were determined in vitro using difference spectroscopy. Additionally, sera from 15 infants requiring parenteral nutrition were obtained before, during, and after the administration of a 1.0 g/kg intravenous dose of safflower oil emulsion, and determinations of FFA/Alb molar ratios and reserve bilirobin binding capacities were made for in vivo confirmation. The in vitro experiments demonstrated that increasing the linoleic acid/Alb molar ratio from 0 to 3.5 produced a 37% increase in binding capacity, but further increases to 9 ultimately resulted in a 32% decrease. Similar results were obtained using Alb at pH 7.4 and using defatted whole human serum. Using salicylate to block secondary binding sites demonstrated that linoleic acid enhanced binding at primary sites. In contrast to linoleic acid, octanoic acid did not alter binding at primary sites but lowered total binding capacity when its concentration exceeded 2.5 times that of the Alb in the sample. The in vivo measurements demonstrated that the total reserve bilirubin binding capacity dropped to 30% below base line only when the FFA/Alb molar ratio was greater than 7:1. Increases in total reserve bilirubin binding capacity above 30% over base line occurred in the range of FFA/Alb molar ratios of 1.6:4.0. Binding at primary sites was enhanced in a like manner at moderate FFA concentrations and did not fall below base line even at very high concentrations. These data support the concept of a positive cooperative binding effect between fatty acids and bilirubin at moderate fatty acid/Alb molar ratios and reconfirm the negative effect of fatty acids on bilirubin binding at high molar ratios. These data suggest that hyperbilirubinemic infants may be offered the nutritional benefits of intravenous safflower oil emulsion without additional risk of kernicterus as long as the FFA/Alb molar ratio is kept below 4 or the reserve bilirubin binding capacity is not decreased.

Time- and Concentration-dependent Inhibition of the Clonogenic Growth of N-[4-(5-Nitro-2-furyl)-2-thiazolyl]formamide-induced Murine Bladder Tumor Cell Lines by cis-Diamminedichloroplatinum(II)

Abstract: The influence of the concentration and time of exposure to cis -diamminedichloroplatinum on the inhibition of the clonogenic growth of three N -[4-(5-nitro-2-furyl)-2-thiazolyl]formamide mouse bladder tumor cell lines was evaluated in a tumor colony assay. Drug testing was performed in the murine model, and tumor cells were removed from the animals for in vitro testing. Murine drug testing revealed marked cis -diamminedichloroplatinum sensitivity of all three mouse bladder tumor lines. One-hr incubation in cis -diamminedichloroplatinum was an inadequate time of drug exposure to produce in vitro colony survival curves predictive of in vivo sensitivity to the drug. Furthermore, it was found that 6- to greater than 24-hr exposure to the drug was required to produce colony survival curves in the tumor colony assay predictive of tumor sensitivity. High drug concentrations using 1-hr drug incubation or continuous incubation in drug both produced colony survival curves predictive of tumor sensitivity. Both methods, however, would require higher products of the drug concentration multiplied by time curves than could theoretically be clinically achievable in the murine model. Until pharmacokinetic data on cis -diamminedichloroplatinum are available in this murine model, higher drug sensitivity boundaries than are presently being used for other chemotherapeutic agents will have to be utilized when testing these mouse bladder tumor cell lines for their sensitivity to cis -diamminedichloroplatinum in a tumor colony assay.