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Biomedical subjects

P T Manning

Publications and source records attributed to P T Manning.

29 records · Page 2Linked to original sources
PubMed1995

Dual inhibition of nitric oxide and prostaglandin production contributes to the antiinflammatory properties of nitric oxide synthase inhibitors.

We have recently put forward the hypothesis that the dual inhibition of proinflammatory nitric oxide (NO) and prostaglandins (PG) may contribute to the antiinflammatory properties of nitric oxide synthase (NOS) inhibitors. This hypothesis was tested in the present study. A rapid inflammatory response characterized by edema, high levels of nitrites (NO2-, a breakdown product of NO), PG, and cellular infiltration into a fluid exudate was induced by the administration of carrageenan into the subcutaneous rat air pouch. The time course of the induction of inducible nitric oxide synthase (iNOS) protein in the pouch tissue was found to coincide with the production of NO2-. Dexamethasone inhibited both iNOS protein expression and NO2- synthesis in the fluid exudate (IC50 = 0.16 mg/kg). Oral administration of N-iminoethyl-L-lysine (L-NIL) or NG-nitro-L-arginine methyl ester (NO2Arg) not only blocked nitrite accumulation in the pouch fluid in a dose-dependent fashion but also attenuated the elevated release of PG. Finally, carrageenan administration produced a time-dependent increase in cellular infiltration into the pouch exudate that was inhibited by dexamethasone and NOS inhibitors. At early times, i.e., 6 h, the cellular infiltrate is composed primarily of neutrophils (98%). Pretreatment with colchicine reduced both neutrophil infiltration and leukotriene B4 accumulation in the air pouch by 98% but did not affect either NO2- or PG levels. In conclusion, the major findings of this paper are that (a) selective inhibitors of iNOS are clearly antiinflammatory agents by inhibiting not only NO but also PG and cellular infiltration and (b) that neutrophils are not responsible for high levels of NO and PG produced.

Amino Acid Oxidoreductases↗
PubMed1994

Selective inhibition of inducible cyclooxygenase 2 in vivo is antiinflammatory and nonulcerogenic.

We have examined the role of cyclooxygenase 2 (COX-2) in a model of inflammation in vivo. Carrageenan administration to the subcutaneous rat air pouch induces a rapid inflammatory response characterized by high levels of prostaglandins (PGs) and leukotrienes in the fluid exudate. The time course of the induction of COX-2 mRNA and protein coincided with the production of PGs in the pouch tissue and cellular infiltrate. Carrageenan-induced COX-2 immunoreactivity was localized to macrophages obtained from the fluid exudate as well as to the inner surface layer of cells within the pouch lining. Dexamethasone inhibited both COX-2 expression and PG synthesis in the fluid exudate but failed to inhibit PG synthesis in the stomach. Furthermore, NS-398, a selective COX-2 inhibitor, and indomethacin, a nonselective COX-1/COX-2 inhibitor, blocked proinflammatory PG synthesis in the air pouch. In contrast, only indomethacin blocked gastric PG and, additionally, produced gastric lesions. These results suggest that inhibitors of COX-2 are potent antiinflammatory agents which do not produce the typical side effects (e.g., gastric ulcers) associated with the nonselective, COX-1-directed antiinflammatory drugs.

Amino Acid Sequence↗
PubMed1987

MHC-specific cytotoxic T lymphocyte killing of dissociated sympathetic neuronal cultures.

Experiments were conducted to determine whether neurons in culture can serve as targets for immunologic attack mediated by major histocompatibility complex (MHC)-specific cytotoxic T lymphocytes (CTLs) which recognize Class I antigens. Allogeneic C3H/He primary neuronal cultures were quickly destroyed after CTL addition, while syngeneic C57BL/6J neurons were not lysed. Alterations in the distribution of chromatin were the first ultrastructural changes that occurred, followed by loss of nuclear morphology, cytosolic changes, and eventually fragmentation of both the nucleus and cytosol. With Campenot chambers, it was possible to separate the membrane and nuclear lesions. CTLs exposed to neurites, but separated from the cell body by the chamber barrier, caused degeneration of neurites but did not cause lysis and cell death. Neuronal lysis mediated by antibody and complement appeared to be distinct from CTL-mediated lysis. These experiments demonstrate that neurons in culture are targets for MHC-specific CTLs, and therefore probably express functional levels of Class I antigens. The signal for killing by CTLs is not retrogradely transported from the neurite to the cell body, and morphologic events following CTL-neuron interaction resemble those that occur in dividing tumor target cell populations.

Animals↗
PubMed1986

Species and structural specificity of the lipopigment accumulation and neuronal destruction induced by N-(2-guanidinoethyl)-4-methyl-1,2,5,6-tetrahydropyridine (guanacline).

Guanacline, a guanidinium adrenergic neuron blocking agent similar to guanethidine, was studied clinically and experimentally during the late 1960s. Like guanethidine, it has been reported to produce sympathetic neuronal destruction in rats. Unlike guanethidine, it has been reported to produce irreversible sympathetic deficits in man and to produce fluorescent lipopigment in rat sympathetic neurons. Guanacline and its derivative in which the double bond of the tetrahydropyridine ring is reduced (saturated analog of guanacline, SAG) were prepared. Several species were treated chronically with varying doses of guanethidine, guanacline or SAG; the superior cervical ganglia were examined light microscopically for neuronal destruction and for osmiophilic fluorescent lipopigment accumulation. All 3 drugs produced rapid neuronal destruction in rats accompanied by massive small-cell infiltration. In striking contrast, treatment for many weeks with doses up to 100 mg/kg/day produced no small-cell infiltration or apparent neuronal destruction in mice or guinea pigs. The neuronal destruction produced by guanacline and SAG in the rat, like that caused by guanethidine, was prevented by immunosuppression or gamma-irradiation, indicating that all 3 agents produce neuronal destruction in rats by an immune-mediated mechanism. Thus, the ability of the drug to produce sympathectomy is species specific but not drug specific. The opposite was found with respect to fluorescent lipopigment accumulation. Guanacline, but not guanethidine or SAG, produced fluorescent lipopigment in all species examined. Therefore, the double bond of the tetrahydropyridine ring plays a critical role in the production of the fluorescent lipopigment.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Atriopeptins: circulating volume regulatory hormones with potential therapeutic role in chronic renal failure.

Sprague-Dawley rats given bolus intravenous injections of vasoconstrictors, including 1-deamino-Arg8-vasopressin (dAVP), demonstrated remarkable increases in plasma immunoreactivity (APir) to atriopeptin (AP). These elevations were accompanied by increases in systemic blood pressure, right atrial pressure and urinary volume excretion. Fractionated plasma APir peaks obtained by stimulation with dAVP were identified as primarily AP 28, with a smaller amount of AP 24, suggesting that AP 28 is the predominant circulating atrial peptide. Rats with reduced renal mass have increased single-nephron glomerular filtration rates (GFR). Despite these increases, AP 24 stimulated a marked increase in total GFR and promoted a profound natriuresis and diuresis. Atriopeptin 24 may therefore have potential as a therapeutic tool in the management of volume overload in chronic renal failure.

Animals↗
PubMed1985

Protection from guanethidine-induced neuronal destruction by nerve growth factor: effect of NGF on immune function.

The chronic administration of guanethidine causes an immune-mediated destruction of sympathetic neurons in rats. Destruction can be prevented by various immunosuppressive agents, including gamma-irradiation and cyclophosphamide, as well as by administration with nerve growth factor (NGF). Experiments were conducted to determine whether: (1) NGF prevented accumulation of guanethidine within sympathetic neurons; and (2) NGF caused an inhibition of immune function by either blocking proliferation of immune-competent cells or by blocking effector function even in the presence of antigen and activated immune cells. NGF did not prevent accumulation of guanethidine within sympathetic ganglia in vivo, a necessary prerequisite for neuronal destruction, nor was it inhibitory on immune function using several assay systems. NGF, purified by either conventional methods or additionally by HPLC ("ultrapure'), did not inhibit either proliferation of cloned cytotoxic T lymphocytes (CTL) to antigen (class I major histocompatibility antigens) or lysis of target cells bearing the appropriate antigens. In addition, NGF did not exhibit growth stimulating effects in this assay system (i.e. it could not substitute for T cell growth factor). NGF also did not cause an inhibition of either murine or rat allogeneic mixed lymphocyte responses measured by lysis of appropriate target cells or proliferation, respectively. Finally, NGF did not inhibit, but rather appeared to stimulate the antibody response to sheep red blood cells generated in vivo in young rats. Thus NGF does not appear to prevent the immune-mediated neural destruction induced by guanethidine by acting as an immunosuppressive agent, but rather acts by some other mechanism such as preventing expression or recognition of antigen(s) on the sympathetic neuron.

Animals↗
PubMed1985

Vasopressin-stimulated release of atriopeptin: endocrine antagonists in fluid homeostasis.

Administration of pharmacological doses of arginine-vasopressin, related peptides, and other pressor agents induced a profound release of atriopeptin immunoreactivity into the circulation. The stimulated release of atriopeptin apparently was related to increased arterial blood pressure. Neither the nonpressor vasopressin analog 1-deamino-D-Arg8-vasopressin nor arginine-vasopressin in the presence of a specific pressor antagonist caused atriopeptin to be released into the circulation. Urine output was correlated with the level of atriopeptin released. Physiological levels of arginine-vasopressin suppress diuresis and produced vasoconstriction. Pharmacological levels of the hormone stimulated the cardiac endocrine system to release atriopeptin, which may cause diuresis and vasodilation to physiologically antagonize the effects of vasopressin.

Adrenocorticotropic Hormone↗
PubMed1985

Ser-Leu-Arg-Arg-atriopeptin III: the major circulating form of atrial peptide.

Vasopressin induces a concentration-dependent increase in atriopeptin immunoreactivity in plasma. Rat plasma, rat atrial extract, and synthetic atriopeptin III (APIII) produced parallel displacement curves of iodine-125-labeled APIII binding to specific antiserum. Fractionation of plasma atriopeptin immunoreactivity by reverse-phase high-performance liquid chromatography showed that the major portion consists of two species of low molecular weight peptides in a ratio of 10 to 1. Both peaks exhibited potent vasorelaxant activity, suggesting the presence of the carboxyl terminal Phe-Arg sequence of atriopeptin in each species. Sequence determination of the purified peptides indicated that the major peptide is Ser-Leu-Arg-Arg-APIII and the minor peptide APIII. It appears that the former is the major species of atrial peptide in the rat circulation and that it is the product of selective cleavage of the high molecular weight precursor.

Animals↗
PubMed1982

Immunosuppressive agents prevent guanethidine-induced destruction of rat sympathetic neurons.

Chronic administration of guanethidine to rats causes destruction of peripheral sympathetic neurons. Neuronal destruction, characterized morphologically by small cell infiltration and the reduction in the number of neurons within sympathetic ganglia, and biochemically by a marked reduction in tyrosine hydroxylase activity, occurred reproducibly by day 7 of treatment following 5 daily injections of 50 mg/kg guanethidine sulfate. Several observations in the literature suggested that guanethidine-induced destruction may occur by an immunologically mediated mechanism. Experiments were therefore designed to test the effects of immunosuppressive agents on guanethidine sympathectomy. A single exposure to either gamma-irradiation or cyclophosphamide, administered 8 h prior to the initiation of guanethidine treatment, protected against guanethidine-induced destruction in a dose-related manner and was virtually complete with either 900 rads of irradiation or with 100 or 150 mg/kg of cyclophosphamide. Cyclophosphamide afforded complete protection only if administered immediately prior to guanethidine treatment suggesting that it was acting during the proliferative phase of an immune response rather than non-specifically. Pretreatment with either irradiation or cyclophosphamide had no effect on the sympathectomy produced by treatment with either 6-hydroxydopamine or antibodies to nerve growth factor, nor did it prevent the accumulation of guanethidine within the sympathetic ganglia. Concurrent treatment with either azathioprine or dexamethazone also provided partial protection against guanethidine sympathectomy. These results strongly suggest that the destruction of sympathetic neurons induced by guanethidine occurs by an immunologically mediated mechanism.

Animals↗