Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 3 de 3
Filter
Add more filters










Database
Language
Publication year range
1.
Cytokine ; 9(8): 582-6, 1997 Aug.
Article in English | MEDLINE | ID: mdl-9245486

ABSTRACT

Intraperitoneal administration of the phosphodiesterase type 4 (PDE4) inhibitor rolipram (1-30 mg/kg) caused a dose-dependent increase in the circulating levels of both corticosterone and adrenaline in male Balb/c mice. These increases were maximal 0.5-1 h after administration of rolipram and had declined to control levels by 4 h. Rolipram (10 mg/kg i.p.) substantially inhibited the production of tumour necrosis factor alpha (TNF-alpha) ex vivo in blood from normal mice but was ineffective in adrenalectomized mice, suggesting that the inhibitory effect of rolipram is dependent on intact adrenal function. The corticosterone antagonist, RU 486, and the beta-adrenoceptor antagonist, propranolol, both partially reversed the inhibitory activity of rolipram while the combination of RU 486 and popranolol abrogated the effect of the rolipram to the same degree as adrenalectomy. These data suggest the release of both corticosterone and adrenaline contribute to the ability of rolipram to inhibit TNF-alpha production in mouse blood ex vivo.


Subject(s)
Corticosterone/physiology , Epinephrine/physiology , Phosphodiesterase Inhibitors/pharmacology , Pyrrolidinones/pharmacology , Tumor Necrosis Factor-alpha/biosynthesis , Adrenalectomy , Adrenergic beta-Antagonists/pharmacology , Animals , Corticosterone/blood , Epinephrine/blood , Hormone Antagonists/pharmacology , Male , Mice , Mice, Inbred BALB C , Mifepristone/pharmacology , Monocytes/drug effects , Monocytes/physiology , Propranolol/pharmacology , Rolipram
2.
Br J Pharmacol ; 119(6): 1101-8, 1996 Nov.
Article in English | MEDLINE | ID: mdl-8937711

ABSTRACT

1. The ability of 2-amino-4-methylpyridine to inhibit the catalytic activity of the inducible NO synthase (NOS II) enzyme was characterized in vitro and in vivo. 2. In vitro, 2-amino-4-methylpyridine inhibited NOS II activity derived from mouse RAW 264.7 cells with an IC50 of 6 nM. Enzyme kinetic studies indicated that inhibition is competitive with respect to arginine. 2-Amino-4-methylpyridine was less potent on human recombinant NOS II (IC50 = 40 nM) and was still less potent on human recombinant NOS I and NOS III (IC50 = 100 nM). NG-monomethyl-L-arginine (L-NMMA), N6-iminoethyl-L-lysine (L-NIL) and aminoguanidine were much weaker inhibitors of murine NOS II than 2-amino-4-methylpyridine but, unlike 2-amino-4-methylpyridine, retained similar activity on human recombinant NOS II. L-NMMA inhibited all three NOS isoforms with similar potency (IC50S 3-7 microM). In contrast, compared to activity on human recombinant NOS III, L-NIL displayed 10 x selectivity for murine NOS II and 11 x selectivity for human recombinant NOS II while aminoguanidine displayed 7.3 x selectivity for murine NOS II and 3.7 x selectivity for human recombinant NOS II. 3. Mouse RAW 264.7 macrophages produced high levels of nitrite when cultured overnight in the presence of lipopolysaccharide (LPS) and interferon-gamma. Addition of 2-amino-4-methylpyridine at the same time as the LPS and IFN-gamma, dose-dependently reduced the levels of nitrite (IC50 = 1.5 microM) without affecting the induction of NOS II protein. Increasing the extracellular concentration of arginine decreased the potency of 2-amino-4-methylpyridine but at concentrations up to 10 microM, 2-amino-4-methylpyridine did not inhibit the uptake of [3H]-arginine into the cell. Addition of 2-amino-4-methylpyridine after the enzyme was induced also dose-dependently inhibited nitrite production. Together, these data suggest that 2-amino-4-methylpyridine reduces cellular production of NO by competitive inhibition of the catalytic activity of NOS II, in agreement with results obtained from in vitro enzyme kinetic studies. 4. When infused i.v. in conscious unrestrained rats, 2-amino-4-methylpyridine inhibited the rise in plasma nitrate produced in response to intraperitoneal injection of LPS (ID50 = 0.009 mg kg-1 min-1). Larger doses of 2-amino-4-methylpyridine were required to raise mean arterial pressure in untreated conscious rats (ED50 = 0.060 mg kg-1 min-1) indicating 6.9 x selectivity for NOS II over NOS III in vivo. Under the same conditions, L-NMMA was nonselective while L-NIL and aminoguanidine displayed 5.2 x and 8.6 x selectivity respectively. All of these compounds caused significant increases in mean arterial pressure at doses above the ID50 for inhibition of NOS II activity in vivo. 5. 2-Amino-4-methylpyridine also inhibited LPS-induced elevation in plasma nitrate after either subcutaneous (ID50 = 0.3 mg kg-1) or oral (ID50 = 20.8 mg kg-1) administration. 6. These data indicate that 2-amino-4-methylpyridine is a potent inhibitor of NOS II activity in vitro and in vivo with a similar degree of isozyme selectivity to that of L-NIL and aminoguanidine in rodents.


Subject(s)
Nitric Oxide Synthase/antagonists & inhibitors , Picolines/pharmacology , Animals , Cell Line , Humans , Lipopolysaccharides/pharmacology , Male , Mice , Nitrates/metabolism , Nitric Oxide/biosynthesis , Rats , Rats, Wistar
3.
Br J Pharmacol ; 117(7): 1530-4, 1996 Apr.
Article in English | MEDLINE | ID: mdl-8730750

ABSTRACT

1. The role of adrenal hormones in the regulation of the systemic and local production of tumour necrosis factor (TNF alpha) was examined in male Balb/c mice. 2. Intraperitoneal injection of 0.3 mg E. coli lipopolysaccharide (LPS, 0111:B4) led to high levels of circulating TNF alpha without stimulating TNF alpha production in the peritoneal cavity. Systemic production of TNF alpha in response to LPS was increased in adrenalectomized animals and in normal animals treated with the beta-adrenoceptor antagonist, propranolol. The glucocorticoid antagonist, RU 486, did not modify systemic TNF alpha production. These results indicate that systemic TNF alpha production is regulated by adrenaline but not by corticosterone. 3. When mice were primed with thioglycollate, TNF alpha was produced in the peritoneal cavity in response to low dose LPS (1 micrograms). The levels of TNF alpha in the peritoneal cavity were not enhanced by adrenalectomy or by treatment with either propranolol or RU 486, indicating local production of TNF alpha in the peritoneal cavity is not regulated by adrenaline or corticosterone. 4. The phosphodiesterase type IV (PDE-IV) inhibitor, rolipram, inhibited both the systemic production of TNF alpha in response to high dose endotoxin (ED50 = 1.3 mg kg-1) and the local production of TNF alpha in the peritoneal cavity in response to low dose endotoxin (ED50 = 9.1 mg kg-1). In adrenalectomized mice there was a slight reduction in the ability of rolipram to inhibit the systemic production of TNF alpha (ED50 = 3.3 mg kg-1) while the ability of rolipram to inhibit the local production of TNF alpha in the peritoneal cavity was virtually abolished (24% inhibition at 30 mg kg-1). The glucocorticoid antagonist, RU 486, also reduced the ability of rolipram to inhibit local TNF alpha production while propranolol was without effect. 5. Systemic treatment with rolipram increased the plasma concentrations of corticosterone in normal mice but not in adrenalectomized mice indicating that rolipram can cause adrenal stimulation in vivo. 6. In summary, these data indicate that systemic production of TNF alpha in response to high dose endotoxin is controlled differently from the local production of TNF alpha in response to low dose endotoxin. The systemic production of TNF alpha is regulated by catecholamines, but not by corticosterone, while the local production of TNF alpha in the peritoneal cavity is not regulated by basal levels of either catecholamines or corticosterone. 7. These data also show that the ability of rolipram to inhibit the local production of TNF alpha is dependent on the release of corticosterone from the adrenal glands.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Pyrrolidinones/pharmacology , Tumor Necrosis Factor-alpha/metabolism , Adrenalectomy , Animals , Corticosterone/blood , Escherichia coli , Lipopolysaccharides , Male , Mice , Mice, Inbred BALB C , Mifepristone/pharmacology , Phosphodiesterase Inhibitors/pharmacology , Propranolol/pharmacology , Rolipram , Tumor Necrosis Factor-alpha/antagonists & inhibitors
SELECTION OF CITATIONS
SEARCH DETAIL
...