Naunyn-Schmiedeberg's archives of pharmacology
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Naunyn Schmiedebergs Arch. Pharmacol. · Aug 1998
Eukaliuric natriuresis and diuresis in response to disprocynium24: studies on the tubular site of action.
We previously described that 1,1'-diisopropyl-2,4'-cyanine (disprocynium24, DP24) exerts an eukaliuric diuresis and natriuresis in the anesthetized rat. The purpose of the present study was to localize the tubular site of action of DP24. Employing micropuncture experiments in anesthetized rats, we first tested the effect of systemic application of DP24 (300 microg/kg + 300 microg/kg h, i.v.) on whole kidney excretion rates as well as on fluid, sodium and potassium ion delivery to the early distal tubule (V(ED), Na+(ED), K+(ED)). ⋯ Intratubular DP24 did not affect reabsorption in the distal tubule. In summary, the present findings indicate that: (1) the diuretic and natriuretic effect of DP24 resides predominantly in the proximal tubule, and (2) DP24 may act from the intratubular site. Since DP24 increased V(ED) and Na+(ED) without apparently affecting sodium or potassium ion transport in the distal tubule, the mechanism of the eukaliuric response remains unclear.
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Naunyn Schmiedebergs Arch. Pharmacol. · Aug 1998
Riluzole, a glutamate release inhibitor, and motor behavior.
Riluzole (2-amino-6-trigluoromethoxy benzothiazole) has neuroprotective, anticonvulsant, anxiolytic and anesthetic qualities. These effects are mediated by blockade of glutamate transmission, stabilizing of sodium channels and blockade of gamma-aminobutyric acid (GABA) reuptake. The action profile of riluzole is dominated by its effects on glutamate transmission which are predominately mediated by N-methyl-D-aspartate (NMDA) receptor-linked processes in vitro. ⋯ The results indicate that when given alone, riluzole has a behavioral profile resembling that of competitive NMDA receptor antagonists. However, coadministration of riluzole with NMDA/AMPA receptor ligands suggests that this assumption is incorrect, and that riluzole affects glutamatergic transmission by a more indirect mechanism. Nevertheless, the profile of riluzole together with its pre- and postsynaptic blockade of glutamatergic transmission implies beneficial properties in diseases where an overactive glutamate system induces chronic neurotoxicity and/or acute behavioral effects.
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Naunyn Schmiedebergs Arch. Pharmacol. · Aug 1998
A study on possible modulating and direct effects of gamma2-MSH and ACTH-(1-24) on the cardiovascular system of the rat.
In conscious rats, gamma2-melanocyte-stimulating hormone (gamma2-MSH) dose-dependently increases blood pressure and heart rate, whereas adrenocorticotropin-(1-24) [ACTH-(1-24)] dose-dependently decreases blood pressure, an effect which was accompanied by a reflectory tachycardia. As the exact mechanism involved in these cardiovascular effects of the two melanocortins is as yet not known, we undertook a series of experiments to investigate the possibility that these peptides have modulating or direct effect on the cardiovascular system of the rat. In pithed rats gamma2-MSH, administered intravenously (i.v.) in doses of 5-200 nmol/kg, had no significant effect on systolic and diastolic blood pressure and on heart rate, whereas ACTH-(1-24), 5-500 nmol/kg, i.v., dose-dependently decreased blood pressure and increased heart rate. ⋯ These data show that gamma2-MSH does not exert its cardiovascular effects via a peripheral site of action at the level of the vascular system and the heart, nor directly on pre- or postganglionic sympathetic outflow. These results are in support for the notion that the peptide acts via a brain region localised outside the blood-brain barrier. The acute depressor effect of ACTH-(1-24), however, seems to be due to a direct effect on the vasculature in the periphery.
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Naunyn Schmiedebergs Arch. Pharmacol. · Aug 1998
Effect of colchicine on nerve growth factor-induced leukocyte accumulation and thermal hyperalgesia in the rat.
In addition to its neuronal effects, nerve growth factor (NGF) is known to act on inflammatory and immune cells. The aim of the present study was to investigate the effect of colchicine on NGF-induced leukocyte accumulation and thermal hyperalgesia. Initial experiments showed that intradermal injection of recombinant human (rh) NGF (0.8 and 4 microg) caused a longlasting increase in tissue myeloperoxidase (MPO) indicating leukotactic activity of NGF. ⋯ In vitro, colchicine (0.4-12 microg/ml) did not significantly influence NGF (10 ng/ml)-induced histamine release from rat peritoneal cells, suggesting that a mast cell stabilizing effect of colchicine did not contribute to inhibition of NGF-induced thermal hyperalgesia. The results show that NGF causes localized indometacin-resistant thermal hyperalgesia that can be blocked by the microtubule disrupting agent colchicine. These results raise the possibility that a mechanism by which NGF produces peripheral sensitization is related to its leukotactic effect.
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Naunyn Schmiedebergs Arch. Pharmacol. · Aug 1998
Protective effects of a PAF receptor antagonist and a neutrophil elastase inhibitor on multiple organ failure induced by cerulein plus lipopolysaccharide in rats.
The inhibitory effects of YM264, a selective platelet activating factor (PAF) receptor antagonist, and 2-(3-methylsulfonylamino-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl)-N-( 3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide (compound 1), a neutrophil elastase inhibitor, on mortality, and pancreatic, hepatic, renal and pulmonary dysfunction were evaluated in a rat model of multiple organ failure (MOF) accompanying acute pancreatitis. MOF was produced by intraperitoneal injection of lipopolysaccharide (LPS, 30 mg/kg) in rats with cerulein-induced pancreatitis. LPS dose-dependently increased the mortality in rats with or without pancreatitis. ⋯ In conclusion, pancreatic, hepatic, renal and pulmonary dysfunctions are observed in this rat MOF model. The PAF receptor antagonist and neutrophil elastase inhibitor reduce the mortality rate in rats with MOF due to their inhibitory effects on organ dysfunction, indicating that PAF and neutrophil elastase may play important roles in the development of MOF. These results in the present model are largely consistent with those in patients with MOF, indicating that this model is suited for MOF in humans and may be used as a model to test new therapeutic approaches.