Naunyn-Schmiedeberg's archives of pharmacology
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Naunyn Schmiedebergs Arch. Pharmacol. · Dec 2000
The influence of chronic inhibition of nitric oxide synthesis on contractile and relaxant properties of rat carotid and mesenteric arteries.
Balloon denudation of the rat carotid artery leads to an immediate decrease in beta-adrenoceptor-medi-ated vasodilator response. However, this arterial function becomes significantly enhanced during subsequent formation of neointima with the endothelial cell lining still being absent. It was therefore hypothesized that chronic suppression of endothelium-dependent nitric oxide (NO) synthesis may eventually upregulate the beta-adrenoceptor system on vascular smooth muscle. ⋯ From these data, it may be concluded that chronic L-NAME treatment results in a stable impairment of the endothelium-dependent NO system in the rat carotid but not mesenteric arteries. The stated hypothesis fails as the beta-adrenoceptor-induced vasorelaxation of carotid and mesenteric arteries became significantly impaired, rather than enhanced. Taken together, the beta-adrenoceptor function in the rat carotid artery is apparently more dependent on endothelial NO synthesis than that in the rat mesenteric artery.
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Naunyn Schmiedebergs Arch. Pharmacol. · Sep 2000
Acute renal response to the non-peptide vasopressin V2-receptor antagonist SR 121463B in anesthetized rats.
Vasopressin V2-receptor antagonists are promising agents for the use in water-retaining diseases. Potential renal mechanisms of action include effects on water permeability in the collecting duct as well as on electrolyte transport in the thick ascending limb of Henle's loop (TALH). To elucidate sites of action upstream of the distal tubule, e.g., in TALH, micropuncture experiments were performed in anesthetized rats during application of the V2-receptor antagonist SR 121463B. ⋯ As compared to vehicle application, SR 121463B did not significantly alter single nephron GFR (39+/-2 nl/min vs. 39+/-1 nl/min, n=22 and 23 nephrons, respectively) or the FR up to the early distal tubule of fluid (76+/-2% vs. 76+/-1%), sodium (92+/-1% vs. 93+/-1%), potassium (91+/-1% vs. 90+/-1%) or chloride (90+/-1% vs. 91+/-1%). Together these data indicate a predominant aquaretic effect of SR 121463B which is located downstream of the early distal tubule. This response is compatible with blockade of vasopressin V2-receptors in the collecting duct and, as directly demonstrated by immunohistochemistry, subsequent retrieval of aquaporin-2 from apical plasma membrane, which inhibits water permeability and transport.
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Naunyn Schmiedebergs Arch. Pharmacol. · Sep 2000
Recombinant human 5-HT3A receptors in outside-out patches of HEK 293 cells: basic properties and barbiturate effects.
The patch-clamp technique was used on excised (outside-out) patches to characterize h5-HT3A receptors stably transfected in HEK 293 cells and to compare the effects of the barbiturate anaesthetics methohexital and pentobarbital on this ligand-gated cation channel. At negative membrane potentials 5-HT induced inward currents in a concentration-dependent manner (EC50=8.6 microM, Hill coefficient =1.5). The mean peak current induced by 30 microM 5-HT was -110 pA at -100 mV. ⋯ Another difference between both barbiturates involves the rate of inactivation of 5-HT3 receptor-mediated currents: whereas high concentrations of methohexital (> or = 300 microM) were necessary to induce moderate (< or = twofold) acceleration of this parameter, pentobarbital produced such an effect at all concentrations and the extent of acceleration increased with increasing concentration (1.5- to fivefold). In conclusion, two barbiturates, chemically closely related but of different lipophilicity, clearly differ with respect to the kinetics of their effect on 5-HT3 receptor channels; one possible explanation involves drug access to an amphipathic site of action via both an aqueous and a hydrophobic pathway. Pentobarbital, in contrast to methohexital, inhibits hS-HT3A receptor-mediated currents at anaesthetic concentrations (approximately 90 microM).
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Naunyn Schmiedebergs Arch. Pharmacol. · May 2000
Cloning, expression, functional coupling and pharmacological characterization of the rat dopamine D4 receptor.
It has been difficult to observe functional coupling of the D4 receptor to second messenger systems and a robust functional assay system for this receptor is still lacking. In the present study, the rat dopamine D4 receptor was cloned from rat retina. Sequence comparison revealed identity with the published sequence of Ashgari and co-workers, including the two amino acid insertions (V-Q) at position 92 which are not present in the published sequence of O'Malley and coworkers. ⋯ However, the receptor did not couple to phosphatidylinositol turnover or to intracellular Ca2+. Thus, expression of the rat dopamine D4 receptor in CCL39 cells provided several functional assay systems, of which inhibition of cAMP appeared to be the most robust one. These functional models can be used to evaluate the activity of compounds at the rat dopamine D4 receptor.
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Naunyn Schmiedebergs Arch. Pharmacol. · Mar 2000
Effects of peptidase inhibitors on anti-nociceptive action of dynorphin-(1-8) in rats.
Previous in vitro studies showed that the degradation of dynorphin-(1-8) [dyn-(1-8)] by cerebral membrane preparations is almost completely prevented by a mixture of three peptidase inhibitors (PIs), amastatin, captopril and phosphoramidon. In the present investigations, effects of the three PIs on the anti-nociception induced by the intra-third-ventricular (i.t.v.) administration of dyn-(1-8) were examined. The inhibitory effect of dyn-(1-8) on the tail-flick response was increased more than 100-fold by the i.t.v. pretreatment of rats with the three PIs. ⋯ The antagonistic effectiveness of naloxone, a relatively selective mu-opioid antagonist, indicates that dyn-(1-8)-induced inhibition of tail-flick response in rats pretreated with three PIs is mediated by mu-opioid receptors. Furthermore, mu-receptor-mediated inhibition induced by dyn-(1-8) was significantly greater than that produced by [Met5]-enkephalin in rats pretreated with three PIs. The data obtained in the present investigations together with those obtained in previous studies strongly indicate that dyn-(1-8) not only has well-known kappa-agonist activity but also has high mu-agonist activity.