This study has investigated the role of the α₂-adrenoceptor subtypes involved in the inhibition of the cardiac sympathetic outflow induced by intravenous (i.v) infusions of agmatine. Therefore, we analysed the effect of an i.v. bolus injections of the selective antagonists BRL 44408 (300μg/kg; α_2A), imiloxan (3000μg/kg; α_2B), and JP-1302 (300μg/kg; α_2C) given separately, and their combinations: BRL 44408 plus Imiloxan, JP 1302 plus imiloxan, BRL 44408 plus JP-1302, BRL 44408 plus imiloxan plus JP-1302 on the cardiac sympatho-inhibition of agmatine. Also, the effect of the combination BRL 44408 plus JP-1302 plus AGN 192403 (3000μg/kg; I₁ antagonist) was evaluated. In this way, i.v. infusions of 1000μg/kg min of agmatine, but not 300, inhibited the tachycardic response induced by electrical stimulation. Furthermore, the antagonists used or their combinations had no effect on the electrically-induced tachycardic response. On the other hand, the inhibitory response of agmatine was: (1) partially antagonized by BRL 44408 or JP-1302 given separately, a similar response was observed when we administered their combination with imiloxan, but not by imiloxan alone, (2) antagonized in greater magnitude by the combination BRL 44408 plus JP-1302 or the combination BRL 44408 plus imiloxan plus JP-1302, and (3) abolished by the combination BRL 44408 plus JP-1302 plus AGN 192403. Taken together, these results demonstrate that the α_2A- and α_2C-adrenoceptor subtypes and I₁-imidazoline receptors are involved in the inhibition of the cardiac sympathetic outflow induced by agmatine.

2014-09-01·Brain Research Bulletin3区 · 医学

Evidence for the gastric cytoprotective effect of centrally injected agmatine

3区 · 医学

Article

作者: Zádori, Zoltán S ; Németh, József ; Fehér, Ágnes ; Philipp, Kirsch ; Tóth, Viktória E ; Gyires, Klára

Agmatine (decarboxylated arginine) exerts cytoprotective action in several tissues, such as in the brain, heart or kidneys, but there is still controversy over the effects of agmatine on the gastric mucosa. The aim of the present study was to reveal the potential gastroprotective action of agmatine by using an acid-independent ulcer model to clarify which receptors and peripheral factors are involved in it. Gastric mucosal damage was induced by acidified ethanol. Mucosal levels of calcitonin gene-related peptide (CGRP) and somatostatin were determined by radioimmunoassay. For analysis of gastric motor activity the rubber balloon method was used. It was found that agmatine given intracerebroventricularly (i.c.v., 0.044-220 nmol/rat) significantly inhibited the development of ethanol-induced mucosal damage, while in the case of intraperitoneal injection (0.001-50mg/kg i.p.) it had only a minor effect. The central gastroprotective action of agmatine was completely antagonized by mixed alpha2-adrenoceptor and imidazoline I1 receptor antagonists (idazoxan, efaroxan), but only partially by yohimbine (selective alpha2-adrenoceptor antagonist) and AGN 192403 (selective I1 receptor ligand, putative antagonist). It was also inhibited by the non-selective opioid-receptor antagonist naloxone and the selective δ-opioid receptor antagonist naltrindole, but not by β-funaltrexamine and nor-Binaltorphimine (selective μ- and κ-opioid receptor antagonists, respectively). Furthermore, the effect of agmatine was antagonized by bilateral cervical vagotomy and by pretreatment with indomethacin and NG-nitro-l-arginine. Agmatine also reversed the ethanol-induced reduction of gastric mucosal CGRP and somatostatin content, but did not have any significant effect on gastric motor activity. These results indicate that agmatine given centrally induces gastric cytoprotection, which is mediated by central imidazoline I1 receptors, alpha2-adrenoceptors and δ-opioid receptors. Activation of these receptors induces the release of different mucosal protective factors, such as NO, prostaglandins, CGRP and somatostatin by a vagal-dependent mechanism. Alterations of gastric motility are not likely to contribute to the observed protective effect.

2013-04-01·European Journal of Pharmacology3区 · 医学

Imidazoline versus alpha2-adrenoceptors in the control of gastric motility in mice

3区 · 医学

Article

作者: Mahmoud Al-Khrasani ; Serena B. Brancati ; Ágnes Fehér ; Lutz Hein ; Klára Gyires ; Viktória E. Tóth ; Péter Mátyus ; Zoltán S. Zádori ; Erzsébet Lackó

Several lines of evidence suggest that imidazoline receptors mediate various physiological processes. It is rather difficult, however, to distinguish the imidazoline receptor-mediated effects from the alpha₂-adrenoceptor-mediated ones due to the reasonable affinity of most imidazoline ligands for the alpha₂-adrenoceptors. In the present study the effects of different imidazoline ligands were tested on the electrical field stimulation (EFS)-induced gastric contractions in wild-type (WT), alpha₂A-, alpha₂B- and alpha₂C-adrenoceptor knockout (KO) mice in order to analyze, whether imidazoline I₁ and I₂ receptors take part in the regulation of gastric motor activity. Clonidine, moxonidine and rilmenidine inhibited the EFS-induced gastric contractions in a concentration dependent manner in WT, alpha₂B- and alpha₂C-adrenoceptor KO mice, whereas they had no or only weak effect in alpha₂A-adrenoceptor KO mice. Their effects in WT mice were inhibited by idazoxan and BRL 44408, but not by ARC 239, AGN 192403 and BU 224. The endogenous imidazoline receptor ligand agmatine failed to affect the EFS-induced contractions, while harmane (an other endogenous imidazoline receptor ligand) and 2-BFI (a selective imidazoline I2 receptor agonist) exerted a slight effect in both WT and alpha2A-adrenoceptor KO mice, but this was not reversible by idazoxan, AGN 192403 and BU 224. It can be concluded, that the inhibitory effect of the tested imidazoline compounds on cholinergic gastric contractions is mediated mainly by alpha₂A-adrenoceptors. Although at higher concentrations other receptors may also contribute to their effects, the lack of inhibition by AGN 192403 and BU 224 suggests that these are not imidazoline I₁ and I₂ receptors.

100 项与 AGN 192403 相关的药物交易

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