• Medientyp: E-Artikel
  • Titel: Clonidine‐induced nitric oxide‐dependent vasorelaxation mediated by endothelial α2‐adrenoceptor activation
  • Beteiligte: Figueroa, Xavier F; Poblete, M Inés; Boric, Mauricio P; Mendizábal, Victoria E; Adler‐Graschinsky, Edda; Huidobro‐Toro, J Pablo
  • Erschienen: Wiley, 2001
  • Erschienen in: British Journal of Pharmacology
  • Umfang: 957-968
  • Sprache: Englisch
  • DOI: 10.1038/sj.bjp.0704320
  • ISSN: 0007-1188; 1476-5381
  • Schlagwörter: Pharmacology
  • Zusammenfassung: <jats:p> <jats:list list-type="explicit-label"> <jats:list-item><jats:p>To assess the involvement of endothelial α<jats:sub>2</jats:sub>‐adrenoceptors in the clonidine‐induced vasodilatation, the mesenteric artery of Sprague Dawley rats was cannulated and perfused with Tyrode solution (2 ml min<jats:sup>−1</jats:sup>). We measured perfusion pressure, nitric oxide (NO) in the perfusate using chemiluminescence, and tissue cyclic GMP by RIA.</jats:p></jats:list-item> <jats:list-item><jats:p>In phenylephrine‐precontracted mesenteries, clonidine elicited concentration‐dependent vasodilatations associated to a rise in luminal NO. One hundred n<jats:sc>M</jats:sc> rauwolscine or 100 μ<jats:sc>M</jats:sc> L<jats:sup>ω</jats:sup>‐nitro‐<jats:sc>L</jats:sc>‐arginine antagonized the clonidine‐induced vasodilatation. Guanabenz, guanfacine, and oxymetazoline mimicked the clonidine‐induced vasorelaxation.</jats:p></jats:list-item> <jats:list-item><jats:p>In non‐contracted mesenteries, 100 n<jats:sc>M</jats:sc> clonidine elicited a maximal rise of NO (123±13 pmol); associated to a peak in tissue cyclic GMP. Endothelium removal, L<jats:sup>ω</jats:sup>‐nitro‐<jats:sc>L</jats:sc>‐arginine, or rauwolscine ablated the rise in NO. One hundred n<jats:sc>M</jats:sc> aminoclonidine, guanfacine, guanabenz, UK14,304 and oxymetazoline mimicked the clonidine‐induced surge of NO. Ten μ<jats:sc>M</jats:sc> ODQ obliterated the clonidine‐induced vasorelaxation and the associated tissue cyclic GMP accumulation; 10 – 100 n<jats:sc>M</jats:sc> sildenafil increased tissue cyclic GMP accumulation without altering the clonidine‐induced NO release.</jats:p></jats:list-item> <jats:list-item><jats:p>α<jats:sub>2</jats:sub>‐Adrenergic blockers antagonized the clonidine‐induced rise in NO. Consistent with a preferential α<jats:sub>2D</jats:sub>‐adrenoceptor activation, the K<jats:sub>B</jats:sub>s for yohimbine, rauwolscine, phentolamine, WB‐4101, and prazosin were: 6.8, 24, 19, 165, and 1489 n<jats:sc>M</jats:sc>, respectively.</jats:p></jats:list-item> <jats:list-item><jats:p>Rat pretreatment with 100 mg kg<jats:sup>−1</jats:sup> 6‐hydroxydopamine reduced 95% tissue noradrenaline and 60% neuropeptide Y. In these preparations, 100 n<jats:sc>M</jats:sc> clonidine elicited a rise of 91.9±15.5 pmol NO. Perfusion with 1 μ<jats:sc>M</jats:sc> guanethidine or 1 μ<jats:sc>M</jats:sc> guanethidine plus 1 μ<jats:sc>M</jats:sc> atropine did not modify the NO surge evoked by 100 n<jats:sc>M</jats:sc> clonidine.</jats:p></jats:list-item> <jats:list-item><jats:p>Clonidine and congeners activate endothelial α<jats:sub>2D</jats:sub>‐adrenoceptors coupled to the <jats:sc>L</jats:sc>‐arginine pathway, suggesting that the antihypertensive action of clonidine involves an endothelial vasorelaxation mediated by NO release, in addition to presynaptic mechanisms.</jats:p></jats:list-item> </jats:list> </jats:p><jats:p><jats:italic>British Journal of Pharmacology</jats:italic> (2001) <jats:bold>134</jats:bold>, 957–968; doi:<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" xlink:href="10.1038/sj.bjp.0704320">10.1038/sj.bjp.0704320</jats:ext-link></jats:p>
  • Beschreibung: <jats:p>
    <jats:list list-type="explicit-label">
    <jats:list-item><jats:p>To assess the involvement of endothelial α<jats:sub>2</jats:sub>‐adrenoceptors in the clonidine‐induced vasodilatation, the mesenteric artery of Sprague Dawley rats was cannulated and perfused with Tyrode solution (2 ml min<jats:sup>−1</jats:sup>). We measured perfusion pressure, nitric oxide (NO) in the perfusate using chemiluminescence, and tissue cyclic GMP by RIA.</jats:p></jats:list-item>
    <jats:list-item><jats:p>In phenylephrine‐precontracted mesenteries, clonidine elicited concentration‐dependent vasodilatations associated to a rise in luminal NO. One hundred n<jats:sc>M</jats:sc> rauwolscine or 100 μ<jats:sc>M</jats:sc> L<jats:sup>ω</jats:sup>‐nitro‐<jats:sc>L</jats:sc>‐arginine antagonized the clonidine‐induced vasodilatation. Guanabenz, guanfacine, and oxymetazoline mimicked the clonidine‐induced vasorelaxation.</jats:p></jats:list-item>
    <jats:list-item><jats:p>In non‐contracted mesenteries, 100 n<jats:sc>M</jats:sc> clonidine elicited a maximal rise of NO (123±13 pmol); associated to a peak in tissue cyclic GMP. Endothelium removal, L<jats:sup>ω</jats:sup>‐nitro‐<jats:sc>L</jats:sc>‐arginine, or rauwolscine ablated the rise in NO. One hundred n<jats:sc>M</jats:sc> aminoclonidine, guanfacine, guanabenz, UK14,304 and oxymetazoline mimicked the clonidine‐induced surge of NO. Ten μ<jats:sc>M</jats:sc> ODQ obliterated the clonidine‐induced vasorelaxation and the associated tissue cyclic GMP accumulation; 10 – 100 n<jats:sc>M</jats:sc> sildenafil increased tissue cyclic GMP accumulation without altering the clonidine‐induced NO release.</jats:p></jats:list-item>
    <jats:list-item><jats:p>α<jats:sub>2</jats:sub>‐Adrenergic blockers antagonized the clonidine‐induced rise in NO. Consistent with a preferential α<jats:sub>2D</jats:sub>‐adrenoceptor activation, the K<jats:sub>B</jats:sub>s for yohimbine, rauwolscine, phentolamine, WB‐4101, and prazosin were: 6.8, 24, 19, 165, and 1489 n<jats:sc>M</jats:sc>, respectively.</jats:p></jats:list-item>
    <jats:list-item><jats:p>Rat pretreatment with 100 mg kg<jats:sup>−1</jats:sup> 6‐hydroxydopamine reduced 95% tissue noradrenaline and 60% neuropeptide Y. In these preparations, 100 n<jats:sc>M</jats:sc> clonidine elicited a rise of 91.9±15.5 pmol NO. Perfusion with 1 μ<jats:sc>M</jats:sc> guanethidine or 1 μ<jats:sc>M</jats:sc> guanethidine plus 1 μ<jats:sc>M</jats:sc> atropine did not modify the NO surge evoked by 100 n<jats:sc>M</jats:sc> clonidine.</jats:p></jats:list-item>
    <jats:list-item><jats:p>Clonidine and congeners activate endothelial α<jats:sub>2D</jats:sub>‐adrenoceptors coupled to the <jats:sc>L</jats:sc>‐arginine pathway, suggesting that the antihypertensive action of clonidine involves an endothelial vasorelaxation mediated by NO release, in addition to presynaptic mechanisms.</jats:p></jats:list-item>
    </jats:list>
    </jats:p><jats:p><jats:italic>British Journal of Pharmacology</jats:italic> (2001) <jats:bold>134</jats:bold>, 957–968; doi:<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" xlink:href="10.1038/sj.bjp.0704320">10.1038/sj.bjp.0704320</jats:ext-link></jats:p>
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