Essential role of L‐arginine uptake and protein tyrosine kinase activity for NO‐dependent vasorelaxation induced by stretch, isometric tension and cyclic AMP in rat pulmonary arteries
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Medientyp:
E-Artikel
Titel:
Essential role of L‐arginine uptake and protein tyrosine kinase activity for NO‐dependent vasorelaxation induced by stretch, isometric tension and cyclic AMP in rat pulmonary arteries
Beteiligte:
Hucks, David;
Khan, Nayeem M;
Ward, Jeremy P T
Beschreibung:
<jats:p>
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<jats:list-item><jats:p>The NO‐dependent component of cyclic AMP‐induced vasorelaxation in rat pulmonary arteries is critically dependent on extracellular <jats:sc>L</jats:sc>‐arginine but independent of endothelial cell intracellular [Ca<jats:sup>2+</jats:sup>]. We examined whether <jats:sc>L</jats:sc>‐arginine uptake was also essential for NO production induced by passive stretch or isometric tension, processes also reported to be Ca<jats:sup>2+</jats:sup>‐independent.</jats:p></jats:list-item>
<jats:list-item><jats:p>The passive length‐tension curve was depressed by physiological concentrations of <jats:sc>L</jats:sc>‐arginine (400 μ<jats:sc>M</jats:sc>; <jats:italic>P</jats:italic><0.05). Inhibition of the y<jats:sup>+</jats:sup> transporter with 10 m<jats:sc>M L</jats:sc>‐lysine, NO synthase with <jats:sc>L</jats:sc>‐NAME (100 μ<jats:sc>M</jats:sc>), or protein tyrosine kinase with erbstatin A (30 μ<jats:sc>M</jats:sc>) caused identical upward shifts (<jats:italic>P</jats:italic><0.001), alone or in combination. Tyrphostin 23 was similar to erbstatin A, whilst the inactive analogue tyrphostin A1 and genistein were without effect.</jats:p></jats:list-item>
<jats:list-item><jats:p><jats:sc>L</jats:sc>‐arginine (400 μ<jats:sc>M</jats:sc>) shifted the PGF<jats:sub>2α</jats:sub> concentration‐response curve under isometric conditions to the right (<jats:italic>P</jats:italic><0.05), whereas <jats:sc>L</jats:sc>‐NAME or <jats:sc>L</jats:sc>‐lysine caused a leftward shift (<jats:italic>P</jats:italic><0.001). Tyrphostin 23 (30 μ<jats:sc>M</jats:sc>) more than reversed the <jats:sc>L</jats:sc>‐arginine‐induced suppression of PGF<jats:sub>2α</jats:sub>‐induced tension; subsequent addition of <jats:sc>L</jats:sc>‐NAME had no effect. The <jats:sc>L</jats:sc>‐lysine‐sensitive component of CPT cyclic AMP‐induced vasorelaxation was abolished by erbstatin A.</jats:p></jats:list-item>
<jats:list-item><jats:p>ACh‐induced vasorelaxation was ∼80% inhibited by <jats:sc>L</jats:sc>‐NAME, but was not affected by <jats:sc>L</jats:sc>‐lysine or 400 μ<jats:sc>M L</jats:sc>‐arginine. Erbstatin A reduced the vasorelaxation by only ∼25%.</jats:p></jats:list-item>
<jats:list-item><jats:p>We conclude that activation of NO production by stretch, isometric tension, or cyclic AMP in rat pulmonary arteries is critically dependent on the presence and uptake of physiological concentrations of extracellular <jats:sc>L</jats:sc>‐arginine, and protein tyrosine kinase activity. This directly contrasts with ACh‐induced vasorelaxation, which was independent of extracellular <jats:sc>L</jats:sc>‐arginine, and relatively unaffected by tyrosine kinase inhibition.</jats:p></jats:list-item>
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</jats:p><jats:p><jats:italic>British Journal of Pharmacology</jats:italic> (2000) <jats:bold>131</jats:bold>, 1475–1481; doi:<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" xlink:href="10.1038/sj.bjp.0703718">10.1038/sj.bjp.0703718</jats:ext-link></jats:p>