Article date: December 2000
By: David Hucks, Nayeem M Khan, Jeremy P T Ward in Volume 131, Issue 7, pages 1475-1481
The NO‐dependent component of cyclic AMP‐induced vasorelaxation in rat pulmonary arteries is critically dependent on extracellular L‐arginine but independent of endothelial cell intracellular [Ca2+]. We examined whether L‐arginine uptake was also essential for NO production induced by passive stretch or isometric tension, processes also reported to be Ca2+‐independent.
The passive length‐tension curve was depressed by physiological concentrations of L‐arginine (400 μM; P<0.05). Inhibition of the y+ transporter with 10 mM L‐lysine, NO synthase with L‐NAME (100 μM), or protein tyrosine kinase with erbstatin A (30 μM) caused identical upward shifts (P<0.001), alone or in combination. Tyrphostin 23 was similar to erbstatin A, whilst the inactive analogue tyrphostin A1 and genistein were without effect.
L‐arginine (400 μM) shifted the PGF2α concentration‐response curve under isometric conditions to the right (P<0.05), whereas L‐NAME or L‐lysine caused a leftward shift (P<0.001). Tyrphostin 23 (30 μM) more than reversed the L‐arginine‐induced suppression of PGF2α‐induced tension; subsequent addition of L‐NAME had no effect. The L‐lysine‐sensitive component of CPT cyclic AMP‐induced vasorelaxation was abolished by erbstatin A.
ACh‐induced vasorelaxation was ∼80% inhibited by L‐NAME, but was not affected by L‐lysine or 400 μM L‐arginine. Erbstatin A reduced the vasorelaxation by only ∼25%.
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 L‐arginine, and protein tyrosine kinase activity. This directly contrasts with ACh‐induced vasorelaxation, which was independent of extracellular L‐arginine, and relatively unaffected by tyrosine kinase inhibition.
The NO‐dependent component of cyclic AMP‐induced vasorelaxation in rat pulmonary arteries is critically dependent on extracellular L‐arginine but independent of endothelial cell intracellular [Ca2+]. We examined whether L‐arginine uptake was also essential for NO production induced by passive stretch or isometric tension, processes also reported to be Ca2+‐independent.
The passive length‐tension curve was depressed by physiological concentrations of L‐arginine (400 μM; P<0.05). Inhibition of the y+ transporter with 10 mM L‐lysine, NO synthase with L‐NAME (100 μM), or protein tyrosine kinase with erbstatin A (30 μM) caused identical upward shifts (P<0.001), alone or in combination. Tyrphostin 23 was similar to erbstatin A, whilst the inactive analogue tyrphostin A1 and genistein were without effect.
L‐arginine (400 μM) shifted the PGF2α concentration‐response curve under isometric conditions to the right (P<0.05), whereas L‐NAME or L‐lysine caused a leftward shift (P<0.001). Tyrphostin 23 (30 μM) more than reversed the L‐arginine‐induced suppression of PGF2α‐induced tension; subsequent addition of L‐NAME had no effect. The L‐lysine‐sensitive component of CPT cyclic AMP‐induced vasorelaxation was abolished by erbstatin A.
ACh‐induced vasorelaxation was ∼80% inhibited by L‐NAME, but was not affected by L‐lysine or 400 μM L‐arginine. Erbstatin A reduced the vasorelaxation by only ∼25%.
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 L‐arginine, and protein tyrosine kinase activity. This directly contrasts with ACh‐induced vasorelaxation, which was independent of extracellular L‐arginine, and relatively unaffected by tyrosine kinase inhibition.
British Journal of Pharmacology (2000) 131, 1475–1481; doi:10.1038/sj.bjp.0703718
DOI: 10.1038/sj.bjp.0703718
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