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Receptor-mediated activation of nitric oxide synthesis by arginine in endothelial cells.

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Title: Receptor-mediated activation of nitric oxide synthesis by arginine in endothelial cells.
Authors: Mahesh S. Joshi1 mjoshi20@yahoo.com, Bruce Ferguson Jr.1, Johnson, Fruzsina K.2, Johnson, Robert A.3, Parthasarathy, Sampath2 mjoshi20@yahoo.com, Lancaster Jr., Jack R.4
Source: Proceedings of the National Academy of Sciences of the United States of America. 6/12/2007, Vol. 104 Issue 24, p9982-9987. 6p. 5 Graphs.
Subjects: Nitric oxide, Arginine, Ligands (Biochemistry), Imidazolines, Adrenergic receptors, Nifedipine
Abstract: Arginine contains the guanidinium group and thus has structural similarity to ligands of imidazoline and α-2 adrenoceptors (α-2 AR). Therefore, we investigated the possibility that exogenous arginine may act as a ligand for these receptors in human umbilical vein endothelial cells and activate intracellular nitric oxide (NO) synthesis. Idazoxan, a mixed antagonist of imidazoline and α-2 adrenoceptors, partly inhibited ʟ-arginine-initiated NO formation as measured by a Griess reaction. Rauwolscine, a highly specific antagonist of α-2 AR, at very low concentrations completely inhibited NO formation. Like ʟ-arginine, agmatine (decarboxylated arginine) also activated NO synthesis, however, at much lower concentrations. We found that dexmedetomidine, a specific agonist of α-2 AR was very potent in activating cellular NO, thus indicating a possible role for α-2 AR in ʟ-arginine-mediated NO synthesis, o-arginine also activated NO production and could be inhibited by imidazoline and α-2 AR antagonists, thus indicating nonsubstrate actions of arginine. Pertussis toxin, an inhibitor of G proteins, attenuated ʟ-arginine-mediated NO synthesis, thus indicating mediation via G proteins. ʟ-type Ca2+ channel blocker nifedipine and phospholipase C inhibitor U73122 inhibited NO formation and thus implicated participation of a second messenger pathway. Finally, in isolated rat gracilis vessels, rauwolscine completely inhibited the ʟ-arginine-initiated vessel relaxation. Taken together, these data provide evidence for binding of arginine to membrane receptor(s), leading to the activation of endothelial NO synthase (eNOS) NO production through a second messenger pathway. These findings provide a previously unrecognized mechanistic explanation for the beneficial effects of ʟ-arginine in the cardiovascular system and thus provide new potential avenues for therapeutic development. [ABSTRACT FROM AUTHOR]
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Abstract:Arginine contains the guanidinium group and thus has structural similarity to ligands of imidazoline and α-2 adrenoceptors (α-2 AR). Therefore, we investigated the possibility that exogenous arginine may act as a ligand for these receptors in human umbilical vein endothelial cells and activate intracellular nitric oxide (NO) synthesis. Idazoxan, a mixed antagonist of imidazoline and α-2 adrenoceptors, partly inhibited ʟ-arginine-initiated NO formation as measured by a Griess reaction. Rauwolscine, a highly specific antagonist of α-2 AR, at very low concentrations completely inhibited NO formation. Like ʟ-arginine, agmatine (decarboxylated arginine) also activated NO synthesis, however, at much lower concentrations. We found that dexmedetomidine, a specific agonist of α-2 AR was very potent in activating cellular NO, thus indicating a possible role for α-2 AR in ʟ-arginine-mediated NO synthesis, o-arginine also activated NO production and could be inhibited by imidazoline and α-2 AR antagonists, thus indicating nonsubstrate actions of arginine. Pertussis toxin, an inhibitor of G proteins, attenuated ʟ-arginine-mediated NO synthesis, thus indicating mediation via G proteins. ʟ-type Ca2+ channel blocker nifedipine and phospholipase C inhibitor U73122 inhibited NO formation and thus implicated participation of a second messenger pathway. Finally, in isolated rat gracilis vessels, rauwolscine completely inhibited the ʟ-arginine-initiated vessel relaxation. Taken together, these data provide evidence for binding of arginine to membrane receptor(s), leading to the activation of endothelial NO synthase (eNOS) NO production through a second messenger pathway. These findings provide a previously unrecognized mechanistic explanation for the beneficial effects of ʟ-arginine in the cardiovascular system and thus provide new potential avenues for therapeutic development. [ABSTRACT FROM AUTHOR]
ISSN:00278424
DOI:10.1073/pnas.0506824104