Inhibition of cerebral neurogenic vasodilation by L-glutamine and nitric oxide synthase inhibitors and its reversal by L-citrulline.
The possibility that L-citrulline is able to reverse inhibition of neurogenic vasodilation in isolated porcine cerebral arteries produced by nitric oxide synthase (NOS) inhibitors and Gln was examined by using in vitro tissue bath techniques. The results indicated that transmural nerve stimulation elicited a frequency-dependent and tetrodotoxin-sensitive vasodilation in isolated ring segments of arteries with or without endothelial cells. The dilation was abolished by L-N-omega-nitro-L-Arg and L-N-omega-L-Arg methyl ester and was completely reversed by L-citrulline, but not by D-citrulline. In parallel studies, the transmural nerve stimulation-induced relaxation was blocked in part by Gln. The blockade was completely reversed by L-citrulline and L-Arg, but not by their D-enantiomers. The time courses of relaxation after L-citrulline reversal of inhibition of vasodilation produced by Gln and NOS inhibitors were identical to that of relaxation in the control. The residual relaxation after L-citrulline reversal was abolished by L-NNA and L-N-omega-nitro-L-Arg. At 1 mM, L-glutamate, tau-aminobutyric acid or NH4Cl did not block transmural nerve stimulation-induced relaxation, nor did Gln inhibit sodium nitroprusside-induced relaxation or neuronal NOS activity. These results provide pharmacological evidence that cerebral perivascular nerves can recycle L-citrulline to L-Arg for synthesizing nitric oxide to induce neurogenic vasodilation. Although the exact mechanism of action of Gln in inhibiting nitric oxidergic neurovascular transmission remains undetermined, Gln does not seem to act by releasing ammonium ions, inhibiting NOS or modifying the nitric oxide-cyclic GMP pathway. Cerebral metabolism of Gln may play an important role in regulating nitric oxidergic neurogenic vasodilation.
Lee
T J
TJ
Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, USA.
Sarwinski
S
S
Ishine
T
T
Lai
C C
CC
Chen
F Y
FY
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002536:Cerebral Arteries / Q000187:drug effects* / Q000502:physiology; D002956:Citrulline / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D018698:Glutamic Acid / Q000494:pharmacology; D005973:Glutamine / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D019331:NG-Nitroarginine Methyl Ester; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D019335:Nitroarginine; D013552:Swine; D014664:Vasodilation / Q000187:drug effects*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D004791:Enzyme Inhibitors; D005973:Glutamine; D019335:Nitroarginine; D002956:Citrulline; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D001120:Arginine; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester