The Journal of Experimental Medicine
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*Substance via MeSH
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*(L)-ARGININE
*NITRIC OXIDE
*SODIUM
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Journal of Experimental Medicine, Vol 174, 1009-1021, Copyright © 1991 by Rockefeller University Press

ARTICLES

Nitric oxide derived from L-arginine impairs cytoplasmic pH regulation by vacuolar-type H+ ATPases in peritoneal macrophages

CJ Swallow, S Grinstein, RA Sudsbury and OD Rotstein
Department of Surgery, Toronto General Hospital, Ontario, Canada.

The ability of macrophages (Mos) to function within an acidic environment has been shown to depend on cytoplasmic pH (pHi) regulation by vacuolar-type H+ ATPases. Mos metabolize L-arginine via an oxidative pathway that generates nitric oxide, nitrate, and nitrite. Since each of these products could potentially inhibit vacuolar-type H+ ATPases, we investigated the effect of L-arginine metabolism on Mo pHi regulation in thioglycolate-elicited murine peritoneal Mos. H+ ATPase- mediated pHi recovery from an imposed cytoplasmic acid load was measured fluorometrically. When Mos were incubated with L-arginine (0.25-2.0 mM), their rate of pHi recovery declined progressively from 2 to 6 h of incubation. By contrast, the recovery rate of cells incubated in arginine-free medium remained stable over the same period. The impairment of pHi recovery was specific for L-arginine, and was blocked competitively by NG-monomethyl-L-arginine, demonstrating its dependence on L-arginine metabolism. In addition, the inhibition of pHi recovery was enhanced by lipopolysaccharide, an agent known to stimulate L- arginine metabolism by Mos. Scavenging the L-arginine metabolite nitric oxide with either ferrous sulphate or ferrous myoglobin prevented the inhibition of pHi recovery, implying that L-arginine-derived nitric oxide was the species responsible for the inhibition. This concept was supported by the finding of elevated nitrite levels in the supernatant of cells incubated in L-arginine. Furthermore, incubation of Mos with sodium nitroprusside mimicked the L-arginine-dependent inhibition of H+ ATPase activity. Treatment with the cyclic GMP analogue, 8- bromoguanosine 3':5'-cyclic monophosphate, similarly impaired Mo pHi recovery, suggesting that a nitric oxide-stimulated elevation of cyclic GMP may contribute to the L-arginine-dependent inhibition of pHi regulation.
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