Low nitric oxide bioavailability contributes to the genesis of experimental cerebral malaria.
The role of nitric oxide (NO) in the genesis of cerebral malaria is controversial. Most investigators propose that the unfortunate consequence of the high concentrations of NO produced to kill the parasite is the development of cerebral malaria. Here we have tested this high NO bioavailability hypothesis in the setting of experimental cerebral malaria (ECM), but find instead that low NO bioavailability contributes to the genesis of ECM. Specifically, mice deficient in vascular NO synthase showed parasitemia and mortality similar to that observed in control mice. Exogenous NO did not affect parasitemia but provided marked protection against ECM; in fact, mice treated with exogenous NO were clinically indistinguishable from uninfected mice at a stage when control infected mice were moribund. Administration of exogenous NO restored NO-mediated signaling in the brain, decreased proinflammatory biomarkers in the blood, and markedly reduced vascular leak and petechial hemorrhage into the brain. Low NO bioavailability in the vasculature during ECM was caused in part by an increase in NO-scavenging free hemoglobin in the blood, by hypoargininemia, and by low blood and erythrocyte nitrite concentrations. Exogenous NO inactivated NO-scavenging free hemoglobin in the plasma and restored nitrite to concentrations observed in uninfected mice. We therefore conclude that low rather than high NO bioavailability contributes to the genesis of ECM.
Gramaglia
Irene
I
La Jolla Bioengineering Institute, 505 Coast Boulevard, La Jolla, California 92037, USA.
Sobolewski
Peter
P
Meays
Diana
D
Contreras
Ramiro
R
Nolan
John P
JP
Frangos
John A
JA
Intaglietta
Marcos
M
van der Heyde
Henri C
HC
D000475:Alkenes / Q000008:administration & dosage / Q000097:blood; D000818:Animals; D001120:Arginine / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism; D006454:Hemoglobins / Q000032:analysis; D016779:Malaria, Cerebral / Q000209:etiology* / Q000378:metabolism / Q000401:mortality; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D008954:Models, Biological; D009569:Nitric Oxide / Q000097:blood / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D009573:Nitrites / Q000097:blood; D010962:Plasmodium berghei; D014018:Tissue Distribution
D000475:Alkenes; D006454:Hemoglobins; D009573:Nitrites; C453079:dipropylenetriamine-NONOate; D009569:Nitric Oxide; D001120:Arginine; D052247:Nitric Oxide Synthase Type II; D006152:Cyclic GMP