title: Pharmacological assessment of the role of nitric oxide in mice infected with lethal and nonlethal species of malaria.
abstract: This pharmacological investigation sought to determine whether nitric oxide (NO) had an antiparasitic effect and/or mediated pathology in mice infected with nonlethal P. chabaudi or lethal P. berghei. Nitric oxide synthase (NOS) inhibitors were evaluated for their ability to inhibit the rise in reactive nitrogen intermediates (RNI) induced by bacterial lipopolysaccharide (LPS) in mice. The more effective compound, aminoguanidine (AG) inhibited the rise in RNI induced by P. chabaudi and increased mortality, but had no effect on parasitaemia. Inducers and donors of NO were screened for their ability to increase RNI and the most effective agents evaluated for their ability to modify P. berghei infection. S-Nitrosoglutathione had little effect, but LPS decreased parasitaemia and mortality. An inconsistent relationship is evident between the abilities of these agents to modify NO activity and their effects on malaria in mice. Increased mortality in mice with P. chabaudi treated with AG indicates a reduction in resistance. The absence of an effect on parasitaemia by a NOS inhibitor or NO donor indicates either RNI have insignificant antimalarial action in vivo or the efficacy of the compounds is inadequade. Resistance to P. berghei in LPS-treated mice demonstrates an antiparasitic effect, but this may be attributable to factors other than NO.
authors.affiliation: School of Biological Sciences, The University of Manchester, UK. mike.dascombe@man.ac.uk
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Dascombe
authors.forename: Hossein
authors.initials: H
authors.lastname: Nahrevanian
mesh_terms: D000818:Animals; D021461:Animals, Outbred Strains; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008288:Malaria / Q000469:parasitology / Q000473:pathology*; D051379:Mice; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D010962:Plasmodium berghei / Q000187:drug effects* / Q000254:growth & development / Q000472:pathogenicity
chemical_list: D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse