ELEVATED BLOOD PRESSURES IN MICE LACKING ENDOTHELIAL NITRIC-OXIDE SYNTHASE

Nitric oxide produced in endothelial cells affects vascular tone, To i nvestigate the role of endothelial nitric oxide synthase (eNOS) in blo od pressure regulation, we have generated mice heterozygous (+/-) or h omozygous (-/-) for disruption of the eNOS gene. Immunohistochemical s taining with anti-eNOS antibodies shelved reduced amounts of eNOS prot ein in +/- mice and absence of eNOS protein in -/- mutant mice, Male o r female mice of all three eNOS genotypes were indistinguishable in ge neral appearance and histology, except that -/- mite had lower body we ights than +/- or +/- mice, Blood pressures tended to be increased (by approximately 4 mmHg) in +/- mice compared with +/+, while -/- mice h ad a significant increase in pressure compared with +/+ mice (approxim ate to 18 mmHg) or +/- mice (approximate to 14 mmHg), Plasma renin con centration in the -/- mice was nearly twice that of +/+ mice, although kidney renin mRNA was modestly decreased in the -/- mice. Heart rates in the -/- mice were significantly lower than in +/- or +/+ mice, App ropriate genetic controls show that these phenotypes in Fz mice are du e to the eNOS mutation and are not due to sequences that might differ between the two parental strains (129 and C57BL/6J) and are linked eit her to the eNOS locus or to an unlinked chromosomal region containing the renin locus. Thus eNOS is essential for maintenance of normal bloo d pressures and heart rates. Comparisons between the current eNOS muta nt mice and previously generated inducible nitric oxide synthase mutan ts showed that homozygous mutants for the latter differ in having unal tered blood pressures and heart rates; both are susceptible to lipopol ysaccharide-induced death.