Locus for the inducible, but not a constitutive, nitric oxide synthase cosegregates with blood pressure in the Dahl salt-sensitive rat.

Abstract

Alleles of the inducible nitric oxide synthase locus (Nos2) cosegregated highly significantly (P < 0.0001) with blood pressure in an F2 population [F2(S x MNS), n = 171] derived from a cross of inbred Dahl salt-sensitive (S) rats with Milan normotensive rats (MNS). In contrast, alleles at the constitutive brain nitric oxide synthase locus (Nos1) did not cosegregate with blood pressure in several F2 populations. Nos2 was mapped on rat chromosome 10. Nine genetic markers, including the angiotensin-converting enzyme (Ace) and Nos2 loci spanning roughly 46 cM on rat chromosome 10, all cosegregated strongly with blood pressure in the F2(S x MNS) population. Nos2 showed the highest LOD score of 6.3. Ace and Nos2 are 30 cM apart. In an F2 population [F2(S x WKY), n = 159] derived from a cross of S rats with Wistar-Kyoto (WKY) rats, Nos2 alleles did (P = 0.0070), but Ace alleles did not (P = 0.91), cosegregate with blood pressure. We conclude that the Nos2 locus rather than the Nos1 locus is a candidate for influencing blood pressure in the S rat. There are probably two separate but linked quantitative trait loci (QTL) for blood pressure on rat chromosome 10, one marked by Ace and the other marked by Nos2. In F2(S x MNS) functionally variant alleles at both QTL influence blood pressure, but in F2(S x WKY) only the QTL marked by Nos2 is segregating alleles influencing blood pressure.