Genetic mapping of soluble guanylyl cyclase genes - Implications for linkage to blood pressure in the Dahl rat

The nitric oxide (NO) signaling system, consisting of NO synthases, soluble guanylyl cyclase, and cGMP, plays a prominent role in salt handling and regulation of blood pressure. Soluble guanylyl cyclases are heme-containing heterodimers (alpha/beta). The alpha 1/beta 1 isoform has greater NO sensitivity than the alpha 1/beta 2. It has recently been shown that expression of the beta subunits is altered in the kidney of the Dahl salt-sensitive rat, ie, the beta 1 subunit is decreased and the beta 2 subunit increased. However, whether soluble guanylyl cyclase is linked to salt sensitivity is not known. In the present study, we investigated linkage of guanylyl cyclase genes to blood pressure. alpha 1 and beta 1 gene loci for soluble guanylyl cyclase were mapped to rat chromosome 2, and the beta 2 gene locus was mapped to rat chromosome 5 using fluorescent in situ metaphase hybridization. By use of a rat radiation hybrid panel, the gene loci were then further mapped with respect to known quantitative trait locus markers of salt-sensitive hypertension in the Dahl rat on chromosomes 2 and 5, Genes for alpha 1 and beta 1 were closely Inked by two-point analysis to Na+,K+-ATPase alpha 1 isoform (LOD of 15.1 and 14.0, respectively) and calmodulin-dependent protein kinase II-delta loci (LOD of 14.3 and 12.9, respectively), which have been previously shown to flank a quantitative trait locus for blood pressure in the Dahl rat. The alpha 1 and beta 1 genes were closely linked (LOD of 11.3; theta, 0.4). The beta 2 gene locus was closely linked to the endothelin-2 (ET-2) locus (LOD of 13.0), which has been shown to cosegregate with blood pressure. We conclude that soluble guanylyl cyclase subunit loci, ie, alpha 1, beta 1, and beta 2, are good candidates for genes controlling salt-sensitive hypertension in the Dahl rat.