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(Hypertension. 1997;29:131.)
© 1997 American Heart Association, Inc.

Research Articles (Issue 1, Part 1)

Role of the -, ß-, and -Subunits of Epithelial Sodium Channel in a Model of Polygenic Hypertension

Reinhold Kreutz; Berthold Struk; Speranza Rubattu; Norbert Hübner; Josiane Szpirer; Claude Szpirer; Detlev Ganten; Klaus Lindpaintner

the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, and Department of Cardiology, Children's Hospital, Harvard Medical School, Boston, Mass (R.K., B.S., S.R., N.H., K.L.); Department of Molecular Biology, Université Libre de Bruxelles (Belgium) (J.S., C.S.); Istituto Neurologico Mediterraneo Neuromed, Pozzilli (IS), Italy (S.R.); Max Delbrück Centre for Molecular Medicine, Berlin, Germany (D.G., K.L.); and Division of Biological Sciences, Harvard School of Public Health, Boston, Mass (K.L.)

Correspondence to Klaus Lindpaintner, MD, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis St, Thorn 1103, Boston, MA 02115. E-mail kl@calvin.bwh.harvard.edu.

The pathophysiological basis of Liddle's syndrome, a rare autosomal dominant form of arterial hypertension, has been found to rest on missense mutations or truncations of the ß- and -subunits of the epithelial sodium channel. The hypothesis has been advanced that molecular variants of these genes might also contribute to the common polygenic forms of hypertension. We tested this hypothesis by performing a cosegregation study in a reciprocal cross between the stroke-prone spontaneously hypertensive rat (SHRSP_HD) and a Wistar-Kyoto rat (WKY-1_HD) reference strain. We carried out genetic mapping and chromosomal assignment of the -, ß-, and -subunits of the epithelial sodium channel using both linkage analysis and fluorescent in situ hybridization techniques. We demonstrate that in the rat, the ß- and -subunits, as in humans, are in close linkage; they map to rat chromosome 1 and cosegregate with systolic pressure after dietary NaCl (logarithm of the odds [LOD] score, 3.7), although the peak LOD score of 5.0 for this quantitative trait locus was detected 4.4 cM away from the ß-/-subunit locus. The -subunit was mapped to chromosome 4 and exhibited no linkage to blood pressure phenotype. Comparative analysis of the complete coding sequences of all three subunits in the SHRSP_HD and WKY-1_HD strains revealed no biologically relevant mutations. Furthermore, Northern blot comparison of mRNA levels for all three subunits in the kidney showed no differences between SHRSP_HD and WKY-1_HD. Our results fail to support a material contribution of the epithelial sodium channel genes to blood pressure regulation in this model of polygenic hypertension.

Key Words: genetics • sodium channels • rats, inbred strains • rats, inbred WKY • in situ hybridization, fluorescence • cytogenetics

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