NATRIURETIC PEPTIDE RECEPTOR-1 EXPRESSION INFLUENCES BLOOD PRESSURES OF MICE IN A DOSE-DEPENDENT MANNER

Activation of the natriuretic peptide system lowers blood pressure and causes the excretion of salt, Atrial natriuretic peptide and B-type n atriuretic peptide are the humoral mediators of this effect; they act primarily by binding to membrane-bound natriuretic peptide receptor A (NPRA) and stimulating its intrinsic guanylate cyclase activity, To st udy whether genetically determined differences in NPRA expression affe ct blood pressure we have generated mice with one, two, three, or four copies of the gene encoding NPRA (Npr1 in the mouse), Atrial natriure tic peptide-dependent guanylate cyclase activity ranged progressively from approximately one-half normal in one-copy animals to twice normal in four-copy animals (P < 0.001), On different diets (0.05%, 2%, and 8% NaCl), the blood pressures of F-1 male mice having only one copy of Npr1 averaged 9.1 mmHg (1 mmHg = 133 Pa) above those of wild-type two -copy males (P < 0.001), whereas males with three copies of the gene h ad blood pressures averaging 5.2 mmHg below normal (P < 0.01), The blo od pressures of the one-copy F-1 animals were significantly higher (by 6.2 mmHg; P < 0.01) on the high-salt than on the low-salt diet, The b lood pressures of four-copy F-3 males were significantly lower (by 7 m mHg; P < 0.05) on the high-salt than on the low-salt diet, These resul ts demonstrate that below normal Npr1 expression leads to a salt-sensi tive increase in blood pressure, whereas above normal Npr1 expression lowers blood pressures and protects against high dietary salt.