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 natriuretic 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 study whether genetically determined differences in NPRA expression affect blood pressure we have generated mice with one, two, three, or four copies of the gene encoding NPRA (Npr1 in the mouse). Atrial natriuretic 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 F1 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 had blood pressures averaging 5.2 mmHg below normal (P < 0.01). The blood pressures of the one-copy F1 animals were significantly higher (by 6.2 mmHg; P < 0.01) on the high-salt than on the low-salt diet. The blood pressures of four-copy F3 males were significantly lower (by 7 mmHg; P < 0.05) on the high-salt than on the low-salt diet. These results demonstrate that below normal Npr1 expression leads to a salt-sensitive increase in blood pressure, whereas above normal Npr1 expression lowers blood pressures and protects against high dietary salt.
Oliver
P M
PM
Department of Pathology, University of North Carolina, Chapel Hill, NC 27599, USA.
John
S W
SW
Purdy
K E
KE
Kim
R
R
Maeda
N
N
Goy
M F
MF
Smithies
O
O
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003433:Crosses, Genetic; D004039:Diet, Sodium-Restricted; D005260:Female; D005838:Genotype; D006162:Guanylate Cyclase / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D006400:Hematocrit; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009929:Organ Size; D017461:Receptors, Atrial Natriuretic Factor / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D012982:Sodium, Dietary / Q000494:pharmacology
D012982:Sodium, Dietary; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A