Natriuretic peptide receptor 1 expression influences blood pressures of mice in a dose-dependent manner

Abstract

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 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 had blood pressures averaging 5.2 mmHg below normal (P < 0.01). The blood 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 blood pressures of four-copy F 3 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.

Beneficial Effects of Phosphodiesterase 5 Inhibition in Pulmonary Hypertension Are Influenced by Natriuretic Peptide Activity

“…12 The development of phenotype with continued breeding of the colony is well recognized. 15 Our findings support the view that the natriuretic peptides contribute to the low pulmonary vascular tone associated with the normal adult in a normal oxygen environment. Interestingly, 3 weeks of treatment with sildenafil had no effect on the elevated RVSP or on altered cyclic GMP levels in normoxic NPR-A Ϫ/Ϫ mice.…”

A modest decrease in endothelial NOS in mice comparable to that associated with human NOS3 variants exacerbates diabetic nephropathy

“…However, in other cases, such as the natriuretic peptide receptor A (Npr1), the phenotype of heterozygous knockout mice is readily distinguishable from that of WT (21). Our present study accordingly was aimed at removing uncertainly about whether the mild genetic decrease in eNOS expression which occurs in eNOS +/− mice is sufficient to cause DN.…”

Association of CT Dinucleotide Repeat Polymorphism in the 5'-Flanking Region of the Guanylyl Cyclase (GC)-A Gene with Essential Hypertension in the Japanese

“…The important physiological role played by the natriuretic peptide/GC-A system in the regulation of arterial blood pressure (BP) and blood volume is now well documented in studies carried out in a variety of genetically engineered mouse models. For instance, targeted deletion of GC-A leads to chronic hypertension (8)(9)(10), whereas its overexpression leads to a "dose-dependent" fall in BP (11). Although hypertension is a multifactorial disease controlled by multiple genes and environmental factors, these results demonstrating GC-A's critical role in the regulation of BP suggest that variations in GC-A gene expression could contribute significantly to the pathogenesis of essential hypertension in humans.…”