Genetic Decreases in Atrial Natriuretic Peptide and Salt-Sensitive Hypertension

Abstract

To determine if defects in the atrial natriuretic peptide (ANP) system can cause hypertension, mice were generated with a disruption of the proANP gene. Homozygous mutants had no circulating or atrial ANP, and their blood pressures were elevated by 8 to 23 millimeters of mercury when they were fed standard (0.5 percent sodium chloride) and intermediate (2 percent sodium chloride) salt diets. On standard salt diets, heterozygotes had normal amounts of circulating ANP and normal blood pressures. However, on high (8 percent sodium chloride) salt diets they were hypertensive, with blood pressures elevated by 27 millimeters of mercury. These results demonstrate that genetically reduced production of ANP can lead to salt-sensitive hypertension.

Atrial natriuretic peptide (ANP) gene promoter variant and increased susceptibility to early development of hypertension in humans

“…1,2 The gene encoding ANP, a cardiac hormone with natriuretic diuretic and vasodilatory properties, 3 has been shown to favour development of high BP levels in genetically manipulated animal models. 4,5 Similar results were obtained with the manipulation of NPRA (natriuretic peptide receptor type A) gene. 6 Furthermore, the efficacy of a regulatable ANP gene therapy for hypertension has been recently demonstrated.…”

“…3 K The gene encoding ANP is a plausible contributor to increased susceptibility to develop hypertension. In fact, ablation of ANP gene leads to a form of salt-sensitive hypertension, 4 whereas overexpression of ANP causes hypotension. 5 What this study adds: K A molecular variant of ANP gene, which falls within the promoter region and has been previously associated to reduced NT-proANP plasma levels, 10 is associated with significantly higher blood pressure levels and with an increased prevalence of hypertension in young male subjects.…”

Participation of renal and circulating endothelin in salt-sensitive essential hypertension

“…Examples include: (a) exogenous inhibition of the natriuretic sensory nervous system, 32 nitric oxide, [33][34][35] or natriuretic eicosanoids; 36 (b) knockout of the proANP gene in mice; 37 (c) inbreeding of biochemical abnormalities such as deficient renal medullary natriuretic 20-HETE 38 or nitric oxide 33,34,39 in Dahl SS rats; and (d) blunting of ANP, 40 nitric oxide, 41 kallikrein, 10,11 dopaminergic, 15 and ␤2 adrenergic 42 systems as described in salt-sensitive hypertensive humans.…”

The Regulation and Physiological Roles of the Guanylyl Cyclase Receptors.

“…ANP Null Mice ANP null mice were once reported to exhibit saltdependent blood pressure elevation; blood pressures of ANP null mice measured by the tail-cuff method were 8 mmHg higher than those of wild-type mice on a standard-salt diet (0.5% NaCI), but mean intra-arterial pressures increased to 23 mmHg above those in wild-type mice on a diet of higher salt concentration (2% NaCI) [172]. The magnitude of intra-arterial blood pressure elevation in ANP null mice, however, was similar to that in GC-A null mice when fed either a low-salt diet (0.008% NaCI) or a high-salt diet (8% NaCI) [183].…”

“…Gene deletion of murine GC-A, GC-C, ANP, BNP, and CNP along with transgenic over-expression of ANP and BNP have pointed to some of the fundamental roles of these receptors and ligands in murine physiology [168][169][170][171][172][173][174][175][176].…”