In response to an increase in atrial distension, ANP is released into the circulation and mediates natriuretic, diuretic, and vasorelaxant effects. High levels of endogenous ANP are thought to compensate the condition of patients with heart failure by reducing preload and afterload. Evidence suggests that a high plasma ANP-BNP level is a prognostic predictor in humans with heart failure (257-259). Studies with ANP-deficient genetic strains of mice demonstrated that a defect in the ANP synthesis can cause hypertension (210). The blood pressures of homozygous null mutant animals were elevated by 8-12 mmHg when they were fed with standard or intermediate salt diets. Heterozygous animals showed normal blood pressures and normal amount of circulatory ANP, however, they became hypertensive and blood pressure was elevated by 20-27 mmHg if these animals were fed with high salt diets (207,210,260). Those previous findings clearly demonstrated that genetically reduced production of ANP can lead to salt-sensitive hypertension. On the other hand, the disruption of Npr1 gene indicated that the blood pressure of homozygous mutant mice remained elevated and unchanged in response to either minimal or high salt diets (211). These investigators suggested that NPRA may exert its major effect at the level of vasculature and probably does so independently of salt. On the contrary, Oliver et al. (213) reported that disruption of Npr1 gene resulted in chronic elevation of blood pressure in mice fed with high salt diets. Indeed, more studies are needed to clarify the relationship between salt-sensitivity and blood pressures in Npr1 gene-targeted mice.
Transgenic mice overexpressing ANP developed sustained hypotension with arterial pressure that was 25-30 mmHg lower than their nontransgenic siblings (189,207,261). A recent study demonstrated that somatic delivery of ANP gene in spontaneously hypertensive rat (SHR) induced a sustained reduction of systemic blood pressure, raising the possibility of using ANP as therapeutic agent for treatment of human hypertension (262). Genetic mouse models with disruption of both ANP and NPRA genes have provided strong support for the role of this hormone-receptor system in the regulation of arterial pressure and other physiological functions (15,16,198,207,210-214,216,263). Therefore, the genetic defects that reduce the activity of ANP and its receptor system can be considered as candidate contributors to essential hypertension and CHF (16,210, 212,216,264,265). Interestingly, complete absence of NPRA causes hypertension in mice and leads to altered renin and ANG II levels, cardiac hypertrophy, and lethal vascular events similar to those seen in untreated human hypertensive patients (15,16,198). In contrast, increased expression of NPRA reduces the blood pressure and increases the second messenger cGMP, corresponding to the increasing number of Npr1 gene copies (16,213,214).
ANP affects blood pressure directly through its natriuretic, diuretic, and vasodilatory actions (187). It also affects blood pressure indirectly, for example, by inhibiting the RAAS, which is known to cause hypertension and cardiovascular diseases, if excessively stimulated (266). Genetic defects that reduce the activity or influence the ANP-NPRA system greatly contribute to the development of hypertension. The mechanistic role of ANP-NPRA system in counteracting the pathophysiology of hypertension is not well understood. Although the expression of ANP and BNP is markedly increased in patients with hypertrophic or failing heart, it is unclear if the NP system is activated to play a protective role by reducing the detrimental effects of high blood pressure caused by sodium retention and fluid volume, inhibiting the RAAS, or it is simply a consequence of the hypertrophic changes occurring in heart. Recent studies indicated that intrarenal renin in newborn Npr1 homozygous null mutant pups (2 days after birth) was 2.5-fold higher than in 2-copy wild-type counterparts (198). However, adult (16-wk) hypertensive Npr1 null mutant mice showed 50-70% reduction in plasma renin concentrations and renal renin contents as compared with wild-type control animals. In contrast, the adrenal renin contents and mRNA expression levels were elevated approx 1.5- to 2.0-fold in adult homozygous null mutant mice than wild-type mice. However, the factors that modulate renin gene expression in the adrenal gland have not been clearly identified. Together, the studies in both SHR and Npr1 gene-knockout hypertensive mouse models suggest that in hypertension, both kidney and circulatory renin concentrations are decreased, however, as a compensatory event, the adrenal renin is increased (198). Thus in light of those previous findings, it can be suggested that ANP-NPRA system may play a key regulatory role in the synthesis and maintenance of both systemic and tissue levels of RAAS components in both physiological and pathological conditions.
Studies in patients with chronic CHF have suggested that their plasma ANP levels decreased, whereas plasma cGMP levels increased significantly from femoral artery to the femoral vein, however, in patients with mild CHF, the plasma cGMP level correlated with ANP level (257). Furthermore, these authors suggested that among patients with severe CHF, plasma cGMP levels reached a plateau despite high levels of plasma ANP, and the molar ratio of cGMP production to ANP in peripheral circulation was significantly lower than those in patients with mild CHF. The findings of those previous studies further indicated that downregulation of NPRA may also occur in the peripheral vascular bed of patients with chronic severe CHF. On the other hand, it is widely believed that ANP concentrations are markedly increased both in cardiac tissues and in plasma of CHF patients (258,259). In hypertrophied heart, ANP and BNP genes are overexpressed, suggesting that autocrine and/or paracrine effects of natriuretic peptides predominate and might serve as an endogenous protective mechanism against maladaptive pathological cardiac hypertrophy (242,243,265). Inactivation of either ANP or Npr1 gene in mice increases the cardiac mass to a great extent (15,210). A significant inverse relationship has been found between myocardial ANP mRNA expression or peptide levels and increases in left ventricular cardiac mass (245). Those previous findings suggested that ANP expression plays a protective role in hypertrophied heart. Cosegregation analysis of genetic crosses suggested a protective role for ANP against ventricular hypertrophy (245). Those previous findings demonstrated that low ventricular ANP gene expression can be linked genetically to high cardiac mass independently of blood pressure that is consistent with a protective role for ANP against left ventricular cardiac hypertrophy. Furthermore, it has been shown that functional alterations of ANP promoter are linked to cardiac hypertrophy in progenies of crosses between Wistar-Kyoto (WKY) and Wistar-Kyoto-derived hypertensive (WKYH) rats (267). These authors suggested that a single nucleotide polymorphism altered the transcriptional activity of ANP gene promoter, and implicated that ANP may protect car-diomyocytes against hypertrophy as a strong candidate gene for the determination of left ventricular mass. Based on these findings it is speculated that a similar mutation in the NPRA might be of potential significance to elicit the cardiac hypertrophy in human population in that ANP-NPRA-dependent cGMP may play a critical role in the protection against ventricular cardiac hypertrophy and CHF.
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