Atrial Natriuretic Peptide Modifies Arterial Blood Pressure Through Nitric Oxide Pathway in Rats

Abstract

Abstract-The aim of the present study was to determine the relationship between the hypotensive effect of the atrial natriuretic peptide (ANP) and the nitric oxide (NO) pathway. N G -nitro-L-arginine methyl ester bolus (L-NAME, 1 mg/kg) reverted the decrease in mean arterial pressure induced by ANP administration (5 g/kg bolus and 0.2 g ⅐ kg Ϫ1 ⅐ min Ϫ1 infusion), and the injection of L-NAME before peptide administration suppressed the ANP hypotensive response. To confirm these findings, a histochemical reaction was used to determine NADPH-diaphorase activity (a NO synthase marker) in the endothelium and smooth muscle of aorta and arterioles of the small and large intestine. ANP increased aorta and arteriole endothelium staining after both in vivo administration and in vitro tissue incubation. In both cases, L-NAME prevented the ANP effect on NADPH-diaphorase activity. Tissues incubated with 8-bromoguanosine 3Ј, 5Ј-cyclic monophosphate mimicked ANP action. In addition, ANP administration increased urinary excretion of NO x end products. These findings indicate that ANP increases NO synthesis capability and NO production and suggest that the cGMP pathway may be involved. In conclusion, the NO pathway could be an intercellular messenger in the ANP endothelium-dependent vasorelaxation mechanism. (Hypertension. 2000;35:1119-1123.) Key Words: natriuretic peptides Ⅲ nitric oxide Ⅲ arterial pressure Ⅲ NADPH diaphorase Ⅲ cyclic GMP Ⅲ vasodilation A trial natriuretic peptide (ANP) and nitric oxide (NO), a free radical in the form of a highly diffusible gas, are vasoactive substances that induce hypotension through their vasorelaxant effects. 1 -3 Several factors, such as an increase in intracellular cGMP levels, a decrease in cytosolic Ca 2ϩ levels, and the activation of calcium-gated potassium channels, are involved in the cellular vasorelaxation mechanism. 4,5 An increase in cGMP results in the activation of cGMPdependent protein kinases and the phosphorylation of proteins involved in the dephosphorylation of myosin light chains, which is a precondition for smooth muscle relaxation. 6 Both ANP and NO induce an increase in intracellular cGMP levels, but they do so through different pathways. The cellular effects of ANP are mainly mediated by the guanylyl cyclase-coupled natriuretic receptors, natriuretic peptide receptor (NPR)-A and NPR-B. 7,8 These receptors are expressed on the surface of different types of cells, including renal endothelial cells, both arterial and venous smooth muscle and endothelial cells, etc. 6 These receptors present an intracellular protein kinaselike domain (KLD), a domain with an autoinhibitory function that mediates adenine nucleotide effects on the guanylyl cyclase domain. On binding of ANP to the extracellular domain of the receptor, a conformational change would ensue, allowing binding of ATP to the KLD. This, in turn, would lead to a further conformational change, freeing the guanylyl cyclase domain from the inhibitory constraint of the KLD and enabling cGMP production. 9 NO is produced ...

Renal actions of atrial natriuretic peptide in spontaneously hypertensive rats: the role of nitric oxide as a key mediator

“…NOS blockade blunted the ANP hypotensive effect in both groups, but L-NAME treatment had a more marked impact on normotensive ones. These results confirm our previous findings indicating that the NO system is involved in the hypotensive effect induced by ANP and that this response is impaired in hypertensive animals (6,9). Thus our results suggest that ANP's hypotensive effects involve different mechanisms in SHR and in WKY, indicating that the NO system plays a more Table 4 …”

“…In previous studies, we have demonstrated that ANP exerts its hypotensive, natriuretic, and diuretic effects, at least in part, through activation of cardiovascular and renal NOS (7,9). Furthermore, we have reported that the NPR-C natriuretic receptor mediates activation of NOS by ANP in the kidney (4,11).…”

Vasopeptidase Inhibition Prevents Endothelial Dysfunction of Resistance Arteries in Salt-Sensitive Hypertension in Comparison With Single ACE Inhibition

“…Accordingly, a recent study showed that ANP enhances NOS activity and NO production, suggesting that the NO pathway may be a second messenger for ANP. 41 The observed altered vascular responses could be related not only to a reduced production of NO but also to an altered responsiveness of VSMCs to NO due to an impaired activation of second messengers such as cGMP. 8 However, we found that basal cGMP levels were slightly increased in mesenteric arteries of DS rats on a high-salt diet, demonstrating that impaired endothelial function is not related to the altered VSMC reactivity to NO.…”

Vasopeptidase inhibition and endothelial function in hypertension

“…Differences in plasma ANP levels in the omapatrilat and captopril groups may help improve endotheliumdependent relaxations. Accordingly, a recent study showed that ANP enhances NO synthesis capability and NO production in endothelial cells, suggesting that the L-arginine-NO pathway may be a second messenger for ANP [82]. However, either omapatrilat or captopril normalized decreased eNOS protein expression as well as total NO 3 /NO 2 levels to a similar degree in the aortas of Dahl rats with salt-induced hypertension [50].…”