Role of nitric oxide as a key mediator on cardiovascular actions of atrial natriuretic peptide in spontaneously hypertensive rats

Abstract

The objective was to study atrial natriuretic peptide (ANP) effects on mean arterial pressure (MAP) and cardiovascular nitric oxide (NO) system in spontaneously hypertensive rats (SHRs), investigating the receptors and signaling pathways involved. In vivo, SHRs and Wistar-Kyoto (WKY) rats were infused with saline (0.05 ml/min) or ANP (0.2 microg.kg(-1).min(-1)) for 1 h. MAP and nitrites and nitrates excretion (NOx) were determined. NO synthase (NOS) activity and endothelial (eNOS), neuronal (nNOS) and inducible (iNOS) NOS expression were measured in the heart and aorta. In vitro, heart and aortic NOS activity induced by ANP was determined in the presence of iNOS and nNOS inhibitors, natriuretic peptide receptor (NPR)-A/B blocker, G(i) protein, and calmodulin inhibitors. As a result, ANP diminished MAP and increased NOx in both groups. Cardiovascular NOS activity was higher in SHRs than in WKY rats. ANP increased NOS activity, but the activation was lower in SHRs than in WKY rats. ANP had no effect on NOS isoform expression. NOS activity induced by ANP was not modified by iNOS and nNOS inhibitors. NPR-A/B blockade blunted NOS stimulation via ANP in ventricle and aorta but not in atria. Cardiovascular NOS response to ANP was reduced by G(i) protein and calmodulin inhibitors in both groups. In conclusion, in atria, ventricle, and aorta, ANP interacts with NPR-C receptors, activating Ca(2+)-calmodulin eNOS through G(i) protein. In ventricle and aorta, NOS activation also involves NPR-A/B. The NOS response to ANP was impaired in heart and aorta of SHRs. The impaired NO-system response to ANP in hypertensive animals, involving alterations in the signaling pathway, could participate in the maintenance of high blood pressure in this model of hypertension.

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

“…Our results have shown that the renal effects of ANP would be mediated, at least in part, by interaction with the NO system in this genetic model of hypertension, as shown previously with regard to the cardiovascular effects of the peptide in SHR (6). In addition, we have demonstrated that ANP infusion augmented renal NOS activity in SHR, without modifying its expression.…”

“…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 …”

“…We have recently found evidence that demonstrates that the cardiovascular NOS response to ANP is impaired in SHR (6). In view of previous findings and existence of a link between both NO and ANP (3) and the role of the kidney in arterial blood pressure regulation, we hypothesize that the alterations in the interaction between both systems are involved in the development and/or maintenance of high levels of blood pressure in this experimental model of spontaneous hypertension.…”

Chronic Treatment with Atrial Natriuretic Peptide in Spontaneously Hypertensive Rats: Beneficial Renal Effects and Sex Differences

“…Nishikimi T et al have demonstrated, in mice, that ANP has antifibrotic effects on the kidney, involving the activation of NPR-A and/or C-type natriuretic peptide receptor (NPR-C), producing an increase in renal cGMP levels and a decrease in transforming growth factor beta (TGF-β) expression and collagen I and III content [7]. Further, in our laboratory we provided evidence that ANP exerts a hypotensive effect through enhancement of cardiovascular and renal NOS activity, in both, normotensive and hypertensive rats [8–10]. …”

Role of Musclin in the Pathogenesis of Hypertension in Rat

“…Recently, it has been reported that ANP interacts with NPR-C in atria, ventricles, and the aorta to activate Ca 2+ -loaded calmodulin and endothelial nitric oxide synthase (eNOS) through the Gi protein [12]. In particular, impairment of the eNOS response to ANP has been observed in SHR as compared to normotensive WKY, thus suggesting that dysfunctions in the NPR-C signaling pathway, which leads to the reduced NO availability, may contribute to the maintenance of hypertension in SHR [13]. Musclin-induced increase in the concentration of intracellular calcium was observed in the widely used cultured vascular cells A7r5 [14].…”