Abstract-C-Atrial natriuretic peptide (ANP) 4-23 , a ring deleted analog of ANP that specifically interacts with natriuretic peptide receptor-C (NPR-C), has been shown to decrease the enhanced expression of Giα proteins implicated in the pathogenesis of hypertension. In the present study, we investigated whether in vivo treatment of spontaneously hypertensive rats (SHRs) with C-ANP 4-23 could attenuate the development of high blood pressure (BP) and explored the underlying mechanisms responsible for this response. Intraperitoneal injection of C-ANP 4-23 at the concentration of 2 or 10 nmol/kg body weight to prehypertensive SHRs attenuated the development of high BP, and at 8 weeks it was decreased by ≈20 and 50 mm Hg, respectively; however, this treatment did not affect BP in Wistar-Kyoto rats. C-ANP 4-23 treatment of adult SHRs for 2 weeks also attenuated high BP, heart rate, and restored the impaired vasorelaxation toward control levels. In addition, the enhanced levels of superoxide anion (O 2 − ), peroxynitrite, NADPH oxidase activity, and the enhanced expression of Giα proteins, NOX4, p47 phox , nitrotyrosine, and decreased levels of endothelial nitric oxide synthase (eNOS or NOS3) and NO in SHRs were attenuated by C-ANP 4-23 treatment; however, the altered levels of NPR-A/NPR-C were not affected by this treatment. In conclusion, these results indicate that NPR-C activation by C-ANP 4-23 attenuates the development of high BP in SHRs through the inhibition of enhanced levels of Giα proteins and nitroxidative stress and not through eNOS/ cGMP pathway and suggest that NPR-C ligand may have the potential to be used as therapeutic agent in the treatment of
Li et al NPR-C and Blood Pressure Regulation 847injection of pertussis toxin in prehypertensive rats (2-week-old SHRs) has been reported to prevent the development of BP,22 suggesting the implication of enhanced expression of Gi proteins in the pathogenesis of hypertension. C-ANP 4-23 that specifically interacts with NPR-C has been reported to decrease the levels of Giα proteins in A10 vascular smooth muscle cell (VSMC) 23 and in VSMC from SHRs. 24 In addition, C-ANP 4-23 was also shown to attenuate the enhanced oxidative stress in VSMC from SHRs 24 that contributes to the enhanced expression of Giα proteins in SHRs.25 Taken together, it may be possible that C-ANP 4-23 treatment of SHRs could also attenuate the high BP in SHRs. The present study was undertaken to investigate the effect of in vivo administration of C-ANP 4-23 on the development of high BP in SHRs. We have provided the first evidence that the treatment of prehypertensive SHRs with C-ANP 4-23 , an activator of NPR-C, attenuates the development of high BP in SHRs through the inhibition of enhanced expression of Gi proteins and oxidative stress.We have provided the first evidence that NPR-C activation by C-ANP 4-23 attenuates high BP through decreasing the enhanced oxidative stress and the augmented levels of Giα proteins. From these results it may be suggested that C-ANP [4][5][6][7][8][9][10][...