Natriuretic peptide receptor-C attenuates hypertension in spontaneously hypertensive rats: role of nitroxidative stress and Gi proteins.
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-ANP4-23 could attenuate the development of high blood pressure (BP) and explored the underlying mechanisms responsible for this response. Intraperitoneal injection of C-ANP4-23 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-ANP4-23 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 (O2(-)), 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-ANP4-23 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-ANP4-23 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 cardiovascular complications including hypertension.
Department of Physiology, Faculty of Medicine, University of Montreal, C.P. 6128, Succ. Centre-ville, Montréal, Québec H3C 3J7, Canada. madhu.anand-srivastava@umontreal.ca.
Yuan
Y
Li
Oli
O
Sarkar
Michèle
M
Brochu
Madhu B
MB
Anand-Srivastava
D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D006152:Cyclic GMP / Q000502:physiology; D004195:Disease Models, Animal; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000502:physiology*; D006339:Heart Rate / Q000502:physiology; D006973:Hypertension / Q000503:physiopathology* / Q000517:prevention & control*; D007274:Injections, Intraperitoneal; D008297:Male; D019001:Nitric Oxide Synthase / Q000502:physiology*; D052250:Nitric Oxide Synthase Type III / Q000502:physiology; D018384:Oxidative Stress / Q000502:physiology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017461:Receptors, Atrial Natriuretic Factor / Q000008:administration & dosage / Q000627:therapeutic use*; D015398:Signal Transduction / Q000502:physiology; D016896:Treatment Outcome
D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D017461:Receptors, Atrial Natriuretic Factor; C073616:atrial natriuretic factor receptor C; D006152:Cyclic GMP
atrial natriuretic peptides receptor; blood pressure; nitric oxide synthase type III; oxidative stress; rats, inbred SHR