GI PROTEINS, NATRIURETIC PEPTIDE RECEPTOR C AND REGULATION OF BLOOD PRESSURE
Madhu B. Anand-Srivastava, Ph.D.,
University of Montreal, Montreal, Quebec, Canada
Objectives: C-ANP4-23, a ring deleted analog of atrial natriuretic peptide (ANP) that specifically interacts with natriuretic peptide receptor-C (NPR-C) has been shown to decrease the enhanced expression of Gialpha proteins, implicated in the pathogenesis of hypertension. In the present study, we investigated whether in vivo treatment of spontaneously hypertensive rats (SHR) with C-ANP4-23 could attenuate the development of high blood pressure (BP) and explore the underlying mechanism/s responsible for this response.
Methods and Results: The BP started increasing in SHR at 4 weeks and increased to about 190 mmHg at 8 weeks. However, intraperitoneal injection of C-ANP4-23 at the concentration of 2 or 10 nmole/kg body weight to prehypertensive SHR attenuated the development of high BP and at 8 weeks it was decreased by about 20 mmHg and 50 mmHg respectively but not in WKY rats. The C-ANP4-23 treatment also decreased the enhanced levels of Gi alphanproteins in heart and aorta as determined by Western blotting. In addition, the enhanced levels of superoxide anion, peroxynitrite, NADPH oxidase activity and the enhanced expression of NOX-4, P47phox, nitrotyrosine and decreased levels of eNOS were attenuated by C-ANP4-23 treatment, however, the altered levels of NPR-A/NPR-C were not affected by this treatment.
Conclusions: These results indicate that NPR-C activation by C-ANP4-23 attenuates the development of high BP in SHR through the inhibition of enhanced levels of Ginalpha proteins and nitroxidative stress and not through eNOS /cGMP pathway and suggest that NPR-C ligand may be used as therapeutic agent in the treatment of cardiovascular complications including hypertension(Supported by CIHR).