Abstract 2568: Effects of Natriuretic Peptides on Hypertrophic Myocytes of Wild Type and Natriuretic Peptide Receptor C-Deficient Mice
Natriuretic peptide receptor C (NPR-C) is mainly involved in the clearance of the peptides and may affect the role of natriuretic peptide on cardiac function in normal and hypertrophic hearts. We tested the hypothesis that the negative functional effects of brain natriuretic peptide (BNP) or C type natriuretic peptide (CNP) would be altered in myocytes from NPR-C knockout (NPRC-KO) and hypertrophic NPRC-KO mouse hearts. Ventricular myocytes from wild type (WT, n=12), NPRC-KO (n=12), aortic stenosis-induced hypertrophic WT (n=12) and NPRC-KO (n=12) mouse hearts were used. Functional changes were measured using a video edge detector at baseline and after 10-7 M BNP or 10-7 M CNP followed by 10-6 M KT5823, a cGMP protein kinase inhibitor. Changes in particulate and soluble guanylyl cyclase activity were assessed. BNP caused a significant decrease in WT and NPRC-KO myocyte percent shortening (WT 4.3±0.2% baseline to 3.2±0.2% with BNP 10-7 M, NPRC-KO 4.7±0.1% baseline to 3.3±0.2% with BNP 10-7 M). KT5823 reduced the effects of BNP and myocyte percent shortening increased to 3.6±0.3% in WT and 3.7±0.1% in NPRC-KO. Similarly, CNP decreased percent shortening of WT and NPRC-KO myocytes and KT5823 reduced the effects of CNP. Particulate and soluble forms of guanylyl cyclase activity were similar in WT and NPRC-KO myocytes. Basal percentage shortening was similar in control and hypertrophic myocytes from WT and NPRC-KO mouse heart. BNP and CNP both decreased percent shortening of WT hypertrophic myocytes to a lesser extent than that in non-hypertrophic myocytes and KT5823 did not restore BNP or CNP reduced myocyte function in WT. Interestingly, the effects of KT5823 were better maintained in hypertrophic NPRC-KO myocytes treated with BNP or CNP than that of hypertrophic WT myocytes. We conclude that in WT hypertrophic cardiac myocytes effects of BNP and CNP were blunted and cGMP-dependent protein kinase activity was decreased. However, in NPRC-KO hypertrophic myocytes while cGMP pathway was also partially blunted there is a shift in cGMP-kinase signaling pathway.