Abstract 11341: The Newly Designed Dual Guanylyl Cyclase A and B Activator, CU-NP, Elicits Favorable Cardiorenal Hemodynamic Actions without Hypotension and Activates the Second Messenger cGMP in Isolated Cardiac Fibroblasts and Glomeruli
Background: Urodilatin (URO), a human renal peptide, is a guanlylyl cyclase A (GC-A) activator with arterial vasodilating, natriuretic and diuretic actions. Its therapeutic potential in acute heart failure (AHF) is mitigated by undesirable hypotensive effects. In comparison, human C-type natriuretic peptide (CNP), the endogenous GC-B agonist, is venodilating and anti-fibrotic with less systemic hypotension and renal actions. Considering the complementary properties of URO and CNP, we designed a novel chimeric peptide (CU-NP) and tested whether this peptide would co-activate both GC-A and GC-B, and defined the anti-fibrotic actions in cardiac fibroblasts (CFs) and in isolated glomeruli. We further investigated its cardiac hemodynamic, renal, and humoral effects in dogs.
Methods: CU-NP activation of cGMP was tested in in GC-A or GC-B transfected human embryonic kidney 293 cells (HEK293), in CFs and in isolated glomeruli compared to URO and CNP. The cardiorenal and humoral actions of CU-NP were determined in normal anesthetised dogs.
Results: In HEK293 cells, while URO and CNP were selective activators of GC-A and GC-B, respectively, CU-NP induced equal cGMP activation from both GC-A and GC-B cells. In cardiac fibroblasts, CU-NP markedly activated cGMP and inhibited cell proliferation. Studies in isolated glomeruli demonstrated that CU-NP mediated cGMP activation greater (p<0.05) than CNP and similar to URO. In vivo, CU-NP (50 ng/kg/min) increased plasma cGMP, urinary cGMP excretion, net renal cGMP generation, urine flow, urinary sodium excretion, and glomerular filtration rate (all p<0.05). CU-NP significantly reduced pulmonary capillary wedge pressure and right atrial pressure (p<0.05, both) without hypotensive effects. CU-NP suppressed renin and angiotensin II (p<0.05, both).
Conclusion: We report an engineered dual GC-A and GC-B activator (CU-NP) consisting entirely of human amino acid sequences from URO and CNP has favorable cardiorenal, RAAS suppressing and antifibrotic properties while minimizing blood-pressure lowering effects. The cellular, humoral, and hemodynamic actions of such peptide could be useful for the treatment of acute and chronic heart failure.
- © 2012 by American Heart Association, Inc.