Soluble guanylate cyclase stimulator praliciguat attenuates inflammation, fibrosis, and end-organ damage in the Dahl model of cardiorenal failure.

Abstract

Reduced nitric oxide (NO) and a decrease in cGMP signaling mediated by soluble guanylate cyclase (sGC) has been linked to the development of several cardiorenal diseases. Stimulation of sGC is a potential means for enhancing cGMP production in conditions of reduced NO bioavailability. The purpose of our studies was to determine the effects of praliciguat, a clinical-stage sGC stimulator, in a model of cardiorenal failure. Dahl salt-sensitive rats fed a high-salt diet to induce hypertension and organ damage were treated with the sGC stimulator praliciguat to determine its effects on hemodynamics, biomarkers of inflammation, fibrosis, tissue function, and organ damage. Praliciguat treatment reduced blood pressure, improved cardiorenal damage, and attenuated the increase in circulating markers of inflammation and fibrosis. Notably, praliciguat affected markers of renal damage at a dose that had minimal effect on blood pressure. In addition, liver fibrosis and circulating markers of tissue damage were attenuated in praliciguat-treated rats. Stimulation of the NO-sGC-cGMP pathway by praliciguat attenuated or normalized indicators of chronic inflammation, fibrosis, and tissue dysfunction in the Dahl salt-sensitive rat model. Stimulation of sGC by praliciguat may present an effective mechanism for treating diseases linked to NO deficiency, particularly those associated with cardiac and renal failure. Praliciguat is currently being evaluated in patients with diabetic nephropathy and heart failure with preserved ejection fraction.

• Authors: Courtney M Shea, Gavrielle M Price, Guang Liu, Renee Sarno, Emmanuel S Buys, Mark G Currie, Jaime L Masferrer
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 318 Issue 1 Pg. F148-F159 (01 01 2020) ISSN: 1522-1466 [Electronic] United States
• PMID: 31608671 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers
• Chemokine CCL2
• Guanylyl Cyclase C Agonists
• Peptide Fragments
• Pyrazoles
• Pyrimidines
• Tissue Inhibitor of Metalloproteinase-1
• pro-brain natriuretic peptide (1-76)
• Osteopontin
• Natriuretic Peptide, Brain
• Nitric Oxide
• Soluble Guanylyl Cyclase
• Cyclic GMP
• praliciguat

Topics

• Animals
• Biomarkers (blood)
• Blood Pressure (drug effects)
• Chemokine CCL2 (blood)
• Cyclic GMP (metabolism)
• Fibrosis (drug therapy, pathology)
• Guanylyl Cyclase C Agonists (pharmacology, therapeutic use)
• Inflammation (drug therapy, pathology)
• Kidney (drug effects, pathology)
• Male
• Natriuretic Peptide, Brain (blood)
• Nitric Oxide (metabolism)
• Osteopontin (blood)
• Peptide Fragments (blood)
• Pyrazoles (pharmacology, therapeutic use)
• Pyrimidines (pharmacology, therapeutic use)
• Rats
• Rats, Inbred Dahl
• Renal Insufficiency (drug therapy, pathology)
• Signal Transduction (drug effects)
• Soluble Guanylyl Cyclase (metabolism)
• Tissue Inhibitor of Metalloproteinase-1 (blood)