Soluble guanylate cyclase stimulator praliciguat attenuates inflammation, fibrosis, and end-organ damage in the Dahl model of cardiorenal failure
Autor: | Guang Liu, Jaime L. Masferrer, Gavrielle M Price, Renee Sarno, Mark G. Currie, Courtney Shea, Emmanuel S. Buys |
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Rok vydání: | 2020 |
Předmět: |
Male
0301 basic medicine Physiology End organ damage Blood Pressure Inflammation Stimulation 030204 cardiovascular system & hematology Pharmacology Kidney Nitric Oxide Nitric oxide 03 medical and health sciences chemistry.chemical_compound Soluble Guanylyl Cyclase 0302 clinical medicine Fibrosis Natriuretic Peptide Brain medicine Animals Renal Insufficiency Cyclic GMP Chemokine CCL2 Rats Inbred Dahl Tissue Inhibitor of Metalloproteinase-1 Chemistry Guanylyl Cyclase C Agonists Soluble Guanylate Cyclase Stimulator Cgmp signaling medicine.disease Peptide Fragments Rats Pyrimidines 030104 developmental biology cardiovascular system Pyrazoles Osteopontin medicine.symptom Biomarkers Signal Transduction Guanylate cyclase |
Zdroj: | American Journal of Physiology-Renal Physiology. 318:F148-F159 |
ISSN: | 1522-1466 1931-857X |
Popis: | 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. |
Databáze: | OpenAIRE |
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