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.

Effects of the Soluble Guanylate Cyclase Stimulator Praliciguat in Diabetic Kidney Disease

“…Praliciguat (IW-1973) is an orally available sGC stimulator characterized by extensive distribution to tissues, including the kidney medulla and cortex (23,31,32). Praliciguat inhibited proinflammatory and profibrotic responses in isolated human kidney proximal tubular cells (33) and ameliorated proteinuria and kidney damage in animal models of nephropathy, including at doses that had minimal effects on systemic BP in multiple rat models (34,35). In clinical studies of praliciguat in healthy adults and individuals with type 2 diabetes and hypertension (36,37), oral doses up to 40 mg were generally well tolerated and showed increases in plasma cGMP levels and modest decreases in systemic BP consistent with the expected vascular effects of NO signaling (23).…”

MicroRNA-210-5p Alleviates Cardiac Fibrosis via Targeting Transforming Growth Factor-beta Type I Receptor in Rats on High Salt Diet

“…HSD can cause hypertension, as well as cardiac and renal brosis in salt-sensitive hypertensive rats [8]. High salt intake is associated with a hypertensive response accompanied by the development compensatory hypertrophy of left ventricular and the decompensated congestive heart failure [19].…”

“…Although brosis formation is initially reparative, on-going and excessive myocardial brosis in the long term may lead to arrhythmia, cardiac wall stiffening, and subsequently heart failure [7]. High salt diet (HSD) can induce hypertension and cardiac remodeling in Dahl salt-sensitive rats [8]. HSD markedly accelerates cardiac damage by stimulating the cardiac renin-angiotensin system under higher blood pressure [9].…”

Novel therapeutics for the treatment of hypertension and its associated complications: peptide- and nonpeptide-based strategies

“… Heart failure induced by tachypacing in dogs Improved renal function, protective in heart failure [ 118 ] 11. sGC stimulator Praliciguat (IW-1973) 10 mg/kg/Day, oral Dahl salt-sensitive (DSS) rat Attenuated hypertension and NO deficiency-related diseases [ 119 ] 12. Praliciguat (IW-1973) 10 mg/kg/Day, oral carbon tetrachloride (CCl4)-treated fibrotic livers model Prominent antifibrotic effects by inhibition of TGFβ1 [ 120 ] 13.…”