Despite of established clinical practice recommendations for Chronic Kidney Disease (CKD) and Heart Failure (HF) morbidity and mortality remain high. To meet the medical need of millions of people suffering from these conditions, great efforts in research and development are ongoing. More recently, the NO-sGC-cGMP pathway became target of scientific research, as it plays a pivotal role for the regulation of cardio-vascular & renal function and is well-known to be altered in CKD and HF.
The aim of this master thesis was to evaluate novel compounds modulating the NOsGC-cGMP pathway, namely a sGC activator, a sGC stimulator, and a combination of a sGC activator with a PDE-5 inhibitor, and compare these to established drugs (ACE and PDE-5 inhibitor) in terms of safety and efficacy in a preclinical disease model of cardio-renal impairment. For this purpose, Zucker Fatty/Spontaneously Hypertensive Heart Failure F1-Hybrid (ZSF1) rats, a strain exhibiting a complete metabolic syndrome characterized by hypertension, hyperinsulinemia, hyperlipidemia and obesity, served as preclinical disease model.
Over a dosing period of 9 weeks, the sGC activator and the sGC stimulator, as well as the combination of a sGC activator with an established PDE-5 inhibitor, were administered by daily gavage, whereas the ACE- and PDE-5 inhibitor were administered via drinking water. At least once weekly, food and water consumption, as well as body weights, were captured. Blood cell parameters, glucose homeostasis-related parameters, blood lipids, serum proteins, kidney and liver function parameters, as well as electrolytes and blood biomarkers were quantified. The same applied for the urinary proteins, enzymes, biomarkers and kidney function parameters. Finally, all animals went through gross pathological examination and heart and kidneys were weighed and evaluated histopathologically.
All test compounds demonstrated good tolerability. After administration of the ACE inhibitor, severity and progression of renal impairment, marked as proteinuria and deteriorated histology, did not differ from untreated control. PDE-5 inhibition and sGC stimulation showed less reno-protective potential, characterized by attenuation of proteinuria and morphological amelioration, than the sGC activator. The combination of the sGC activator and the PDE-5 inhibitor treatment did not result in statistically significantly increased efficacy when compared to stand-alone sGC activator treatment. Interestingly, all sGC modulator treatments led to increased body weight gain in spite of an antiglycemic and a blood lipid-lowering effect.
In conclusion, the results reinforce the assumption of reno-protective efficacy attributed to the NO-sGC-cGMP pathway and suggest a key role of sGC modulators. Further investigation of chronic cardio-vascular and renal diseases in animals of other disease etiologies and/or stages of the disease aligned with the age of the model is necessary to fully explore the capability of sGC modulators in chronic kidney disease and heart failure.