The treatment with sGC stimulator improves survival of hypertensive rats in response to volume-overload induced by aorto-caval fistula

Abstract

Heart failure (HF) has been declared as global pandemic and current therapies are still ineffective, especially in patients that develop concurrent cardio-renal syndrome. Considerable attention has been focused on the nitric oxide (NO)/soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP) pathway. In the current study, we aimed to investigate the effectiveness of sGC stimulator (BAY41-8543) with the same mode of action as vericiguat, for the treatment of heart failure (HF) with cardio-renal syndrome. As a model, we chose heterozygous Ren-2 transgenic rats (TGR), with high-output heart failure, induced by aorto-caval fistula (ACF). The rats were subjected into three experimental protocols to evaluate short-term effects of the treatment, impact on blood pressure, and finally the long-term survival lasting 210 days. As control groups, we used hypertensive sham TGR and normotensive sham HanSD rats. We have shown that the sGC stimulator effectively increased the survival of rats with HF in comparison to untreated animals. After 60 days of sGC stimulator treatment, the survival was still 50% compared to 8% in the untreated rats. One-week treatment with sGC stimulator increased the excretion of cGMP in ACF TGR (109 ± 28 nnmol/12 h), but the ACE inhibitor decreased it (-63 ± 21 nnmol/12 h). Moreover, sGC stimulator caused a decrease in SBP, but this effect was only temporary (day 0: 117 ± 3; day 2: 108 ± 1; day 14: 124 ± 2 mmHg). These results support the concept that sGC stimulators might represent a valuable class of drugs to battle heart failure especially with cardio-renal syndrome, but further studies are necessary.

Effects of Angiotensin 1-7 and Mas Receptor Agonist on Renal System in a Rat Model of Heart Failure

“…This surprising behavior could be attributed to the fact that daily urine collection was performed without cooling the tubes, whereas in the acute protocol urine samples were collected into vials kept in ice to prevent degradation of cyclic GMP. Most recently, Gawrys et al demonstrated that administration of Vericiguat (BAY41-8543), a sGC stimulator, into hypertensive rats with experimental HF induced by the placement of A-V fistula, significantly improved survival rate of these rats along with increased ucGMP and decreased blood pressure [51]. Similar results were obtained in clinical trials where treatment with Vericiguat lowered the incidence of death from cardiovascular causes or hospitalization for heart failure among patients with heart failure and reduced ejection fraction [52].…”