cyclic-gmp and Fistula

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.

Topics: Animals; Cardio-Renal Syndrome; Cyclic GMP; Fistula; Guanylate Cyclase; Heart Failure; Humans; Hypertension; Nitric Oxide; Rats; Rats, Transgenic; Soluble Guanylyl Cyclase

The effects of chronic increase in aortic blood flow on arterial wall remodeling were investigated in vivo with the use of an aortocaval fistula (ACF) model in rats. Phasic hemodynamics and aortic wall structure upstream and downstream in 30 male Wistar rats with ACF and 30 sham-operated rats were compared immediately and 2 mo after the ACF was opened in anesthetized rats. Opening the ACF upstream acutely decreased aortic pressure (-30%, P < 0.001) and increased aortic blood velocity (x12, P < 0.001), blood flow (x9, P < 0.001), wall shear stress (x10, P < 0.001) and guanosine 3',5'-cyclic monophosphate (cGMP) wall content (+50%, P < 0.01). After 2 mo, aortic pressure decreased (-22%, P < 0.001) and aortic blood velocity, diameter, and blood flow increased (+114%, P < 0.001; +60%, P < 0.001; and +250%, P < 0.001; respectively) compared with the control group. Aortic wall shear stress and cGMP wall content dropped over time and tended to recover control values; aortic wall tensile stress was higher than in the control group (P < 0.05). Medial cross-sectional area and elastin and collagen contents increased (+38%, P < 0.01; +50%, P < 0.01; and +30%, P < 0.05, respectively) and were associated with smooth muscle cell hypertrophy) (+23%, P < 0.05), despite a decrease in arterial wall thickness (-13%, P < 0.01). Opening the ACF downstream acutely decreased aortic pressure (-30%, P < 0.001) without any change in aortic blood velocity, diameter, blood flow, shear stress, and cGMP wall content. After 2 mo, pressure, blood velocity, shear stress, and cGMP wall content decreased (-22%, P < 0.001; -31%, P < 0.01; -46%, P < 0.02; and -50%, P < 0.05; respectively) and diameter and blood flow were unchanged; smooth muscle cell hypertrophy and hypoplasia were the only observed changes in the aortic wall structure. These results suggest that both shear and tensile stresses are involved in the aortic wall remodeling. Increase in shear stress likely induces expansive remodeling in relation to flow-dependent vasodilation, whereas increase in tensile stress is responsible for medial hypertrophy and fibrosis.

Topics: Animals; Aorta, Abdominal; Blood Flow Velocity; Cyclic GMP; Fistula; Hemodynamics; Male; Rats; Rats, Wistar; Regional Blood Flow; Stress, Mechanical; Time Factors; Venae Cavae