Effect of Entresto (valsartan+sacubitril) in the cardiac function and contractile response of detrusor and corpus cavernosum smooth muscles of heart failure rats.
Authors: Claudino Mario A. , Mora Aline , Janussi Sabrina , Piera Juliana S. , Vanalli Thayz , Silveira Tammyris R. , Motawe Zeinab Y. , Breslin Jerome W. 
Published: April 2020

Introduction

Heart failure (HF) has been closely related to the development of lower urinary tract symptoms (LUTS) and erectile dysfunction (ED). New pharmacological therapies aims to restore the neurohumoral balance, among these new proposals, stands out LCZ696 (Entresto), which consists of the association of the Valsartan (ANG‐II receptor antagonist, AT1R) with a Sacubitril (neprilysin inhibitor). However, there is no evidence evaluating the neurohumoral balance and the impact of Entresto on ED and LUTS associated with HF.

Objective

We aimed to Investigated the effect of in vitro treatment with Entresto (valsartan+sacubitril) on the contractile response of detrusor and corpus cavernosum (CC) muscles of control rats, as well as the effect of long‐term treatment with Entresto in the cardiovascular, urinary and erectile dysfunctions of HF rats.

Methods

For in vitro protocols, response concentration curves were constructed to phenylephrine (PHE; CC) and carbachol (CCh; detrusor), as well as, response frequency curves to electrical field stimulation (EFS; CC and detrusor) in the absence or presence of valsartan (10μM), sacubitril (10μM) or both drugs. For the chronic protocols, HF was surgically induced through the FAC model, and after 8 weeks, these animals were submitted to cardiac function evaluation (echocardiogram) and subdivided into 3 groups: Sham, HF and HF/Entresto (60mg/day for more 4 weeks). Response concentration curve were constructed to PHE (CC) and CCh (detrusor), and response frequency curve to EFS (CC and detrusor) for all groups. Culture human umbilical vein endothelial cell (HUVEC) monolayers were used to model the endothelial barrier. Electric cell‐substrate impedance sensing (ECIs) was used to study the contribution of valsartan, sacubitril or both drugs (10μM, respect.) to endothelial barrier function.

Results

In vitro, valsartan, sacubitril or both drugs did not change the contractile responses in the CC or detrusor, independent of stimulated used in control animals. The HF animals presented both reduced of ejection and shortening fraction (p<0.05), as well present cardiac hypertrophy (p<0.05) when compared to the Sham group. Long‐term treatment with Entresto restored the ejection and shortening fraction in the HF/Entresto group (p<0.05). In the CC of HF group the contractile response mediated by PE and EFS (p<0.05) were increased compared to Sham group, being this hypercontractility restored by the Entresto treatment (p<0.05). CCh and EFS induced detrusor smooth muscle contractions, which were greater in HF rats than in Sham rats. The treatment with Entresto restore the detrusor hypercontractility of HF rats (p<0.05). Additionally, only the valsartan enhance the barrier function (P<0.05) of HUVEC monolayer.

Conclusion

Our data provide evidence that Entresto chronic treatment, restore the detrusor‐ and CC‐contractile response due the improved of endothelial barrier and cardiovascular function in rats with HF, suggesting new multi‐therapeutic properties.

Support or Funding Information

FAPESP 2011/21095‐4, CNPq 423987/2016‐0 and NIH R01GM20774