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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 20...

BackgroundPatients with heart failure (HF) display erectile dysfunction (ED). However, the pathophysiology of ED during HF remains poorly investigated.ObjectiveThis study aimed to characterize the aortocaval fistula (ACF) rat model associated with HF as a novel experimental model of ED. We have undertaken molecular and functional studies to evaluate the alterations of the nitric oxide (NO) pathway, autonomic nervous system and oxidative stress in the penis.MethodsMale rats were submitted to ACF for HF induction. Intracavernosal pressure in anesthetized rats was evaluated. Concentration-response curves to contractile (phenylephrine) and relaxant agents (sodium nitroprusside; SNP), as well as to electrical field stimulation (EFS), were obtained in the cavernosal smooth muscle (CSM) strips from sham and HF rats. Protein expression of endothelial NO synthase (eNOS) and neuronal NO synthase (nNOS) and phosphodiestarese-5 in CSM were evaluated, as well as NOX2 (gp91phox) and superoxide dismutase (SOD) mRNA expression. SOD activity and thiobarbituric acid reactive substances (TBARs) were also performed in plasma.ResultsHF rats display erectile dysfunction represented by decreased ICP responses compared to sham rats. The neurogenic contractile responses elicited by EFS were greater in CSM from the HF group. Likewise, phenylephrine-induced contractions were greater in CSM from HF rats. Nitrergic response induced by EFS were decreased in the cavernosal tissue, along with lower eNOS, nNOS and phosphodiestarese-5 protein expressions. An increase of NOX2 and SOD mRNA expression in CSM and plasma TBARs of HF group were detected. Plasma SOD activity was decreased in HF rats.ConclusionED in HF rats is associated with decreased NO bioavailability in erectile tissue due to eNOS/nNOS dowregulation and NOX2 upregulation, as well as hypercontractility of the penis. This rat model of ACF could be a useful tool to evaluate the molecular alterations of ED associated with HF.

IntroductionHeart failure (HF) is the common endpoint of several cardiovascular diseases. HF and ED share similar pathophysiological mechanisms that contribute to the progression of both disorders, with emphasis on endothelial dysfunction and reduced nitric oxide (NO) bioavailability. Drugs mimic the effect exerted by NO, such as tadalafil, a phosphodiesterase type 5 (PDE5) inhibitor used in the ED treatment. Therefore, tadalafil may be a multi‐therapeutic agent in the treatment of cardiovascular alterations and erectile dysfunction associated with impaired of NO‐sGC‐cGMP signaling pathway? Thus, using the aortocaval fistula model (FAC) we investigated the contribution of tadalafil chronic treatment in the cardiac, vascular and erectile dysfunction of HF rats.MethodsHF 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/Tadalafil (5mg/day IP for more 4 weeks). Intracavernous pressure measurement (ICP) was used to evaluate erectile function in vivo. Response concentration curves were constructed to assess both vascular reactivity in response to phenylephrine (PE), acetylcholine and sodium nitroprusside (SNP), as well as the cavernosal muscle (CC) reactivity in response to PE and SNP. Electrical stimulation (EFS) were obtained to evaluate neurogenic contraction and nitrergic relaxation in CC rat.ResultsAfter 12 weeks, HF group 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. Treatment with tadaladil restored the ejection and shortening fraction in the HF/Tadalafil (p<0.05), and reduced cardiac hypertrophy induced by HF. Moreover, HF animals presented an increase in the contractile vascular response mediated by PE when compared to Sham group (p<0.05), being this vascular hypercontractility restored by the tadalafil treatment (p<0.05). In addition, aorta of HF rats showed reduction of the ACh‐mediated relaxation (p<0.05) compared to the control, and this effect was restored by tadalafil treatment (p<0.05). Regarding erectile function, the data show that HF animals present a reduction of intracavernous pressure (p<0.05) compared to the Sham group, that was restored by tadalafil treatment (p<0.05). The contractile mechanism of CC, in response to PE and neurogenic electrical stimulation (p<0.05) were increased in HF rats, on the other side, the treatment with tadalafil improve the CC hypercontractility in these animals (p<0.05). In addition, tadalafil treatment also restored both SNP (p<0.05) and nitrergic (p<0.05) mediated relaxation in the CC of HF rats.ConclusionOur data show that the chronic treatment with tadalafil improved both vascular‐ and no‐vascular smooth muscle reactivity since exerting beneficial effects in the cardiovascular and erectile function in HF rats. Data suggesting that tadalafil acts is a multi‐therapeutic agent in HF rats.Support or Funding InformationFinancial suport: FAPESP: 2011/21095‐4 / CNPq: 423987/2016‐0This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.