Tadalafil treatment improves cardiac, renal and lower urinary tract dysfunctions in rats with heart failure.

Tadalafil, a phosphodiesterase-5 (PDE5) inhibitor, shown to exert a protection to heart failure (HF) associated damage or lower urinary tract symptoms (LUTS). Thus, we investigated the contribution of tadalafil chronic treatment in the alterations of LUTS in HF rats. Male rats were subjected to aortocaval fistula model for HF induction. Echocardiography, cystometric, renal function and redox cell balance, as well as concentration-response curves to carbachol, KCl, ATP and frequency-response curves to electrical field stimulation (EFS) were evaluated in Sham, HF, Tadalafil and HF-Tadalafil (12 weeks endpoint) groups. HF group to present increased in left-ventricle (LV) mass and in LV end-diastolic- and LV end-systolic volume, with a decreased ejection fraction. Tadalafil treatment was able to decrease in hypertrophy and improve the LV function restoring cardiac function. For micturition function (in vivo), HF animals shown an increase in basal pressure, threshold pressure, no-voiding contractions and decreased bladder capacity, being that the tadalafil treatment restored the cystometric parameters. Contractile mechanism response (in vitro) to carbachol, KCl, ATP and EFS in the detrusor muscles (DM) were increased in the HF group, when compared to Sham group. However, tadalafil treatment restored the DM hypercontractility in the HF animals. Moreover, renal function as well as the oxidative mechanism was impaired in the HF animals, and the tadalafil treatment improved all renal and oxidative parameters in HF group. Our data shown that tadalafil has potential as multi-therapeutic drug and may be used as a pharmacological strategy for the treatment of cardiovascular, renal and urinary dysfunctions associated with HF.

A novel experimental model of erectile dysfunction in rats with heart failure using volume overload.

BACKGROUND: Patients with heart failure (HF) display erectile dysfunction (ED). However, the pathophysiology of ED during HF remains poorly investigated. OBJECTIVE: This 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. METHODS: Male 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. RESULTS: HF 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. CONCLUSION: ED 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.