Tadalafil treatment improves the cardiovascular dysfunction and overactive bladder in heart failure rats

Abstract

Heart failure (HF) is a major public health issue, with an increasing prevalence in the world. Studies have shown a strong association of HF with development of low urinary tract symptoms (LUTS), where approximately 34% of men and 62% of women with HF reported having LUTS. Moreover, 57% of these HF patients present with overactive bladder syndrome. Dysfunction of the autonomic nervous system and alterations in important signaling pathways such as the nitric oxide/cyclic guanosine monophosphate pathway (NO‐GCs‐GMPc) are present in the HF. Therefore, drugs were synthesized to potentiate the effect exerted by NO, such as Tadalafil. Recent studies have shown that daily treatment with Tadalafil has been effective in decreasing symptoms related to urination and urine storage, in addition to improving the quality of life of patients with LUTS who have or not associated erectile dysfunction. Thus, using the aortocaval fistula model (FAC) we investigated the contribution of chronic treatment with tadalafil in the cardiovascular dysfunction and low urinary tract alterations of HF rats. HF was surgically induced through the FAC model and after 8 weeks of the surgical procedure the animals were divided into 4 groups: Sham and HF (0.9% saline solution) and Sham/Tadalafil and HF/Tadalafil (tadalafil 5mg/day for more 4 weeks). After 12 weeks, HF group presented increased left ventricle (LV) mass, decreased ejection fraction and increased LV end‐systolic and diastolic volumes when compared to the respective Sham group (p<0.05). However, tadalafil treatment restored cardiac function in the HF/Tadalafil group, with a decreased in hypertrophy and an improved in LV function when compared to the HF group (p<0.05). In addition, in the assessment of isolated detrusor contractile response (in vitro) to carbachol, KCl, alpha‐beta methyl ATP and EFS were increased in the HF group (p<0.05) compared to Sham group. In agreement with these findings, changes in cystometric parameters also were observed in vivo, with an increased in baseline pressure, threshold pressure, number of involuntary contractions and decreased bladder capacity in the HF group (p<0.05), when compared to the respective Sham. However, after treatment with tadalafil, the HF/Tadalafil group showed a decreased in contractile hyperactivity mediated by carbachol, KCl, alpha‐beta methyl ATP and EFS, as well as restoration of urinary function assessed by cystometry (p<0.05) compared to HF group. Renal function and the REDOX also were changed in the HF group, with increased urea plasma levels, as well as changes in REDOX balance, with increased lipoperoxidation and decreased total antioxidant capacity and activity Enzymatic activity of the superoxide dismutase. However, treatment with tadalafil was able to restore urea levels, decrease lipoperoxidation and increase the activity of the antioxidant system in the HF group (p<0.05). Therefore, chronic treatment with tadalafil showed cardioprotective effect and reversed the detrusor overactivity (in vitro) with improved urinary function (in vivo), as well as restoring renal function and REDOX balance in HF animals.Support or Funding InformationFundação de Amparo à Pesquisa do Estado de São Paulo ‐ FAPESP