Phosphodiestarase‐9 Inhibitor (BAY 73‐6691) Reduces the Cavernous Smooth Muscle Contractile Response and Improves the Effect of Chronic Treatment with Tadalafil in Heart Failure
Authors: Claudino Mario Angelo , Janussi Sabrina , Tartarotti Sabrina , Mora Aline , Andrade Douglas , Barbosa James , Priviero Fernanda 
Published: June 2021

INTRODUCTION

Patients with heart failure (HF) display erectile dysfunction (ED). Currently a pharmacological option for the ED treatment are the phosphodiesterase (PDE) 5 inhibitors, however, these has no complete satisfactory response in all patients. The role of other PDEs to treat the ED remains poorly investigated. PDE‐9 specifically hydrolyzes cyclic‐GMP, and was detected in mice and human corpus cavernosum (CC) moreover, the PDE9 inhibitor selective (BAY 73‐6691) amplifies the NO‐cGMP‐mediated cavernosal responses, may be of therapeutic value for ED treatment associated with HF.

OBJECTIVE

The aims of the present study were to characterize the effect of BAY 73‐6691, both on the contractile response of rats CC submitted to aortocaval fistula (ACF) model, as in the CC contractile response of rats with HF submitted to chronic treatment with tadalafil.

METHODS

Male Sprague‐Dawley rats (250g) were submitted to the ACF. After 48 hours, the animals were divided in SHAM and ACF groups (acute protocol). After 8 weeks, to validation of HF, the animals underwent to echocardiogram and were divided into 4 groups: SHAM and HF groups (0.9% saline solution, daily), and TADALAFIL and HF TADALAFIL groups (treated with Tadalafil 5 mg/daily), the treatment was maintained for 4 weeks (chronic protocol). Echocardiogram were used to evaluate the final cardiac function. In all protocols, cumulative concentration‐response curve to phenylephrine (PE; 10 nM‐100μM) and neurogenic contractile responses induced by electrical‐field stimulation (EFS; 1‐32 Hz) were obtained in cavernous smooth muscle, both in the presence or absence of BAY 73‐6691.

RESULTS

After 48 hours, both the neurogenic contraction as well contractile response to PE were increased in the ACF group when compared to the Sham group (p <0.05). However, BAY 73‐6691 restored adrenergic hypercontractility in the ACF group (p <0.05). After 12 weeks, there was an increase in LV mass and a decrease in ejection fraction in HF group when compared to the Sham group (p <0.05). However, in the HF Tadalafil group, the treatment was able to restore the ventricular function and decrease LV mass (p <0.05). Moreover, the neurogenic contraction and contractile response to PE in CC were increased in the HF group when compared to the Sham group (p <0.05) and the treatment with tadalafil restored adrenergic hypercontractility of CC in the HF Tadalafil group (p <0.05). In addition, the CC hypercontractility, observed in the HF group, in response to EFS and PE were reduced with the addition of BAY 73‐6691 (P<0.05). Moreover, BAY 73‐6691 shown an additive in the reduction of contractile mechanism in the rats CC with HF treated with tadalafil (p <0.05).

CONCLUSION

BAY 73‐6691 reduces the adrenergic hypercontractility in the CC of ACF rat. Treatment with Tadalafil improve the cardiac function and restore the increased of contractile response of rat CC with HF. Moreover, BAY 73‐6691 (in vitro) promote additive effect associated with treatment of tadalafil and restore the adrenergic hypercontractility in the CC of rats with HF.

Support or Funding Information

FAPESP ‐ Grant number: 2011/21095‐4

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.