Effect of PDE9 inhibitor BAY 73‐6691 in the contractile response of cavernosal and detrusor smooth muscle of sickle cell disease mice

Abstract

IntroductionGenitourinary tract function is affected in sickle cell disease (SCD). Modulation of cyclic guanosine monophosphate (cGMP)‐dependent signalling is important for the contractile mechanism of detrusor (DSM) and corpus cavernosum (CC) smooth muscle and may characterize a therapeutic target for theses manifestations in the SCD. Phosphodiesterase‐9 (PDE9) specifically hydrolyzes cGMP, and was detected in CC and bladder urothelium. BAY 73‐6691, selective PDE9 inhibitor, has been used for understanding the role of cGMP signaling in the SCD. However, no previous studies have explored the selective PDE9 inhibition with BAY 73‐6691 in the DSM and CC in SCD.ObjectiveThe aim of this study was to investigate the effect of BAY 73‐6691 on the contractile response of CC and DSM of SCD mice.MethodsBerkeley transgenic sickle cell mice (SS) and C57BL/6 mice (control) were used. Cumulative concentration‐response curves to muscarinic receptor agonist carbachol (CCh; 0.01–100 μM), chloride potassium (KCl; 1–300 mM) and frequency‐response curves for electrical field stimulation (EFS; 1–32 Hz) were obtained in strips of DSM from both control and SS mice. In the CC, cumulative concentration‐response curves to α1‐adrenoceptor agonist phenylephrine (PE; 0.01–100 μM) and frequency‐response curves for electrical field stimulation (EFS; 1–32 Hz) were carried out in the absence and presence of BAY 73‐6691 (100 nM and 1 μM; 30 min).ResultsIn the evaluation of DSM, the SS mice presented an increased in the contractile response mediated by CCh (P<0.05), when compared to control mice. Surprisingly, BAY 73‐6691 increased the contraction mediated by CCh in DSM of SS mice (p<0.05), but did not alter the contraction response in the control mice. Contractile responses induced by KCl were increased in the SS mice (p<0.001) compared to control mice. However, no significant differences for BAY 73‐6671 incubation were found between control and SS group. EFS‐induced neurogenic contractions in the DSM of SS mice were 90% higher in the frequency of 32 Hz (p<0.01) compared to control. Pre‐incubation with BAY 73‐6671 no affect the neurogenic contraction in the control and SCD group. Cavernosal contractile to PE were higher in SS mice compared to control mice (P<0.01). Similarly to DSM, BAY 73‐6691 increased the contraction mediated by PE in CC of SS mice (p<0.05), but did not alter the contraction response in control mice. However, EFS‐induced neurogenic contractions in CC of SS mice were 49% lower in the frequency of 32 Hz (p<0.01) compared to the control. BAY 73‐6691 did not change the neurogenic contraction in both groups.ConclusionOur preliminary data shows that, BAY 73‐6691 promotes increase of contractile response in SS mice, acting in the muscarinic and adrenergic signaling pathway in the DSM and CC, respectively. Further experiments are needed to identify the exact mechanisms of drug‐induced alterations in the contraction of the DSM and CC in SCD.Support or Funding InformationFAPESPThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.