Townes Transgenic Sickle Cell Mouse Model Displays Erectile Dysfunction

Abstract

Introduction: Erectile function alterations result from an imbalance of nitric oxide (NO)-mediated relaxations and sympathetic-mediated vasoconstriction in the erectile tissue. The degree of contraction of corpus cavernosum (CC) smooth muscle determines the functional state of penile flaccidity, tumescence, erection, or detumescence. Patients with sickle-cell disease (SCD) display alterations in erectile function. Priapism is most frequently reported and untreated acute ischaemic priapism results in erectile dysfunction (ED). Previous studies have shown that patients with ED exhibit priapic activity, however, ED unassociated with priapism is still poorly investigated. Transgenic sickle cell mice have been employed to better understand the complex pathophysiology of SCD. The Berkeley murine model displays features of priapism and is associated with an upregulation of the NO-cGMP signaling pathway in the cavernosal tissue, reflecting in an uncontrolled erectile response. Townes mice express human sickle hemoglobin and exhibit the major features found in humans with SCD. However, no detailed study has investigated the pathophysiological alterations of corpus cavernosum (CC) in Townes SCD mice. Thus, the aim of this study was to characterize the erectile function in these animals, focusing on the role of the NO signaling pathway and contractile machinery.Methods: Townes transgenic sickle cell mice and C57BL/6 mice (control) aged 3 to 4 months-old were used (Wu et al Blood 2006). The intracavernous pressure (ICP) was assessed following electrical stimulation of cavernous nerve in anaesthetized mice. In separate protocols, strips of CC were mounted in isolated organ baths, and the relaxing responses to acetylcholine (ACh; endothelium-dependent responses) and sodium nitroprusside (SNP; endothelium-independent responses), as well as electrical-field stimulation (EFS; nitrergic relaxations) were obtained in cavernosal strips precontracted with the α1-adrenergic receptor agonist phenylephrine (3-10 µM). Contracting responses to phenylephrine and EFS were also obtained in both control and SCD mice.Results: The cavernous nervous stimulation caused frequency-dependent increases of ICP in control and SCD groups. However, ICP was 37% lower in SCD mice compared to the control group (P < 0.05). Phenylephrine (0.01 – 100 µM) induced concentration-dependent CC contractions in both control and SCD mice, but maximal contractile responses were significantly greater (P < 0.05) in SCD compared to control mice (1.32 ± 0.11 and 0.80 ± 0.04 mN, respectively). Likewise, EFS-induced neurogenic CC contractions in SCD mice were 50% higher (P < 0.05) compared to the control. The cumulative addition of ACh (0.001 – 10 µM) produced concentration-dependent CC relaxations in both groups, but maximal relaxations were significantly higher in SCD (78 ± 6%; P < 0.05) compared to control mice (50 ± 4%). Similarly, SNP (0.01 – 10 µM) produced concentration-dependent CC relaxations, but, again, the maximal relaxations elicited by this agent were significantly higher in SCD (96 ± 3; P < 0.05) compared to control mice (77 ± 5 %; n=9). The nitrergic relaxations induced by EFS were also significantly higher (P < 0.001) in SCD mice compared to control mice (8 Hz: 90 ± 6 and 65 ± 4 %, respectively; n=5).Conclusion: Our study shows that this type of SCD mouse exhibits enhanced α1-adrenoceptor-mediated vasoconstriction and erectile dysfunction. Interestingly, however, NO-mediated CC relaxations are greater in the SCD mice. It is likely, therefore, that CC vasoconstriction in SCD overcomes the NO-dependent erectile stimulus, making penile tumescence more difficult to occur. These results are in contrast with the data from the Berkeley SCD mice, which indicate exaggerated in vivo erectile responses. The reason to this difference among the two SCD models is not clear. Taken together our results indicate that ED, unassociated with priapism, as seen in the Townes mouse, should be investigated in SCD patients.Financial Support: FAPESP/CNPq. DisclosuresNo relevant conflicts of interest to declare.