Increased Cavernosal Relaxations in Sickle Cell Mice Priapism are Associated with Alterations in the NO-cGMP Signaling Pathway

Abstract

Priapism is defined as prolonged and persistent penile erection, unassociated with sexual interest or stimulation, and is one of the many serious complications associated with sickle cell disease (SCD). The aim of this study was to evaluate the role of the NO-cGMP signaling pathway in priapism in Berkeley murine model of SCD (SS). SS mice and C57BL/6 mice (control) penile tissues were removed and the erectile tissue within the corpus cavernosum (CC) was surgically dissected free. The strips were mounted in 10 mL organ baths containing Krebs solution at 37 degrees C (95% O(2), 5% CO(2), pH 7.4), and vertically suspended between two metal hooks. Cumulative concentration-response curves were constructed for acetylcholine (ACh; endothelium-dependent responses), sodium nitroprusside (SNP; endothelium-independent relaxations) and BAY 41-2272 (a potent activator of NO-independent site of soluble guanylate cyclase) in CC precontracted with phenylephrine. Cavernosal responses induced by frequency-dependent electrical field stimulation (EFS) were also carried out to evaluate the nitrergic cavernosal relaxations. In SS mice, ACh-induced cavernosal relaxations were leftward shifted by 2.6-fold (P < 0.01) that was accompanied by increases in the maximal responses (78 +/- 5% and 60 +/- 3% in SS and C57B6/6J mice, respectively). Similarly, SNP- and BAY 41-2272-induced CC relaxations were leftward shifted by approximately 3.3- and 2.2-fold (P < 0.01) in SS mice, respectively. A significant increase in maximal responses to SNP and BAY 41-2272 in SS mice was also observed (113 +/- 6% and 124 +/- 5%, respectively) compared with C57B6/6J mice (83 +/- 4% and 99 +/- 2%, respectively). The EFS-induced cavernosal relaxations were also significantly higher SS mice. These results showed that SS mice exhibit amplified corpus carvenosum relaxation response mediated by NO-cGMP signaling pathway. Intervention in this signaling pathway may be a potential therapeutic target to treat SCD priapism.