PL 32. Pathophysiology of ischemic priapism: A novel rat model study

Introduction: The molecular basis for priapism is unclear. Recently, transgenic mice have contributed to understanding this disorder, but weaknesses include low percent priapism, cost and unknown initiation/duration. Aim: To validate a novel extended duration rat model of ischemic priapism easily induced with blebbistatin (BLEB), a selective myosin II inhibitor. Methods: BLEB was intracavernously injected (ICI) into rats. After 2h, 4h, 4d and 7d, intracavernous pressure (ICP) was recorded and corpus cavernosum (CC) was harvested. Also CC tissue from patients with priapism and controls were used. Main Outcome Measures: In vivo ICP, organ bath CC in vitro contractility, and histopathological studies were performed. Expression of molecules in major priapism-linked pathways was determined by Real-Time RT-PCR. Results: BLEB relaxed human corpus cavernosum (CC) more potently than either sodium nitroprusside or Rho-kinase inhibitor. ICI of 2.5 μmols BLEB into rats induced priapism validated by visual full erection and ICP/MAP (-0.7) up to 4d with CC vasocongestion present at 2h and 4h. eNOS decreased while expression of contractile molecules PDE5, ROKβ, ETA and MHC increased. In contrast to 2h and 4h post-BLEB, 4d rat ICP is refractory to flushing exhibiting CC thrombosis and fibrosis with eNOS, nNOS and ETB expression increased while PDE5, RhoA, ROKβ, ETA, and MHC decreased. At 7d, priapism dissipated and erectile dysfunction occurred with fibroplasia and necrosis (MHC expression decreased 10-fold). Additionally, fibrosis factor TGFβ1 expression was upregulated as early as 2h. HIF1α (hypoxia inducible factor) decreased at 4h but increased 2- and 4.5-fold at 4d and 7d, respectively. Conclusion: We established a novel, easily initiated, long duration BLEBinduced rat priapism model. Importantly, this model showed CC contractile molecules were upregulated and relaxation molecules downregulated with ICP reversible in the early compensated stage while these pathways were oppositely affected in the later decompensated stage with eventual fibrosis and necrosis.