The effects of hypoxia (pO2: 50 mmHg), acidosis (pH: 6.9) or glucopenia (absence of glucose) in vitro on the tone of the rabbit corpus cavernosum were investigated. The recovery of smooth muscle contractility following exposure to these conditions was also assessed. Hypoxia, acidosis or glucopenia alone or in combination showed a sustained reduction in the tone. Reperfusion of tissue strips showed complete recovery of smooth muscle tone for all conditions except when hypoxia and glucopenia were combined or when hypoxia, glucopenia and acidosis were used in combination. Incomplete recovery of tone was associated with a significant reduction in tissue ATP concentrations and an increase in the number of TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling)-positive nuclei. This indicates that following reversal of hypoxia, acidosis and glucopenia, failure of conventional alpha-adrenergic agonists to produce tumescence in low flow priapism is associated with irreversible smooth muscle cell dysfunction, which is linked to ATP reduction and smooth muscle cell death.