Priapism is defined as a pathological condition where penile erection persists beyond, or is unrelated to sexual stimulation. In patients with ischaemic priapism, corporal blood aspirates show evidence of hypoxia, acidosis and glucopenia. One hypothesis for ischaemic priapism is reduced contractile function of cavernosal smooth muscle (CSM) secondary to these metabolic changes. This study aims to determine the effect of simulated ischaemia on contraction in CSM and which components of ischaemia are central to these changes. Isometric contractions were recorded from strips of guinea pig corpus cavernosum in response to electrical field stimulation (EFS at 60 Hz, sensitive to 1 µM tetrodotoxin) or exposure to 15 µM phenylephrine (PE). Strips were superfused at 37°C with a HCO₃^–/CO₂ buffered solution (pH 7.39). Hypoxia was generated by substituting 95% O₂ for 95% N₂ in the superfusing gas mixture. Glucopenia was achieved by omitting glucose and Na pyruvate. Acidosis in both the intra and extracellular compartments was generated by increasing the gas mixture CO₂ from 5% to 10% (pH 6.99). [HCO₃^–/CO₂] was reduced in the superfusate to create an extracellular acidosis (pH 6.97). Intracellular acidosis was generated by increasing the CO₂ percentage and superfusate [HCO₃^–/CO₂] in proportion (pH 7.44). Superfusate [CaCl₂] was altered appropriately to maintain Ca²⁺ activity (Wu & Fry, 1998). The effects of these interventions were recorded in isolation and in combination on both nerve-mediated and agonist-induced contractions. Data are mean ± s.d. Statistical differences (p<0.05) between data sets were examined with Student’s t tests. A combination of hypoxia, glucopenia and acidosis severely affects contractile function. This effect is irreversible when the muscle is activated via the motor nerves but not when the muscle is directly activated. Intracellular acidosis conferred some protection against the effect of this metabolic depletion when the muscle was activated directly with an agonist, but not when nerve-mediated stimulation was used. The mechanisms by which intracellular acidosis exerts this protective effect on the muscle needs to be assessed.