Kumar, P; (2013) The effect of ischaemia on cavernosal smooth muscle. Doctoral thesis , UCL (University College London).

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Abstract

Ischaemic priapism is a pathological condition characterised by a prolonged painful penile erection. Corporal blood aspirates show a combination of hypoxia, acidosis and glucopenia. Initial treatment includes ice packs, corporal aspiration and subsequent washout with room temperature fluids. The effect of ischaemia on cavernosal smooth function was examined. In vitro guinea-pig cavernosal smooth muscle strip experiments showed that simulated ischaemia caused a significant and marked reduction in phenylephrine-induced (PE) contraction (plateau PE30 response 35±19%, plateau PE60 response 29±16% of control). The degree of depression was similar to that seen in nerve-contraction although there appeared to be some metabolic reserve as shown by early preservation of the peak PE response (peak PE30 response 83±31%, peak PE60 response 36±35% of control). Nerve-contraction did not recover upon reperfusion whereas agonist-contractures demonstrated complete recovery. Experiments recording the effect of the elements of ischaemia showed this depression to be secondary to combined hypoxia and substrate depletion (absence of superfusate glucose and Na pyruvate). Isolated muscle cells showed a significant reduction in agonist-induced calcium transients during similar interventions. Simulated ischaemia markedly reduced nerve- and abolished agonist-relaxation. These detrimental effects were completely reversible upon reperfusion. Nerve-relaxation recovered whereas nerve-contraction did not. This effect was again secondary to the combination of hypoxia and substrate depletion. This suggests that relaxatory nerves are more resistant to ischaemic damage, a finding which would contribute to the pathogenesis of ischaemic priapism and the contractile failure observed in this condition. Intracellular acidification caused a significant and reversible increase in nerve-mediated contraction. Intracellular acidification also augmented PE contractures at 30 min. (peak PE30 response 120±12%, plateau PE30 response 117±9%). Intracellular acidification induced a significant and reversible increase in PE-induced calcium transients in isolated cells. This augmentation of function was via an oxygen-dependent mechanism. Reduction in superfusate temperature significantly suppressed nerve-contraction. This was not due to reduced recruitment of nerve fibres at low temperature. The time-course of phasic nervecontractions and agonist-contractures was prolonged, slowing responses significantly. Nerverelaxation was significantly ameliorated at low temperatures. The phasic relaxation was also prolonged with the return to precontracted tension following EFS-mediated relaxation slowed to a greater degree than the initial relaxatory response. No change in magnitude of agonist-induced relaxation was observed. Overall reduced temperature interventions affect contraction to a greater degree than relaxatory mechanisms. These effects were not due to changes in the viscoelastic properties of the tissue at low temperature. Prolonged ischaemia is detrimental to contractile function before relaxatory responses. Substrate depletion is a late finding in ischaemic priapism, with undetectable blood glucose after 6-12 hours of priapism. Depletion of the energy substrates glucose and Na pyruvate, combined with hypoxia, is central to the contractile failure seen in ischaemic priapism. This depression is irreversible on contractile nerves at an earlier stage when compared to relaxatory nerves and the smooth muscle itself, propagating the ischaemic priapic state. Reversal of these conditions should form part of any treatment regimen for patients who have priapism. Low temperature interventions do not improve CSM function with nerve-mediated function significantly reduced at low temperature as well as slowing CSM contractile responses. It may be beneficial to use oxygenated washout fluids at body temperature which contain energy substrates such as glucose and Na pyruvate to treat ischaemic priapism.

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