Calvert, Robert Charles; (2003) Purinergic signalling in the urinary tract. Doctoral thesis (M.D), UCL (University College London).

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Abstract

This thesis tests the hypothesis that "Purinergic signalling has biological roles in the pathophysiology of conditions affecting the bladder, prostate, penis and ureter". The evidence to support this hypothesis which has already been published is reviewed. In Chapter 2 alterations in the innervation of the rabbit bladder after partial obstruction of the bladder outlet are demonstrated, with an increase in the purinergic component of the nerve-mediated response. In chapter 3 the expression of P2-receptors on human prostate tissue and a prostate cancer cell line is characterised using immunohistochemical techniques. Functional experiments then provide evidence that activation of purinoceptors by adenosine 5'-triphosphate (ATP) enhances prostatic smooth muscle tone in the presence of adrenergic tone. ATP is known to inhibit the growth of prostate cancer cell lines by activating P2 receptors. This action is further characterised using various purinoceptor agonists and antagonists, measuring ATP breakdown and using apoptosis assays. The role of ATP in normal and pathological erectile function is explored in chapter 4. Functional characterisation of purine-mediated rabbit cavernosal smooth muscle relaxation indicate that P2Y1 and P2Y4-purinoceptors may be involved. Alterations of ATP-mediated cavernosal smooth muscle relaxation are demonstrated in rabbit models of diabetes mellitus and partial bladder outlet obstruction. In the final experimental chapter evidence is sought to determine whether ATP is released from the human ureter upon distension and to determine the expression of purinoceptors on human ureter suburothelial sensory nerves. These experiments support a role for ATP and P2X3-purinoceptors in mechanosensory transduction during renal colic. The final chapter includes a discussion of how well the hypothesis has been tested and considers some more general questions raised by these experiments.

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