Khan, Masood Ahmed; (2001) Endothelin-1 and nitric oxide in the pathogenesis of urinary tract disorders secondary to bladder outlet obstruction: Experimental findings. Doctoral thesis (M.D), UCL (University College London).

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Abstract

Bladder outlet obstruction (BOO) is a common disorder that is associated with urinary tract symptoms. Nitric oxide (NO), synthesised by NO synthase (NOS) is a potent vasodilator that is present throughout the urinary tract and the corpus cavernosum. Endothelin-1 (ET-1), conversely is a potent vasoconstrictor that is similarly distributed throughout the urinary tract. ET-1 and NO as well as possessing opposing actions regulate each other's synthesis. The disruption of the balance between ET-1 and NO may be associated with various vascular pathologies. However, their potential roles in the pathogenesis of urinary tract disorders, secondary to BOO, are unknown. New Zealand White rabbits with BOO are considered to be a suitable model of the human condition. Hence, using this model kidney, bladder and cavernosal tissue was obtained to investigate the potential roles of ET-1 and NO in the pathogenesis of urinary tract disorders using functional, autoradiographical, tissue culture, immunohistochemical and ultrastructural techniques. These studies demonstrated that: 1) there is a time-dependent up-regulation of ETa and down-regulation of ETb receptor binding sites and NOS binding sites in the BOO renal medulla. These changes may play a pathophysiological role in renal impairment associated with BOO, 2) ET-1 may mediate bladder smooth muscle hyperplasia associated with BOO, 3) in the BOO bladder, ETb receptor binding sites were up- regulated and mediated detrusor smooth muscle contraction. ETa receptor binding sites were also up-regulated and NOS binding sites were down-regulated. These changes may be associated with detrusor instability associated with BOO, 4) the down-regulation of ETb receptor binding sites, in the six-week BOO cavernosa, may play a pathophysiological role in erectile dysfunction associated with BOO. These findings support the concept that an imbalance between ET-1 and NO may be associated with the pathogenesis of urinary tract disorders. These findings may have therapeutic implications.

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