Kalsi, J.S.; (2011) The effect of soluble guanylate cyclase activators and a nitric oxide releasing PDE 5 inhibitor on cavernosal and anococcygeal smooth muscle function in conditions of nitric oxide deficiency. Doctoral thesis , UCL (University College London).

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Abstract

Introduction: PDE5 inhibitors improve erections by potentiating nitric oxide (NO)- cyclic guanosine monophosphate system. However, long-term diabetic patients have reduced efficacy secondary to dysfunction of NO system. The aim of this thesis was to investigate in-vitro effects of a PDE5 inhibitor (sildenafil), a soluble guanylate cyclase (sGC) activator (BAY41-2272) and an NO-releasing PDE5 inhibitor (NCX-911) on urogenital smooth muscle in conditions of NO deficiency. Method: The effect of these compounds was investigated on tone and electrical field stimulation-induced nitrergic relaxation of cavernosal (human and rabbit) and anococcygeal (rat) smooth muscle and compared to an NO donor (spermine-NONOate) and non-specific sGC activator (YC-1) in the absence/presence of inhibitor of NO synthesis (L-NAME) or inhibitor of sGC (ODQ). In a diabetic rat model, these compounds were assessed in untreated and L-NAME-treated tissues from non-diabetic and diabetic animals. Results: BAY41-2272 was more potent than YC-1 and spermine-NONOate at relaxing rabbit/human cavernosum. ODQ significantly decreased the potency of BAY41-2272 whereas L-NAME did not. BAY41-2272 potentiated nitrergic responses and partially reversed the inhibition of nitrergic responses by L-NAME. NCX-911 and sildenafil were equally potent at relaxing rabbit and human cavernosum. In presence of L-NAME the potency of sildenafil decreased significantly. Both compounds potentiated nitrergic relaxations equally but failed to induce relaxation in the presence of ODQ. Nitrergic relaxation was significantly decreased in the diabetic rats but still potentiated by BAY41-2272 but not by sildenafil or NCX-911. The potencies of NCX-911 and BAY41- 2272 were unaltered but that of sildenafil was significantly reduced in the diabetic animals. Conclusion: The rank of potency in control tissues was BAY41-2272 > NCX-11 = sildenafil; whereas in NO deficiency BAY 41-2272 > NCX-911 > sildenafil. Endogenous NO derived from nitrergic nerves is significantly decreased in diabetes. NO-releasing PDE5 inhibitors and sGC activators may be effective in management of diabetic erectile dysfunction.

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