Altered response to partial bladder outlet obstruction in mice lacking inducible nitric oxide synthase

Introduction: Following prolonged partial bladder outlet obstruction (BOO) in the mouse, cholinergic mediated detrusor contractility decreases. Previo us work has demonstrated an increase in the inducible form of nitric oxide synthase (iNOS) at the mRNA and protein levels soon after obstruction. Sinc e nitric oxide (NO), the product of the action of iNOS on molecular oxygen and l-arginine, produces vasodilation and decreases platelet aggregation, w e believe it is an integral part of the initial detrusor response to obstru ction. These experiments evaluated the detrusor response in mice incapable of producing iNOS. Materials and Methods: Wild type and knockout mice were partially obstructe d for 1, 3, and 5 weeks. Physiologic evaluation consisted of cystometric an alyses, and muscle strip studies in response to cholinergic and electrical stimulation. Strips were also relaxed with L-arginine, sodium nitroprusside , and 8-bromoguanosine 3' - 5' cyclic GMP, after precontraction. Results: After 5 weeks of obstruction, both wild type (WT) and knockout (KO ) mouse bladders increased significantly in weight. WT bladders obstructed for 5 weeks had the greatest capacity (increase of 42%, p = 0.022), and a d ecreased contractile response to carbachol (decrease of 32% at 10(-5) M, p = 0.018). No differences were noted at 1 and 3 weeks of obstruction. In con trast, KO mice had a significantly larger bladder capacity at 1 week of obs truction compared with WT, and had significantly lower responses to electri cal stimulation than WT at the same time (p = 0.03). Additionally, after 5 weeks of obstruction, bladder capacity and contractility returned to baseli ne levels in KO mice, at a time when WT mice had significantly larger capac ity and decreased contractility. Conclusions: Bladder function following partial BOO in mice incapable of pr oducing iNOS differed significantly from the normal response. Our data sugg est that generation of iNOS soon after obstruction is necessary to prevent detrusor dysfunction at that time. Moreover, the enhanced function seen in KO bladders after longer periods of obstruction (5 weeks) in comparison to WT bladders suggests that reactive nitrogen species-induced protein nitrosy lation may be involved in the loss of contractile function observed after m ore prolonged periods of obstruction.