Lipid peroxidation product 4-hydroxynonenal contributes to bladder smooth muscle damage

OBJECTIVES Bladder outlet obstruction is correlated with an increased peroxidation of lipids. The aldehyde 4-hydroxynonenal (HNE) is produced in relative large amounts during lipid peroxidation. The aim of this study was to investigate the effect of HNE on excitation-contraction coupling of detrusor smooth muscle. METHODS We used smooth muscle strips from pig urinary bladder. Contractile responses to electrical field stimulation (EFS) (4 to 32 Hz), carbachol (10(-8) to 3.10(-5) M), and potassium (65.3 mM) were monitored before and after the addition of HNE. We investigated the effect of the synthetic thiol inactivator N-ethylmaleimide (NEM) on the stimulation pathways and compared it with the HNE-mediated effect. RESULTS Responses of detrusor strips to EFS were for the greater part based on neurogenic stimulation and the release of acetylcholine. HNE (100 mu M) diminished contractile responses to EFS and carbachol to the same extent. The pD(2) value of the carbachol concentration response curve did not decrease after exposure to HNE. The maximal effect obtained with carbachol was significantly reduced after 100 mu M HNE treatment. Contractions induced by potassium were affected in a similar degree by HNE compared with EFS- and carbachol-induced responses of comparable amplitude. Incubation of bladder strips with NEM had similar effects on pharmacological responses compared with HNE exposure. CONCLUSIONS 4-Hydroxynonenal affects pig bladder contractility. L-type calcium channels and or the contractile system of the bladder muscle are susceptible to HNE-mediated damage. The cholinergic nerves and the muscarinic receptor signaling system remain largely unaffected. The effects of HNE are most likely mediated via alkylation of sulfhydryl groups.