Abstract
The general anesthetic ketamine has been repurposed by physicians as an anti-depressant and by the public as a recreational drug. However, ketamine use can cause extensive pathological changes, including ketamine cystitis. The mechanisms of ketamine’s anti-depressant and adverse effects remain poorly understood. Here we present evidence that ketamine is an effective L-type Ca2+ channel (Cav1.2) antagonist that directly inhibits calcium influx and smooth muscle contractility, leading to voiding dysfunction. Ketamine prevents Cav1.2-mediated induction of immediate early genes and transcription factors, and inactivation of Cav1.2 in smooth muscle mimics the ketamine cystitis phenotype. Our results demonstrate that ketamine inhibition of Cav1.2 signaling is an important pathway mediating ketamine cystitis. In contrast, Cav1.2 agonist Bay k8644 abrogates ketamine-induced smooth muscle dysfunction. Indeed, Cav1.2 activation by Bay k8644 decreases voiding frequency while increasing void volume, indicating Cav1.2 agonists might be effective drugs for treatment of bladder dysfunction.
Highlights
The general anesthetic ketamine has been repurposed by physicians as an anti-depressant and by the public as a recreational drug
Ketamine cystitis has been attributed to urinary ketamine toxicity, this hypothesis has never been tested by direct ketamine instillation into the bladder
We have described the Cav1.2 antagonist action of ketamine, and further demonstrated that ketamine inhibition of Cav1.2-mediated signaling plays a major role in the pathogenesis of ketamine cystitis
Summary
The general anesthetic ketamine has been repurposed by physicians as an anti-depressant and by the public as a recreational drug. Cav1.2 agonist Bay k8644-potentiated BSM contraction was dosedependently inhibited by ketamine as well as by nifedipine. Prior inhibition of BSM contraction by nifedipine or by ketamine was dose-dependently reversed by subsequent exposure to Cav1.2 agonist Bay k8644 (Fig. 3).
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