Disruption of Cav1.2-mediated signaling is a pathway for ketamine-induced pathology

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 antidepressant and adverse effects remain poorly understood. Here we present evidence that ketamine is an effective L-type Ca 2+ 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.

Molecular mechanisms of voiding dysfunction in a novel mouse model of acute urinary retention

“…CMG was performed with PBS infusion (25 μL/min) as previously described. 32,33 Mice were anesthetized by a F I G U R E 1 AUR mouse model. A, Schematic diagram of AUR mouse model with the application of 50 or 80 cm water pressure.…”

“…BSM strip EFS was carried out with a Grass S48 field stimulator (Grass Technologies, RI, USA) using standard protocols previously described. 32,33 EFS stimulation parameters were set as follows: voltage 50 V; duration: 0.05 ms; trains of stimuli: 3 s per single train; frequencies: 1, 2, 5, 10, 20, and 50 Hz.…”

Molecular pathways underlying tissue injuries in the bladder with ketamine cystitis

“…In cultured smooth muscle cells (SMCs), ketamine induces dose‐dependent inhibitory effects on cell generation 19,20,224 . Among the MAPK family, ERK1/2 is one of the well‐known signal transduction pathways for SMC differentiation and proliferation.…”

“…A previous study found that ketamine suppressed signaling pathways mediated by muscarinic receptors heterologously expressed in Xenopus oocytes, 233 which partially explained the mechanism of the inhibition of smooth muscle contraction in response to cholinergic stimulation with ketamine. However, we recently reported that ketamine and its metabolite nor‐ketamine could dose‐dependently inhibit BSM contraction in response to electrical field stimulation (EFS), high K, carbachol, and α, β‐meATP 20 . Purinergic and cholinergic signaling and high K levels all stimulate smooth muscle contraction by initiating an increase in the intracellular calcium concentration.…”

“…Furthermore, ketamine/nor‐ketamine is mostly eliminated by renal excretion into the urine, and a high concentration is found in the urine of ketamine abusers. Ketamine is a lipophilic drug that easily crosses epithelial cells via passive diffusion, 237,238 which may partially inhibit Cav1.2 on BSM cells, thereby impacting BSM function 20 …”