Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Nat Commun. 2020 Aug 28;11(1):4328. doi: 10.1038/s41467-020-18167-4.
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 Ca 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.
通用麻醉剂氯胺酮已被医生重新用于治疗抑郁症，也被公众用作娱乐性药物。然而，氯胺酮的使用会导致广泛的病理变化，包括氯胺酮膀胱炎。氯胺酮抗抑郁和不良反应的机制仍知之甚少。在这里，我们提供的证据表明，氯胺酮是一种有效的 L 型钙通道（Cav1.2）拮抗剂，可直接抑制钙内流和平滑肌收缩性，导致排尿功能障碍。氯胺酮可防止 Cav1.2 介导的即时早期基因和转录因子的诱导，以及平滑肌中 Cav1.2 的失活模拟了氯胺酮膀胱炎表型。我们的结果表明，氯胺酮抑制 Cav1.2 信号转导是介导氯胺酮膀胱炎的重要途径。相比之下，Cav1.2 激动剂 Bay k8644 可消除氯胺酮引起的平滑肌功能障碍。事实上，Bay k8644 激活 Cav1.2 可降低排尿频率，同时增加排尿量，表明 Cav1.2 激动剂可能是治疗膀胱功能障碍的有效药物。
