Drug repurposing DMSO from an old solvent to a new candidate for the treatment of colitis and sepsis in male mice.

Normal microvascular function is critical for tissue perfusion, and intestinal vascular dysfunction is a major pathological feature of colitis and sepsis. Although dimethyl sulfoxide (DMSO) as a versatile solvent exerts anti-inflammatory and vasoactive properties in conduit vessels, its pharmacological effects on arterioles have not been explored. This study repurposed it as a potential therapeutic agent for these two gut-derived inflammatory diseases, aiming to elucidate its direct effects and underlying mechanisms on intestinal resistance arterioles under both physiological and pathological conditions. Mulvany-style wire myography was used to assess DMSO-induced vasorelaxation in murine mesenteric arterioles. Intracellular Ca2+ dynamics in human umbilical vein endothelial cells (HUVECs) were assessed using Ca2+ imaging, and the membrane potential changes were monitored by patch clamp. Mouse models of dextran sulfate sodium (DSS)-induced colitis and cecal ligation puncture (CLP)-induced sepsis were used. To this end, we showed that DMSO elicited concentration-dependent vasorelaxation of mesenteric arterioles, predominantly mediated by endothelium-dependent hyperpolarization (EDH) mechanism in healthy mice. DMSO activated PLC/IP3/IP3R signaling pathway and store-operated Ca2+ entry (SOCE) in endothelial cells to trigger EDH-mediated vasorelaxation. In colitic and septic mice, DMSO significantly alleviated the severity of the diseases, such as body weight, stool score, colon length, and survival rate. Moreover, DMSO/EDH-mediated vasorelaxation was largely preserved in colitic and septic mice. Importantly, DMSO pretreatment restored the ACh/EDH-mediated vasorelaxation impaired in colitic and septic mice. This study reveals a previously overlooked pharmacological effect of DMSO as a common solvent, strongly suggesting that it could be repositioned as a safe therapeutic agent for improving microcirculation under inflammatory conditions, such as colitis and sepsis.