Severe acidosis deteriorates cardiac injury. Rat coronary arteries (RCAs) are unusually hypercontractive to extracellular (o) acidosis (EA). TMEM16A-encoded anoctamin 1 (ANO1), a Ca²⁺-activated chloride channel (CaCC), plays an important role in regulating coronary arterial tension. We tested the possibility that the activation of CaCCs in the arterial smooth muscle cell (ASMC) contributes to EA-induced RCA constriction. ANO1 expression was detected with immunofluorescence staining and Western blot. TMEM16A mRNA was assessed with quantitative Real-Time PCR. Cl^- currents and membrane potentials were quantified with a patch clamp. The vascular tension was recorded with a myograph. Intracellular (i) level of Cl^- and Ca²⁺ was measured with fluorescent molecular probes. ANO1 was expressed in all tested arterial myocytes, but was much more abundant in RCA ASMCs as compared with ASMCs isolated from rat cerebral basilar, intrarenal and mesenteric arteries. EA reduced [Cl^-]_i levels, augmented CaCC currents exclusively in RCA ASMCs and depolarized RCA ASMCs to a greater extent. Cl^- deprivation, which depleted [Cl^-]_i by incubating the arteries or their ASMCs in Cl^--free bath solution, decreased EA-induced [Cl^-]_i reduction, diminished EA-induced CaCC augmentation and time-dependently depressed EA-induced RCA constriction. Inhibitor studies showed that these EA-induced effects including RCA constriction, CaCC current augmentation, [Cl^-]_i reduction and/or [Ca²⁺]_i elevation were depressed by various Cl^- channel blockers, [Ca²⁺]_i release inhibitors and L-type voltage-gated Ca²⁺ channel inhibitor nifedipine. ANO1 antibody attenuated all observed changes induced by EA in RCA ASMCs. The greater activity of RCA ASMC CaCCs complicated with an enhanced Ca²⁺ mobilization from both [Ca²⁺]_i release and [Ca²⁺]_o influx plays a pivotal role in the distinctive hypercontractility of RCAs to acidosis. Translation of these findings to human beings may lead to a new conception in our understanding and treating cardiac complications in severe acidosis.

Aims: Few treatments are available in the subacute phase of traumatic brain injury (TBI) except rehabilitation training. We previously reported that transient CO₂ inhalation applied within minutes after reperfusion has neuroprotective effects against cerebral ischemia/reperfusion injury. In this study, it was hypothesized that delayed CO₂ postconditioning (DCPC) starting at the subacute phase may promote neurological recovery of TBI.Methods: Using a cryogenic TBI (cTBI) model, mice received DCPC daily by inhaling 5%/10%/20% CO₂ for various time‐courses (one/two/three cycles of 10‐min inhalation/10‐min break) at Days 3–7, 3–14 or 7–18 after cTBI. Beam walking and gait tests were used to assess the effect of DCPC. Lesion size, expression of GAP‐43 and synaptophysin, amoeboid microglia number and glia scar area were detected. Transcriptome and recombinant interferon regulatory factor 7 (Irf7) adeno‐associated virus were applied to investigate the molecular mechanisms.Results: DCPC significantly promoted recovery of motor function in a concentration and time‐course dependent manner with a wide therapeutic time window of at least 7 days after cTBI. The beneficial effects of DCPC were blocked by intracerebroventricular injection of NaHCO₃. DCPC also increased puncta density of GAP‐43 and synaptophysin, and reduced amoeboid microglia number and glial scar formation in the cortex surrounding the lesion. Transcriptome analysis showed many inflammation‐related genes and pathways were altered by DCPC, and Irf7 was a hub gene, while overexpression of IRF7 blocked the motor function improvement of DCPC.Conclusions: We first showed that DCPC promoted functional recovery and brain tissue repair, which opens a new therapeutic time window of postconditioning for TBI. Inhibition of IRF7 is a key molecular mechanism for the beneficial effects of DCPC, and IRF7 may be a potential therapeutic target for rehabilitation after TBI.