Percutaneous Carbon Dioxide Treatment using a Gas Mist Generator Enhances the Collateral Blood Flow in the Ischemic Hindlimb

Abstract

Aim: Highly concentrated carbon dioxide (CO2) is thought to be useful for ischemic diseases. We investigated whether treatment with a few micrometers of CO2 molecules atomized via two fluidnozzles (CO2 mist) exerts an angiogenic effect in a mouse ischemic hindlimb model. Methods: Mice with unilateral hindlimb ischemia were divided into untreated (UT), 100% CO2 gas alone-treated (CG), mixed air (O2; 20%, N2; 80%) mist-treated (AM) and 100% CO2 mist-treated (CM) groups. The lower body of the mice was encased in a polyethylene bag filled with each gaseous agent using a gas mist generator for 10 minutes daily. Results: According to a laser Doppler analysis, the ischemic hindlimb blood flow was persistently higher after the seventh day of induction of ischemia in the CM group than in the UT group. The capillary density was also greater in the CM group on day 28 compared with that observed in the UT group. In addition, the parameters in the AM and CG groups were similar to those obtained in the UT group. The observed effects were abolished by the administration of an inhibitor of nitric oxide synthase (NOS). The vascular endothelial growth factor mRNA expression and protein levels and the phosphorylated endothelial NOS level were increased in the CM group compared with that observed in the UT group. A proteomic analysis using liquid chromatography-tandem mass spectrometry identified novel protein candidates regulated by CO2 mist. Conclusion: Percutaneous CO2 mist therapy may be useful for treating ischemia-induced angiogenesis.J Atheroscler Thromb, 2015; 22:38-51.

Transcutaneous carbon dioxide attenuates impaired oxidative capacity in skeletal muscle in hyperglycemia model

“…eNOS is a key factor for the enhancement of muscle oxidative capacity via up-regulation of PGC-1α expression. In a previous study, application of CO 2 to a hind limb ischemia model enhanced eNOS expression in the skeletal muscle (Irie et al 2005;Izumi et al 2015). Additionally, application of transcutaneous CO 2 to sedentary rats for 12 weeks increased the mRNA level of PGC-1α and SIRT1 and mitochondria number .…”

“…These reports suggest that blood flow appears to be a strong modulator of eNOS levels. On the other hand, Izumi et al (2015) showed that CO 2 therapy promotes blood flow in the subcutaneous tissues, Values are presented as mean ± SEM (two-way ANOVA. * and † significantly different from CON with same intervention and CO 2 (-) vs. CO 2 (+), respectively, at p < 0.05.…”

“…Carbon dioxide (CO 2 ) therapy has long been used in Europe as an effective treatment for cardiac disease and skin lesions (Riggs 1960;Goodman et al 1975;Wells 1999). Exposure to CO 2 elevates blood flow and microcirculation in many tissues as well as partially increases O 2 pressure in the local tissues, a phenomenon known as the Bohr effect (Riggs 1960;Wells 1999;Jensen 2004;Izumi et al 2015). Also, it is well known that CO 2 therapy induces peripheral vasodilation, thereby increasing tissue blood flow (Hartmann et al 1997;Sakai et al 2011).…”

“…Additionally, nitric oxide synthesized by eNOS can increase PGC-1α protein expression in skeletal muscle via activation of cyclic guanosine monophosphate (cGMP) and consequently promote mitochondrial biogenesis and function (Nisoli et al 2003(Nisoli et al , 2004Le Gouill et al 2007;Ventura-Clapier et al 2008;Lira et al 2010). On the other hand, it has been reported that application of CO 2 therapy up-regulates eNOS and cGMP expression in skeletal muscle via an increase in blood flow (Irie et al 2005;Izumi et al 2015). Moreover, the expression of positive regulators of oxidative capacity, including PGC-1α and sirtuin1 (SIRT1) is enhanced by transcutaneous application of CO 2 therapy .…”

Effects of CO2 water-bath treatment on blood flow and angiogenesis in ischemic hind limb of diabetic rat

“…Several medical and surgical interventions are available for the treatment of peripheral artery disease (Carmeliet 2003;Cooke and Losordo 2015;Dhalla et al 2017;Kehler et al 2013;Li et al 1998;Potente et al 2011); however, none of these therapies are satisfactory. Recently, both clinical and experimental studies have indicated the beneficial effects of CO 2 therapy in promoting blood flow in the ischemic limb in peripheral artery disease (Dhalla et al 2017;Hartmann et al 1997a;Hartmann et al 1997b;Irie et al 2005;Izumi et al 2015;Pagourelias et. al.…”