Heat Treatment and Vitamin B6 on Exercise Pressor Reflex in Lower Limb Ischemia-Reperfusion: Role of P2X3

Femoral artery revascularization and supervised exercise intervention are among the most general approaches for the treatment of peripheral artery disease (PAD). However, the surgical procedure of revascularization inevitably induces the ischemia-reperfusion (IR) injury in the re-perfused skeletal muscle tissue. Thus, responses of sympathetic nervous activity (SNA) and blood pressure (BP) induced by skeletal muscle contraction during exercise, termed the “exercise pressor reflex (EPR)”, are still exaggerated following the reperfusion of the blood flow. If not appropriately intervened, a higher risk for cardiovascular events and lower adherence to the exercise intervention remain in post-surgery patients. Accordingly, the major goal of this proposal is to study the beneficial effect of heat treatment (HT) and Vitamin B6 supplementation on IR-induced exaggerated EPR. Based on my published work and pilot data, and the great feasibility of translational network between the animal and human studies in my working Institute, the central hypothesis is that HT and vitamin B6 attenuates the exaggerated EPR in lower limb IR via suppressing the P2X3 receptors in dorsal root ganglion (DRG).1. Firstly, the HT procedure will be performed by increasing muscle temperature (Tm) by two gradients (~1.5 and ~3 degrees in Celsius) in IR 18h (18 hours after IR) rats. It is hypothesized that EPR is enhanced in IR rats and increasing Tm by HT attenuates the amplified reflex. 2. Secondly, the temperature sensitive P2X3 receptor is well known for its role in participating in the EPR. It is hypothesized that IR increases the expression and functions of P2X3 receptor in DRG neurons and HT can attenuate the effect caused by IR. It is further anticipated that the pharmacological inhibition of P2X3 signal in the DRG will attenuate the amplified EPR in IR rats.3. Thirdly, I am going to examine the effect of vitamin B6 supplementation on the EPR in post-revascularization PAD patients. In light of the previous results in both animal and human study, the pressor response in the post-revascularization PAD patients will be examined following 28 days’ vitamin B6 supplementation. It is hypothesized that the post-revascularization PAD patients in vitamin B6 group will enjoy a significantly lower pressor response, compared with the patients in placebo group without vitamin B6 supplementation.