Functional knock out of Acid Sensing Ion Channel 3 prevents the exaggerated exercise pressor reflex in rats exercising on a treadmill.

We have compared the cardiovascular responses to treadmill exercise between wild-type (WT) Wistar Kyoto rats with their ASIC3 knock out (KO) counterparts both before and after their femoral arteries were bilaterally ligated. The rats were instrumented with radiotelemetry devices to measure arterial blood pressure and ran at a treadmill speed of 15-20 m/min. We found no difference in the pressor and cardioaccelerator responses to exercise between the WT and the ASIC3 KO rats when their femoral arteries were freely perfused. In contrast, the WT rats, but not the ASIC3 KO rats, displayed significantly larger peak and integrated pressor responses to treadmill exercise after both femoral arteries were ligated for 3 days. We also examined the effect of bilaterally injecting APETx2 into the substance of the gastrocnemius muscles on the cardiovascular responses to treadmill exercise in both the WT and the ASIC3 KO rats. We found that APETx2, an ASIC3 antagonist, attenuated the integrated pressor responses to exercise in the WT rats, after but not before the femoral arteries were ligated. Injection of APETx2 into the gastrocnemius muscles had no effect on the responses to exercise in the ASIC3 KO rats regardless of whether their femoral arteries were freely perfused or ligated. Our findings in conscious rats exercising on a treadmill extend our previous findings in reduced preparations in which we reported that ASIC3 "receptors" presumably on the intramuscular endings of group IV afferents play an important role in evoking the exaggerated component of the exercise pressor reflex induced by ischemia.