Blockade of acid sensing ion channels attenuates the augmented exercise pressor reflex in rats with chronic femoral artery occlusion

Non-technical summary  In patients with peripheral artery disease arterial blood flow to the legs is adequate at rest, but does not increase to meet metabolic demand of the muscles during exercise. Consequently, the arterial blood pressure response to exercise in these patients is greater than it is in healthy subjects. We tested the hypothesis that this exaggerated arterial pressure response to exercise is caused by the stimulation of the ion channel ASIC3 on the endings of sensory nerves in contracting skeletal muscle. We performed our experiments in decerebrated rats. Three days before the experiment, we ligated the left femoral artery, a manoeuvre which has been shown to simulate the arterial blood flow patterns to hindlimb skeletal muscles that are found in patients with peripheral artery disease. We found that blockade of ASIC3 with two different compounds attenuated the increase in arterial pressure evoked by left hindlimb muscle contraction. Abstract  We found previously that static contraction of the hindlimb muscles of rats whose femoral artery was ligated evoked a larger reflex pressor response (i.e. exercise pressor reflex) than did static contraction of the contralateral hindlimb muscles which were freely perfused. Ligating a femoral artery in rats results in blood flow patterns to the muscles that are remarkably similar to those displayed by humans with peripheral artery disease. Using decerebrated rats, we tested the hypothesis that the augmented exercise pressor reflex in rats with a ligated femoral artery is attenuated by blockade of the acid sensing ion channel (ASIC) 3. We found that femoral arterial injection of either amiloride (5 and 50 μg kg−1) or APETx2 (100 μg kg−1) markedly attenuated the reflex in rats with a ligated femoral artery. In contrast, these ASIC antagonists had only modest effects on the reflex in rats with freely perfused hindlimbs. Tests of specificity of the two antagonists revealed that the low dose of amiloride and APETx2 greatly attenuated the pressor response to lactic acid, an ASIC agonist, but did not attenuate the pressor response to capsaicin, a TRPV1 agonist. In contrast, the high dose of amiloride attenuated the pressor responses to lactic acid, but also attenuated the pressor response to capsaicin. We conclude that ASIC3 on thin fibre muscle afferents plays an important role in evoking the exercise pressor reflex in rats with a compromised arterial blood supply to the working muscles.