Sensory neuron inositol 1,4,5-trisphosphate receptors contribute to chronic mechanoreflex sensitization in rats with simulated peripheral artery disease.

The mechanoreflex is exaggerated in patients with peripheral artery disease (PAD) and in a rat model of simulated PAD in which a femoral artery is chronically (∼72 h) ligated. We found recently that, in rats with a ligated femoral artery, blockade of thromboxane A (TxA) receptors on the sensory endings of thin fiber muscle afferents reduced the pressor response to 1 Hz repetitive/dynamic hindlimb skeletal muscle stretch (a model of mechanoreflex activation isolated from contraction-induced metabolite production). Conversely, we found no effect of TxA receptor blockade in rats with freely perfused femoral arteries. Here, we extended the isolated mechanoreflex findings in "ligated" rats to experiments evoking dynamic hindlimb skeletal muscle contractions. We also investigated the role played by inositol 1,4,5-trisphosphate (IP) receptors, receptors associated with intracellular signaling linked to TxA receptors, in the exaggerated response to dynamic mechanoreflex and exercise pressor reflex activation in ligated rats. Injection of the TxA receptor antagonist daltroban into the arterial supply of the hindlimb reduced the pressor response to 1 Hz dynamic contraction in ligated but not "freely perfused" rats. Moreover, injection of the IP receptor antagonist xestospongin C into the arterial supply of the hindlimb reduced the pressor response to 1 Hz dynamic stretch and contraction in ligated but not freely perfused rats. These findings demonstrate that, in rats with a ligated femoral artery, sensory neuron TxA receptor and IP receptor-mediated signaling contributes to a chronic sensitization of the mechanically activated channels associated with the mechanoreflex and the exercise pressor reflex.