The mechano-gated channel inhibitor GsMTx4 reduces the exercise pressor reflex in rats with ligated femoral arteries

Abstract

Mechanical and metabolic stimuli arising from contracting muscles evoke the exercise pressor reflex. This reflex is greater in a rat model of simulated peripheral arterial disease in which a femoral artery is chronically ligated than it is in rats with freely perfused femoral arteries. The role played by the mechanically sensitive component of the exaggerated exercise pressor reflex in ligated rats is unknown. We tested the hypothesis that the mechano-gated channel inhibitor GsMTx4, a relatively selective inhibitor of mechano-gated Piezo channels, reduces the exercise pressor reflex in decerebrate rats with ligated femoral arteries. Injection of 10 μg of GsMTx4 into the arterial supply of the hindlimb reduced the pressor response to Achilles tendon stretch (a purely mechanical stimulus) but had no effect on the pressor responses to intra-arterial injection of α,β-methylene ATP or lactic acid (purely metabolic stimuli). Moreover, injection of 10 μg of GsMTx4 into the arterial supply of the hindlimb reduced both the integrated pressor area (control 535 ± 21, GsMTx4 218 ± 24 mmHg·s; P < 0.01), peak pressor (control 29 ± 2, GsMTx4 14 ± 3 mmHg; P < 0.01), and renal sympathetic nerve responses to electrically induced intermittent hindlimb muscle contraction (a mixed mechanical and metabolic stimulus). The reduction of the integrated pressor area during contraction caused by GsMTx4 was greater in rats with ligated femoral arteries than it was in rats with freely perfused femoral arteries. We conclude that the mechanically sensitive component of the reflex contributes to the exaggerated exercise pressor reflex during intermittent hindlimb muscle contractions in rats with ligated femoral arteries.

Chronic femoral artery ligation exaggerates the pressor and sympathetic nerve responses during dynamic skeletal muscle stretch in decerebrate rats

“…The mechanically-sensitive component of the exercise pressor reflex during dynamic muscle contractions was found recently to be exaggerated when evoked from a previously ligated hindlimb compared to the reflex evoked from a freely perfused hindlimb (12). That investigation was designed specifically to gain translational mechanistic insights into the larger increases in blood pressure found in PAD patients versus aged-matched healthy counterparts during low-intensity rhythmic plantar flexion exercise (31,39,40), and low-intensity treadmill walking (5, 7).…”

“…Copp et al (12) found recently that the mechanically-sensitive component of the exercise pressor reflex was exaggerated in rats with a ligated femoral artery compared to that found in rats with freely perfused femoral arteries. Specifically, GsMTx4, a relatively selective antagonist for mechano-gated piezo channels (2,6), reduced the pressor and renal sympathetic nerve responses during dynamic hindlimb muscle contraction to a greater extent in "ligated" versus "freely perfused" rats (12).…”

“…Specifically, GsMTx4, a relatively selective antagonist for mechano-gated piezo channels (2,6), reduced the pressor and renal sympathetic nerve responses during dynamic hindlimb muscle contraction to a greater extent in "ligated" versus "freely perfused" rats (12). Femoral artery ligation did not, however, increase piezo1 or piezo2 channel protein expression in L 4 and L 5 dorsal root ganglia (DRG) tissue which suggested that an acute and/or chronic sensitization of mechanoreceptors accounted for the exaggerated mechanicallysensitive component of the exercise pressor reflex rather than increased mechanoreceptor expression.…”

“…In that investigation, however, direct comparisons between dynamic stretch and dynamic contraction were not made and sympathetic nerve activity was not measured. A characteristic feature of the increase in sympathetic nerve activity during dynamic contractions is a bursting pattern that is synchronized with muscle tension development which has been interpreted to suggest that the contractions provided a robust mechanical stimulus (11,12,55). The degree to which 1 Hz dynamic stretch replicates that RSNA bursting pattern is unknown.…”

“…We then used the dynamic stretch protocol to gain mechanistic insight into the exaggerated mechanically-sensitive component of the exercise pressor reflex that was found during dynamic contractions in rats with a ligated femoral artery (12). Specifically, in decerebrate, unanesthetized rats we tested the hypothesis that the increase in blood pressure and RSNA would be greater during dynamic stretch of the hindlimb muscles in which the femoral artery was ligated for 72 hours compared to the increases during stretch of the contralateral freely perfused hindlimb muscles.…”