The Mechano‐gated Channel Inhibitor GsMTx4 Reduces the Exercise Pressor Reflex in Decerebrate Rats

Mechanical and metabolic stimuli arising within contracting skeletal muscles evoke reflex autonomic and cardiovascular adjustments to exercise. In cats and rats, gadolinium has been used to study the role played by the mechanical component of this reflex, termed the exercise pressor reflex. Gadolinium, however, has poor selectivity for mechano‐gated channels and may exert multiple off‐target effects. We tested the hypothesis that GsMTX4, a more selective mechano‐gated channel inhibitor than gadolinium and a particularly potent inhibitor of mechano‐gated Piezo channels, reduced the exercise pressor reflex. We measured the pressor, cardio accelerator, and renal sympathetic nerve responses to 30 seconds of Achilles tendon stretch and 30 seconds of electrically‐induced intermittent hindlimb muscle contraction before and after injection of 10 μg of GsMTx4 into the arterial supply of the hindlimb of decerebrate, unanesthetized rats. In six rats, intra‐arterial injection of GsMTx4 reduced the peak pressor (control: 24±5, GsMTx4: 12±5 mmHg, p<0.01), cardio accelerator and renal sympathetic nerve responses to tendon stretch, which is a purely mechanical stimulus. In contrast, GsMTx4 had no effect on the pressor responses to intra‐arterial injection of α,β‐methylene ATP (20 μg/kg, control: 19±5, GsMTx4: 20±5 mmHg, p=0.72) or lactic acid (24 mM, control: 49±7, GsMTx4: 53±11 mmHg, p=0.71), findings which indicated that GsMTx4 did not block metabolically‐sensitive channels. In eight rats, intra‐arterial injection of GsMTx4 reduced the peak pressor (control: 24±2, GsMTx4: 14±3 mmHg, p<0.01), cardio accelerator, and renal sympathetic nerve responses to electrically‐induced intermittent hindlimb muscle contractions, which is a mixed mechanical and metabolic stimulus. In contrast to intra‐arterial injection, injection of GsMTx4 into the jugular vein had no effect on the pressor, cardio accelerator, or renal sympathetic nerve responses to either tendon stretch (n=5) or intermittent contraction (n=6), findings which indicated that GsMTx4 did not reduce the exercise pressor reflex by exerting effects within the central nervous system. In all experiments the developed tension and the tension‐time integrals were not different between control and GsMTx4 conditions (p>0.05 for all). Quantitative RT‐PCR and Western blot analyses indicated that both classes of Piezo channel isoforms, namely Piezo1 and Piezo2, were natively expressed in rat dorsal root ganglia tissue (n=3). We conclude that GsMTx4 reduced the exercise pressor reflex in decerebrate rats and that the reduction was likely attributable, at least in part, to its effect on mechano‐gated Piezo channels. Our findings may have important implications in conditions such as hypertension, heart failure, and peripheral artery disease in which the mechanically‐sensitive component of the exercise pressor reflex has been found to contribute to the exaggerated pressor responses to exercise seen in those pathophysiological states. Support or Funding Information NIH HL‐096570 and AR‐059397