Augmented exercise pressor reflex function in adenine-induced moderate-stage chronic kidney disease rats: potential role of TRPC6

Background: Blood pressure (BP) responses are exaggerated during exercise in patients with mild to moderate chronic kidney disease (CKD) and in those with end-stage renal disease. A recent study from our group has identified that an overactive exercise pressor reflex (EPR), a reflex originating in contracting skeletal muscle, induces sympathetic overactivation that contributes to hypertensive responses in rats with advanced CKD [estimated glomerular filtration rate (eGFR) < 25% of control]. However, whether the EPR mediates abnormal BP elevations in earlier stages of CKD remains unknown. Transient receptor potential canonical 6 (TRPC6) protein, a calcium-permeable non-selective cation channel, is activated by mechanical stimuli. It is expressed in peripheral nerves and dorsal root ganglia, where it contributes to transmitting peripheral sensory afferent signals to the central nervous system. Previous work by Ducrocq et al. has shown that pharmacological blockade of peripheral TRPC6 channels decreases pressor responses to activation of the EPR including its mechanical component (i.e., the mechanoreflex) in normal healthy rats. However, whether TRPC6 contributes to EPR dysfunction in CKD is unknown. Therefore, the purpose of this preliminary study was to test the hypotheses that the pressor responses to EPR stimulation are augmented in the earlier stages of CKD animals compared with normal healthy control rats, and TRPC6 inhibition attenuates the EPR-mediated pressor responses in CKD animals. Methods: Male Sprague-Dawley rats were randomly divided into either a group fed a control-powdered chow diet or the same powdered food containing adenine (0.25% wt/wt in feed) for 4-7 wks to induce CKD. Subsequently, in decerebrate control (n=4) and CKD (n=5) animals, we measured mean arterial pressure (MAP) and heart rate (HR) in response to isolated EPR activation electrically induced by spinal ventral root stimulation during a 30-s hindlimb muscle contraction (i.e., simulated exercise). In a subset of the CKD group (n=4), cardiovascular responses to EPR stimulation were assessed before and 10-20 min after intra-iliac arterial (IA) administration of 70 μg SAR7334, a potent TRPC6 inhibitor. Results: Adenine treatment induced moderate impairment of kidney function as evidenced by a 57% reduction in eGFR (1.27±0.40 vs. 2.96±0.56 ml/min, P< 0.01, CKD vs. control). We found that CKD animals exhibited augmentations in peak MAP (Δ=41±14 vs. 16±4 mmHg, P< 0.05) and HR (Δ=19±11 vs. 5±2 bpm, P< 0.05) in response to muscle contraction compared with control animals. Importantly, the muscle tension developed during contraction was similar between groups. The integrated changes in MAP (P< 0.05), HR (P< 0.05), and tension presented as area under the curve over 30-s demonstrated similar results. In CKD rats, IA administration of SAR7334 did not significantly reduce the peak MAP response but significantly attenuated the peak HR response (P< 0.05) to muscle contraction. The developed muscle tension during contraction was similar between trials. There was a tendency (P=0.05) for the integrated MAP response to be reduced following IA SAR7334, but did not reach statistical significance. The integrated changes in HR (P< 0.05) and muscle tension showed similar results. Conclusions: Our preliminary findings suggest that EPR function is augmented in moderate-stage CKD (eGFR 40-50% of control), leading to hypertensive responses during exercise. These results also provide evidence supporting further investigation into the potential role of TRPC6 in mediating EPR-induced exaggerated pressor responses during exercise in this disease. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.