Contribution of TRPC channels in evoking the exercise pressor reflex and mechanoreflex in healthy and type 1 diabetic rats

Abstract

The exercise pressor reflex and the mechanoreflex are exaggerated in type 1 diabetes mellitus (T1DM) rats. Studies using GsMTx‐4, which has high potency for Piezo channels, have suggested that Piezo channels play a significant role in evoking this exaggerated response. However, studies have also reported that GsMTx‐4 may block TRPC1 and TRPC6 channels at similar concentrations. Therefore, to account for the possible effects of GsMTx‐4 on TRPC1 and TRPC6 channels, the purpose of this study was to determine whether TRPC channels contribute to the exercise pressor reflex and the mechanoreflex in both healthy and T1DM rats.MethodsStudies were conducted in adult unanesthetized, decerebrated T1DM (STZ; Streptozotocin 50 mg/kg i.p) and healthy control (CTL) Sprague Dawley rats. The exercise pressor reflex was evoked by intermittently contracting the hindlimb for 30 s and the mechanoreflex was evoked by stretching the Achilles tendon for 30 s. Changes in mean arterial pressure (MAP), heart rate (HR) and renal sympathetic nerve activity (RSNA) were continuously measured and compared before and after injecting a TRPC channel antagonist, namely SKF 96365 (0.1ml, 10μM or 100μM).ResultsSKF 96365 (100μM) had no effect on the peak pressor response to muscle contraction in either STZ rats (ΔMAP before: 37 ± 9 mmHg, ΔMAP after: 32 ± 12 mmHg, n=2, p>0.05) or CTL rats (before: 16 ± 3 mmHg, after: 5 ± 2 mmHg, n=3, p>0.05). The cardioaccelerator response to muscle contraction was unaffected by SKF 96365 in STZ rats (before: 25 ± 1 bpm, after: 21 ± 6 bpm, n=2, p>0.05), whereas it was attenuated in CTL rats (before: 13 ± 4 bpm, after: 4 ± 4 bpm, n=3, p<0.05). The sympathetic response to muscle contraction was unaffected by SKF 96365 in CTL rats (%ΔRSNA before: 138 ± 108 %, %ΔRSNA after: 181 ± 41 %, n=2, p>0.05). The peak pressor response to tendon stretch was unaffected by SKF 96365 in STZ (before: 42 ± 9 mmHg, after: 34 ± 10 mmHg, n=3, p>0.05) and CTL rats (before: 16 ± 3 mmHg, after: 16 ± 2 mmHg, n=4, p>0.05). Likewise, the cardioaccelerator response to tendon stretch was unaffected by SKF 96365 in STZ (before: 25 ± 4 bpm, after: 36 ± 12 bpm, n=3, p>0.05) and CTL rats (before: 13 ± 2 bpm, after: 14 ± 2 bpm, n=4, p>0.05). The sympathetic response to tendon stretch was unaffected by SKF 96365 in CTL rats (%ΔRSNA before: 98 ± 94 %, %ΔRSNA after: 94 ± 104 %, n=2, p>0.05). Furthermore, a lower concentration of SKF 96365 (10μM) had no effect on the peak pressor (before: 33 ± 20 mmHg, after: 31 ± 18 mmHg, n=2, p>0.05) or cardioaccelerator (before: 23 ± 9 bpm, after: 22 ± 6 bpm, p>0.05) responses to muscle contraction in STZ rats. Similarly, the peak pressor (before: 29 ± 15 mmHg, after: 16 ± 3 mmHg, n=2, p>0.05) and cardioaccelerator (before: 29 ± 15 bpm, after: 16 ± 3 bpm, n=2, p>0.05) responses to tendon stretch were unaffected by SKF 96365 (10μM) in STZ rats.ConclusionThese preliminary findings suggest that TRPC channels do not play a role in evoking the exercise pressor reflex or the mechanoreflex in T1DM and healthy rats. Thus, it is unlikely that the attenuating effect of GsMTx‐4 on the exercise pressor reflex is due to its effect on TRPC channels.