Interleukin‐1 type 1 receptor blockade attenuates the exaggerated exercise pressor reflex in male UC Davis type 2 diabetic mellitus rats

An exaggerated exercise pressor reflex and peripheral neuropathy are both evoked by the same type of thinly myelinated afferents and are present in patients with type 2 diabetes mellitus (T2DM). Although it is known that the pro-inflammatory cytokine interleukin-1β (IL-1β) contributes to peripheral neuropathy, the effects of IL-1β on the exercise pressor reflex in T2DM are not known. Therefore, we aimed to determine the effect of IL-1 receptors on the exercise pressor reflex in T2DM. We compared changes in peak pressor (mean arterial pressure; ΔMAP), blood pressure index (ΔBPi), heart rate (ΔHR) and heart rate index (ΔHRi) responses to static and intermittent contractions and tendon stretch before and after peripheral IL-1 type 1 receptor blockade (anakinra, Kineret^®) in T2DM and healthy male rats and IL-1 receptor activation (IL-1β) in healthy rats. Blocking IL-1 receptors significantly attenuated the ΔMAP and ΔBPi to static contraction in T2DM rats. Furthermore, blocking IL-1 receptors significantly attenuated the ΔMAP, ΔBPi and ΔHRi to intermittent contraction, and ΔMAP to tendon stretch in T2DM rats (all P < 0.05). In addition, IL-1 receptor activation significantly exaggerated the ΔMAP and ΔBPi to static contraction and ΔMAP, ΔBPi and ΔHR to intermittent contraction in healthy rats, all P < 0.05. Furthermore, circulating IL-1β serum concentrations were significantly greater in T2DM rats than in healthy rats (P < 0.05). We conclude that IL-1 signalling contributes to the exaggerated exercise pressor reflex in T2DM, suggesting for the first time that inflammatory cytokines play a critical role in exaggerated blood pressure responses to exercise in those with T2DM. KEY POINTS: Chronic inflammation, a complication of type 2 diabetes mellitus (T2DM), causes increased production of pro-inflammatory cytokines, such as interleukin (IL)-1β, IL-6, and tumour necrosis factor-α. IL-1β has been shown to sensitize muscle afferents that conduct the exercise pressor reflex. We found blocking of IL-1 receptors by anakinra (Kineret^®), an IL-1 type 1 receptor antagonist, significantly attenuated the exaggerated exercise pressor reflex in T2DM rats, but not in healthy rats. In addition, activating IL-1 receptors with IL-1β significantly augmented the exercise pressor reflex in healthy rats. Our findings suggest that IL-1 receptors, by mediating IL-1β signalling, play a role in exaggerating the exercise pressor reflex in T2DM. These results highlight the complex interplay between inflammation and the autonomic nervous system in regulating cardiovascular function, and the potential for using an FDA-approved IL-1 receptor antagonist, Kineret^®, as a therapeutic approach to reduce adverse cardiovascular events during physical activity in those with T2DM.