Cyclooxygenase products sensitize muscle mechanoreceptors in healthy humans

Abstract

Evidence in healthy animals and humans is accumulating that the muscle mechanoreceptors play an important role in mediating sympathetic activation during exercise, especially rhythmic exercise. Furthermore, muscle mechanoreceptors appear to be sensitized acutely during exercise by metabolic by-products, although the identity of these by-products remains unknown. The purpose of this study was to determine whether the metabolic by-products 1) prostaglandins and/or 2) adenosine sensitize muscle mechanoreceptor control of muscle sympathetic nerve activity (MSNA) in normal humans during rhythmic exercise. MSNA was recorded using microneurography. Muscle mechanoreceptors were activated by low-level rhythmic forearm exercise for 3 min. In 16 healthy humans, intra-arterial indomethacin was infused into the exercising arm to inhibit synthesis of cyclooxygenase products. In 18 healthy humans, intra-arterial aminophylline was infused into the exercising arm to block adenosine receptors. During saline control, MSNA increased significantly during exercise. Inhibition of cyclooxygenase during exercise dramatically and virtually completely eliminated the reflex sympathetic activation. Inhibition of adenosine receptors with aminophylline had no effect on the sympathetic activation during muscle mechanoreceptor stimulation. In conclusion, muscle mechanoreceptors are sensitized by cyclooxygenase products, but not by adenosine, during 3 min of low-level rhythmic handgrip exercise in healthy humans. Further studies of other metabolic by-products and of patients with enhanced muscle mechanoreceptor sensitivity, such as patients with heart failure, are warranted.

Inhibition of cyclooxygenase attenuates the blood pressure response to plantar flexion exercise in peripheral arterial disease

“…The majority of studies in healthy humans have shown that inhibiting exercise-induced prostanoid synthesis attenuates reflex cardiovascular responses (7,8,14,23,25). These studies all used handgrip exercise, and they all administered either indomethacin or ketoprofen.…”

“…Based on the route of administration, we cannot exclude an effect of ketorolac on the central nervous system. An intra-arterial infusion (femoral artery catheter) could theoretically circumvent this problem but would involve a greater risk to the subject; systemic spillover could also occur because the leg has more blood volume than the forearm, which has been used in previous studies (23,24). Moving forward, the key question is whether the heightened exercise pressor response in PAD patients serves a practical purpose (e.g., to improve muscle blood flow and oxygenation) or whether it is just a damaging reflex to the end organs over time (the heart, brain, and kidney).…”

“…A different study (36) in cats showed that intravenous indomethacin attenuated the rise in MAP in response to static hindlimb contraction. Many studies (7,8,14,23,25) in healthy humans have demonstrated that blocking the prostanoid pathway attenuates reflex cardiovascular responses to exercise, although two studies (9, 12) have contradicted these findings. Currently, it is believed that prostanoids are especially important for sensitizing group III afferents during low-intensity dynamic exercise (i.e., before the onset of muscle metaboreflex activation).…”

“…Currently, it is believed that prostanoids are especially important for sensitizing group III afferents during low-intensity dynamic exercise (i.e., before the onset of muscle metaboreflex activation). Indeed, studies in healthy humans (23) and patients with heart failure (24) have shown that intra-arterial indomethacin attenuates the sympathetic nerve response to rhythmic handgrip. The effect of cyclooxygenase inhibition on reflex cardiovascular responses to exercise in patients with PAD is currently unknown.…”

Sweating response to passive stretch of the calf muscle during activation of forearm muscle metaboreceptors in heated humans

“…The former involves muscle metaboreceptor and mechanoreceptor afferent signals integrated at the level of the hypothalamus or medulla oblongata, while the latter involves integration of the two afferents (e.g., sensitization) at the activating muscle level (1,30). When muscle mechanoreceptors and metaboreceptors are activated in the same muscle, both central and peripheral integration would induce physiological responses.…”