Cyclooxygenase inhibition attenuates sympathetic responses to muscle stretch in humans

Abstract

Cui J, Moradkhan R, Mascarenhas V, Momen A, Sinoway LI. Cyclooxygenase inhibition attenuates sympathetic responses to muscle stretch in humans. Am J Physiol Heart Circ Physiol 294: H2693-H2700, 2008. First published April 25, 2008; doi:10.1152/ajpheart.91505.2007.-Passive muscle stretch performed during a period of post-exercise muscle ischemia (PEMI) increases muscle sympathetic nerve activity (MSNA), and this suggests that the muscle metabolites may sensitize mechanoreceptors in healthy humans. However, the responsible substance(s) has not been studied thoroughly in humans. Human and animal studies suggest that cyclooxygenase products sensitize muscle mechanoreceptors. Thus we hypothesized that local cyclooxygenase inhibition in exercising muscles could attenuate MSNA responses to passive muscle stretch during PEMI. Blood pressure (Finapres), heart rate, and MSNA (microneurography) responses to passive muscle stretch were assessed in 13 young healthy subjects during PEMI before and after cyclooxygenase inhibition, which was accomplished by a local infusion of 6 mg ketorolac tromethamine in saline via Bier block. In the second experiment, the same amount of saline was infused via the Bier block. Ketorolac Bier block decreased prostaglandin synthesis to ϳ34% of the baseline. Before ketorolac Bier block, passive muscle stretch evoked significant increases in MSNA (P Ͻ 0.005) and mean arterial blood pressure (P Ͻ 0.02). After ketorolac Bier block, passive muscle stretch did not evoke significant responses in MSNA (P ϭ 0.11) or mean arterial blood pressure (P ϭ 0.83). Saline Bier block had no effect on the MSNA or blood pressure response to ischemic stretch. These observations indicate that cyclooxygenase inhibition attenuates MSNA responses seen during PEMI and suggest that cyclooxygenase products sensitize the muscle mechanoreceptors.exercise pressor reflex; passive exercise; autonomic nervous system; muscle afferents; regional intravenous anesthesia EXERCISE IS A POTENT STIMULUS to activate the sympathetic nervous system (36). Increases in muscle sympathetic nerve activity (MSNA) during exercise are caused, reflexively, by the stimulation of mechanosensitive and chemosensitive afferents within the contracting muscle (27). Groups III and IV afferent fibers in muscles are suggested to be involved in this reflex (28,43). Whereas group III muscle afferents are predominantly mechanically sensitive, unmyelinated group IV muscle afferents are mainly chemically sensitive (1,2,22,24).A number of animal studies have shown that mechanoreceptor stimulation in cats activates sympathetic efferents to muscles (21) and kidneys (17, 42) and can evoke pressor responses to exercise (16,25,39). Recently, we demonstrated in healthy humans that passive stretch of leg or arm muscles evokes a significant increase in MSNA during the first few seconds of the muscle stretch; however, under freely perfused conditions, the magnitude of the response is small and transient, and the evoked hemodynamic consequences are limited (9, 10).Animal st...

Local adenosine receptor blockade accentuates the sympathetic responses to fatiguing exercise

“…However, it is unknown whether the adenosine produced during intense exercise (e.g., fatiguing exercise) contributes to the sensitization of muscle mechanoreceptors, since adenosine concentration will depend on the strength of the exercise stimulus (6,7,14). In previous studies (9,11), our data demonstrate that passive muscle stretch evokes a further increase in the already elevated MSNA levels seen during postexercise circulatory occlusion (PECO) that follows fatiguing handgrip. This suggested that muscle metabolites (9), including prostaglandins (11), sensitize the muscle mechanoreceptors.…”

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.…”

“…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).…”

Autonomic Adjustments to Exercise in Humans

“…In contrast, Cui et al (47) reported that when static passive wrist extension stretch was applied during postexercise ischemia following fatiguing handgrip exercise significant increases in muscle SNA and BP were evoked, whereas no change in muscle SNA or BP were observed when wrist extension was conducted under free-flow conditions. Although, no HR response to static passive wrist extension was observed under either condition, the sensitization effect on muscle SNA and BP was subsequently shown to be diminished following cyclooxygenase inhibition (48). The reason for the conflicting findings of Fisher et al (84) and Cui et al (47) may relate to differences in muscle group (calf, forearm), exercise mode (nonfatiguing, fatiguing) or method used to induce passive stretch.…”