Intrathecal fentanyl abolishes the exaggerated blood pressure response to cycling in hypertensive men

Abstract

The increase in blood pressure observed during physical activities is exaggerated in patients with hypertension, exposing them to a higher cardiovascular risk. Neural signals from the skeletal muscles appear to be overactive, resulting in this abnormal response in hypertensive patients. In the present study, we tested whether the attenuation of these neural signals in hypertensive patients could normalize their abnormal increase in blood pressure during physical activity. Attenuation of the neural signals from the leg muscles with intrathecal fentanyl injection reduced the blood pressure of hypertensive men during cycling exercise to a level comparable to that of normotensive men. Skeletal muscle afferent overactivity causes the abnormal cardiovascular response to exercise and was reverted in this experimental model, appearing as potential target for treatment. Hypertensive patients present an exaggerated increase in blood pressure and an elevated cardiovascular risk during exercise. Although controversial, human studies suggest that group III and IV skeletal muscle afferents might contribute to this abnormal response. In the present study, we investigated whether attenuation of the group III and IV muscle afferent signal of hypertensive men eliminates the exaggerated increase in blood pressure occurring during exercise. Eight hypertensive men performed two sessions of 5 min of cycling exercise at 40 W. Between sessions, the subjects were provided with a lumbar intrathecal injection of fentanyl, a μ-opioid receptor agonist, aiming to attenuate the central projection of opioid-sensitive group III and IV muscle afferent nerves. The cardiovascular response to exercise of these subjects was compared with that of six normotensive men. During cycling, the hypertensive group demonstrated an exaggerated increase in blood pressure compared to the normotensive group (mean ± SEM: +17 ± 3 vs. +8 ± 1 mmHg, respectively; P < 0.05), whereas the increase in heart rate, stroke volume, cardiac output and vascular conductance was similar (P > 0.05). Fentanyl inhibited the blood pressure response to exercise in the hypertensive group (+11 ± 2 mmHg) to a level comparable to that of the normotensive group (P > 0.05). Moreover, fentanyl increased the responses of vascular conductance and stroke volume to exercise (P < 0.05), whereas the heart rate response was attenuated (P < 0.05) and the cardiac output response was maintained (P > 0.05). The results of the present study show that attenuation of the exercise pressor reflex normalizes the blood pressure response to cycling exercise in hypertensive individuals.

Figure 1. Timeline of experimental procedures

The FENT exercise session was identical to the CTRL exercise session, except for the MVC trials. Normotensive subjects performed the CTRL cycling only.

Figure 2. Representative original data

Blood pressure tracing from one hypertensive subject during the trials of cycling before and after intrathecal fentanyl administration.

Figure 3. Blood pressure response to cycling in hypertensive and normotensive subjects

A, responses of mean BP during each minute of cycling. HT CTRL (black circles), hypertensive subjects before fentanyl administration; HT FENT (grey triangles), hypertensive subjects after fentanyl administration; NT (white squares), normotensive subjects; BL, resting baseline. Data are the mean ± SEM. *P < 0.05 HT CTRL vs. NT. †P < 0.05 HT CTRL vs. HT FENT. B, individual mean BP change from resting baseline at the second minute of cycling. Connecting lines indicate that, except for one individual, the BP response of every hypertensive subject to cycling exercise was lower after fentanyl. These statistical comparisons had equivalent results from the first to the fifth minutes. HT CTRL (black circles), hypertensive subjects before fentanyl administration; HT FENT (grey triangles), hypertensive subjects after fentanyl administration; NT (white squares), normotensive subjects.

Figure 4. Cardiovascular responses to cycling in hypertensive and normotensive subjects

Responses of heart rate (A), stroke volume (B), cardiac output (C) and total vascular conductance (D) during each minute of cycling. HT CTRL (black circles), hypertensive subjects before fentanyl administration; HT FENT (grey triangles), hypertensive subjects after fentanyl administration; NT (white squares), normotensive subjects. BL, resting baseline. Data are the mean ± SEM. ^† P < 0.05 HT CTRL vs. HT FENT.