Effect of oxidative stress on sympathetic and renal vascular responses to ischemic exercise.

Reactive oxygen species (ROS), produced acutely during skeletal muscle contraction, are known to stimulate group IV muscle afferents and accentuate the exercise pressor reflex (EPR) in rodents. The effect of ROS on the EPR in humans is unknown. We conducted a series of studies using ischemic fatiguing rhythmic handgrip to acutely increase ROS within skeletal muscle, ascorbic acid infusion to scavenge free radicals, and hyperoxia inhalation to further increase ROS production. We hypothesized that ascorbic acid would attenuate the EPR and that hyperoxia would accentuate the EPR. Ten young healthy subjects participated in two or three experimental trials on separate days. Beat-by-beat measurements of heart rate (HR), mean arterial pressure (MAP), muscle sympathetic nerve activity (MSNA), and renal vascular resistance index (RVRI) were measured and compared between treatments (saline and ascorbic acid; room air and hyperoxia). At fatigue, the reflex increases in MAP (31 ± 3 versus 29 ± 2 mmHg), HR (19 ± 3 versus 20 ± 3 bpm), MSNA burst rate (21 ± 4 versus 23 ± 4 burst/min), and RVRI (39 ± 12 versus 44 ± 13%) were not different between saline and ascorbic acid. Relative to room air, hyperoxia did not augment the reflex increases in MAP, HR, MSNA, or RVRI in response to exercise. Muscle metaboreflex activation and time/volume control experiments similarly showed no treatment effects. While contrary to our initial hypotheses, these findings suggest that ROS do not play a significant role in the normal reflex adjustments to ischemic exercise in young healthy humans.

Aspirin augments carotid-cardiac baroreflex sensitivity during muscle mechanoreflex and metaboreflex activation in humans.

Muscle mechanoreflex activation decreases the sensitivity of carotid baroreflex (CBR)-heart rate (HR) control during local metabolite accumulation in humans. However, the contribution of thromboxane A2 (TXA2) toward this response is unknown. Therefore, the effect of inhibiting TXA2 production via low-dose aspirin on CBR-HR sensitivity during muscle mechanoreflex and metaboreflex activation in humans was examined. Twelve young subjects performed two trials during two visits, preceded by 7 days' low-dose aspirin (81 mg) or placebo. One trial involved 3-min passive calf stretch (mechanoreflex) during 7.5-min limb circulatory occlusion (CO). In another trial, CO was preceded by 1.5 min of 70% maximal voluntary contraction isometric calf exercise to accumulate metabolites during CO and stretch (mechanoreflex and metaboreflex). HR (ECG) and mean arterial pressure (Finometer) were recorded. CBR function was assessed using rapid neck pressures ranging from +40 to -80 mmHg. Aspirin significantly decreased baseline thromboxane B2 production by 84 ± 4% (P < 0.05) but did not affect 6-keto prostaglandin F1α. Following aspirin, stretch with metabolite accumulation significantly augmented maximal gain (GMAX) and operating point gain (GOP) of CBR-HR (GMAX; -0.71 ± 0.14 vs. -0.37 ± 0.08 and GOP; -0.69 ± 0.13 vs. -0.35 ± 0.12 beats·min(-1)·mmHg(-1) for aspirin and placebo, respectively; P < 0.05). CBR-HR function curves were reset similarly with aspirin and placebo during stretch with metabolite accumulation. In conclusion, these findings suggest that low-dose aspirin augments CBR-HR sensitivity during concurrent muscle mechanoreflex and metaboreflex activation in humans. This increased sensitivity appears linked to reduced TXA2 production, which likely plays a role in metabolite sensitization of muscle mechanoreceptors.

Effect of healthy aging on renal vascular responses to local cooling and apnea.

Sympathetically mediated renal vasoconstriction may contribute to the pathogenesis of hypertension in older adults, but empirical data in support of this concept are lacking. In 10 young (26 ± 1 yr) and 11 older (67 ± 2 yr) subjects, we quantified acute hemodynamic responses to three sympathoexcitatory stimuli: local cooling of the forehead, cold pressor test (CPT), and voluntary apnea. We hypothesized that all stimuli would increase mean arterial blood pressure (MAP) and renal vascular resistance index (RVRI) and that aging would augment these effects. Beat-by-beat MAP, heart rate (HR), and renal blood flow velocity (from Doppler) were measured in the supine posture, and changes from baseline were compared between groups. In response to 1°C forehead cooling, aging was associated with an augmented MAP (20 ± 3 vs. 6 ± 2 mmHg) and RVRI (35 ± 6 vs. 16 ± 9%) but not HR. In older adults, there was a positive correlation between the cold-induced pressor response and forehead pain (R = 0.726), but this effect was not observed in young subjects. The CPT raised RVRI in both young (56 ± 13%) and older (45 ± 8%) subjects, but this was not different between groups. Relative to baseline, end-expiratory apnea increased RVRI to a similar extent in both young (46 ± 14%) and older (41 ± 9%) subjects. During sympathetic activation, renal vasoconstriction occurred in both groups. Forehead cooling caused an augmented pressor response in older adults that was related to pain perception.

Tactile stimulation of the oropharynx elicits sympathoexcitation in conscious humans.

Tactile stimulation of the oropharynx (TSO) elicits the gag reflex and increases heart rate (HR) and mean arterial pressure (MAP) in anesthetized patients. However, the interaction between upper-airway defense reflexes and the sympathetic nervous system has not been investigated in conscious humans. In Experiment 1, beat-by-beat measurements of HR, MAP, muscle sympathetic nerve activity (MSNA), and renal vascular resistance (RVR) were measured during TSO and tactile stimulation of the hard palate (Sham) in the supine posture. In Experiment 2, TSO was performed before (pre) and after (post) inhalation of 4% lidocaine via nebulizer. Rate pressure product (RPP) was determined. Compared with Sham, TSO elicited the gag reflex and increased RPP [absolute change (Δ)36 ± 6 vs. 17 ± 5%], MSNA (Δ122 ± 39 vs. 19 ± 19%), and RVR (Δ55 ± 11 vs. 4 ± 4%). This effect occurred within one to two cardiac cycles of TSO. The ΔMAP (12 ± 3 vs. 6 ± 1 mmHg) and the ΔHR (10 ± 3 vs. 3 ± 3 beats/min) were also greater following TSO compared with Sham. Lidocaine inhalation blocked the gag reflex and attenuated increases in MAP (Δpre: 16 ± 2; Δpost: 5 ± 2 mmHg) and HR (Δpre: 12 ± 3; Δpost: 2 ± 2 beats/min) in response to TSO. When mechanically stimulated, afferents in the oropharynx not only serve to protect the airway but also cause reflex increases in MSNA, RVR, MAP, and HR. An augmented sympathoexcitatory response during intubation and laryngoscopy may contribute to perioperative cardiovascular morbidity and mortality.

Renal vasoconstriction is augmented during exercise in patients with peripheral arterial disease.

Peripheral arterial disease (PAD) patients have augmented blood pressure increases during exercise, heightening their cardiovascular risk. However, it is unknown whether patients have exaggerated renal vasoconstriction during exercise and if oxidative stress contributes to this response. Eleven PAD patients and 10 controls (CON) performed 4-min mild, rhythmic, plantar flexion exercise of increasing intensity (0.5-2 kg) with each leg (most and least affected in PAD). Eight patients also exercised with their most affected leg during ascorbic acid (AA) infusion. Renal blood flow velocity (RBFV; Doppler ultrasound), mean arterial blood pressure (MAP; Finometer), and heart rate (HR; electrocardiogram [ECG]) were measured. Renal vascular resistance (RVR), an index of renal vasoconstriction, was calculated as MAP/RBFV. Baseline RVR and MAP were similar while HR was higher in PAD than CON (2.08 ± 0.23 vs. 1.87 ± 0.20 au, 94 ± 3 vs. 93 ± 3 mmHg, and 72 ± 3 vs. 59 ± 3 bpm [P < 0.05] for PAD and CON, respectively). PAD had greater RVR increases during exercise than CON, specifically during the first minute (PAD most: 26 ± 5% and PAD least: 17 ± 5% vs. CON: 3 ± 3%; P < 0.05). AA did not alter baseline RVR, MAP, or HR. AA attenuated the augmented RVR increase in PAD during the first minute of exercise (PAD most: 33 ± 4% vs. PAD most with AA: 21 ± 4%; P < 0.05). In conclusion, these findings suggest that PAD patients have augmented renal vasoconstriction during exercise, with oxidative stress contributing to this response.

Cardiac mechanics are impaired during fatiguing exercise and cold pressor test in healthy older adults.

We sought to determine how the aging left ventricle (LV) responds to sympathetic nervous system (SNS) activation. Three separate echocardiographic experiments were conducted in 11 healthy young (26 ± 1 yr) and 11 healthy older (64 ± 1 yr) adults. Tissue Doppler imaging was used to measure systolic myocardial velocity (S(m)), early diastolic myocardial velocity (E(m)), and late diastolic myocardial velocity (A(m)) during isometric fatiguing handgrip (IFHG), a 2-min cold pressor test (CPT), and 5 min of normobaric hypoxia. Heart rate (HR) and mean arterial pressure (MAP) were also monitored on a beat-by-beat basis; rate pressure product (RPP) was used as an index of myocardial oxygen demand. At peak IFHG, the groups had similar increases in RPP, but the ΔS(m) was significantly greater (i.e., larger impairment) in the older subjects (-0.82 ± 0.13 cm/s) compared with the young subjects (0.37 ± 0.30 cm/s). At peak IFHG, the ΔE(m) was similar between older (-1.59 ± 0.68 cm/s) and young subjects (-1.06 ± 0.76 cm/s). In response to the CPT, both S(m) and E(m) were reduced in the older adults but did not change relative to baseline in the young subjects. Normobaric hypoxia elevated HR and RPP in both groups but did not alter Tissue Doppler parameters. These data indicate that S(m) and E(m) are reduced in healthy older adults during IFHG and CPT. We speculate that suboptimal LV adaptations to SNS stress may partly explain why acute heavy exertion can trigger myocardial ischemia.

Oxidative stress contributes to the augmented exercise pressor reflex in peripheral arterial disease patients.

Exaggerated blood pressure (BP) responses to dynamic exercise predict cardiovascular mortality in patients with peripheral arterial disease (PAD). However, the underlying mechanisms are unclear and no attempt has been made to attenuate this response using antioxidants. Three physiological studies were conducted in patients with PAD and controls. In Protocol 1, subjects underwent 4 min of low-intensity (0.5-2.0 kg), rhythmic plantar flexion in the supine posture. In Protocol 2, patients with PAD received high-dose ascorbic acid intravenously before exercise. In Protocol 3, involuntary exercise was conducted via electrical stimulation of the tibial nerve. The primary outcome measure was Δ mean arterial pressure (MAP) during the first 20 s of exercise (i.e. the onset of sympathoexcitation by muscle afferents). Compared to controls, patients with PAD had significantly greater ΔMAP during plantar flexion, particularly at 0.5 kg with the most affected leg (11 ± 2 vs. 2 ± 1 mmHg) as well as the least affected leg (7 ± 1 vs. 1 ± 1 mmHg). This augmented response occurred before the onset of claudication pain and was attenuated by ∼50% with ascorbic acid. Electrically evoked exercise also elicited larger haemodynamic changes in patients with PAD compared to controls. Further, the ΔMAP during 0.5 kg plantar flexion inversely correlated with the ankle-brachial index, indicating that patients with more severe resting limb ischaemia have a larger BP response to exercise. The BP response to low-intensity exercise was enhanced in PAD. Chronic limb ischaemia may sensitize muscle afferents and potentiate the BP response to muscle contraction in a dose-dependent manner.

Aging attenuates the coronary blood flow response to cold air breathing and isometric handgrip in healthy humans.

The purpose of this echocardiography study was to measure peak coronary blood flow velocity (CBV(peak)) and left ventricular function (via tissue Doppler imaging) during separate and combined bouts of cold air inhalation (-14 ± 3°C) and isometric handgrip (30% maximum voluntary contraction). Thirteen young adults and thirteen older adults volunteered to participate in this study and underwent echocardiographic examination in the left lateral position. Cold air inhalation was 5 min in duration, and isometric handgrip (grip protocol) was 2 min in duration; a combined stimulus (cold + grip protocol) and a cold pressor test (hand in 1°C water) were also performed. Heart rate, blood pressure, O(2) saturation, and inspired air temperature were monitored on a beat-by-beat basis. The rate-pressure product (RPP) was used as an index of myocardial O(2) demand, and CBV(peak) was used as an index of myocardial O(2) supply. The RPP response to the grip protocol was significantly blunted in older subjects (Δ1,964 ± 396 beats·min(-1)·mmHg) compared with young subjects (Δ3,898 ± 452 beats·min(-1)·mmHg), and the change in CBV(peak) was also blunted (Δ6.3 ± 1.2 vs. 11.2 ± 2.0 cm/s). Paired t-tests showed that older subjects had a greater change in the RPP during the cold + grip protocol [Δ2,697 ± 391 beats·min(-1)·mmHg compared with the grip protocol alone (Δ2,115 ± 375 beats·min(-1)·mmHg)]. An accentuated RPP response to the cold + grip protocol (compared with the grip protocol alone) without a concomitant increase in CBV(peak) may suggest a dissociation between the O(2) supply and demand in the coronary circulation. In conclusion, older adults have blunted coronary blood flow responses to isometric exercise.