Does a single oral administration of amiloride affect spontaneous arterial baroreflex sensitivity and blood pressure variability in healthy young adults?

Preclinical models indicate that amiloride (AMD) reduces baroreflex sensitivity and perturbs homeostatic blood pressure (BP) regulation. However, it remains unclear whether these findings translate to humans. This study investigated whether oral administration of AMD reduces spontaneous cardiac and sympathetic baroreflex sensitivity and perturbs BP regulation in healthy young humans. Heart rate (HR; electrocardiography), beat-to-beat BP (photoplethysmography), and muscle sympathetic activity (MSNA, microneurography) were continuously measured in 10 young subjects (4 females) during rest across two randomized experimental visits: 1) after 3 h of oral administration of placebo (PLA, 10 mg of methylcellulose within a gelatin capsule) and 2) after 3 h of oral administration of AMD (10 mg). Visits were separated for at least 48 h. We calculated the standard deviation and other indices of BP variability. Spontaneous cardiac baroreflex was assessed via the sequence technique and cardiac autonomic modulation through time- and frequency-domain HR variability. The sensitivity (gain) of the sympathetic baroreflex was determined via weighted linear regression analysis between MSNA and diastolic BP. AMD did not affect HR, BP, and MSNA compared with PLA. Indexes of cardiac autonomic modulation (time- and frequency-domain HR variability) and BP variability were also unchanged after AMD ingestion. Likewise, AMD did not modify the gain of both spontaneous cardiac and sympathetic arterial baroreflex. A single oral dose of AMD does not affect spontaneous arterial baroreflex sensitivity and BP variability in healthy young adults.NEW & NOTEWORTHY Preclinical models indicate that amiloride (AMD), a nonselective antagonist of the acid-sensing ion channels (ASICs), impairs baroreflex sensitivity and perturbs blood pressure regulation. We translated these findings into humans, investigating the impact of acute oral ingestion of AMD on blood pressure variability and spontaneous cardiac and sympathetic baroreflex sensitivity in healthy young humans. In contrast to preclinical evidence, AMD does not impair spontaneous arterial baroreflex sensitivity and blood pressure variability in healthy young adults.

Effects of acute hyperoxia on autonomic function and coronary tone in patients with peripheral artery disease.

Numerous studies have shown that oxidative stress plays an important role in peripheral artery disease (PAD). Prior reports suggested autonomic dysfunction in PAD. We hypothesized that responses of the autonomic nervous system and coronary tone would be impaired in patients with PAD during exposure to acute hyperoxia, an oxidative stressor. In 20 patients with PAD and 16 healthy, sex- and age-matched controls, beat-by-beat heart rate (HR, from ECG) and blood pressure (BP, with Finometer) were recorded for 10 min during room air breathing and 5 min of hyperoxia. Cardiovagal baroreflex sensitivity and HR variability (HRV) were evaluated as measures of autonomic function. Transthoracic coronary echocardiography was used to assess peak coronary blood flow velocity (CBV) in the left anterior descending coronary artery. Cardiovagal baroreflex sensitivity at rest was lower in PAD than in healthy controls. Hyperoxia raised BP solely in the patients with PAD, with no change observed in healthy controls. Hyperoxia induced an increase in cardiac parasympathetic activity assessed by the high-frequency component of HRV in healthy controls but not in PAD. Indices of parasympathetic activity were lower in PAD than in healthy controls throughout the trial as well as during hyperoxia. Hyperoxia induced coronary vasoconstriction in both groups, while the coronary perfusion time fraction was lower in PAD than in healthy controls. These results suggest that the response in parasympathetic activity to hyperoxia (i.e., oxidative stress) is blunted and the coronary perfusion time is shorter in patients with PAD.NEW & NOTEWORTHY Patients with peripheral artery disease (PAD) showed consistently lower parasympathetic activity and blunted cardiovagal baroreflex sensitivity compared with healthy individuals. Notably, hyperoxia, which normally boosts parasympathetic activity in healthy individuals, failed to induce this response in patients with PAD. These data suggest altered autonomic responses during hyperoxia in PAD.

Central and peripheral modulation of exercise pressor reflex sensitivity after nonfatiguing work.

Autonomic blood pressure control is fundamentally altered during a single bout of exercise, as evidenced by the downward resetting of the baroreflex following exercise (postexercise hypotension). However, it is unclear if an acute bout of exercise is also associated with a change in the sensitivity of the exercise pressor response to a controlled stimulus, such as a static contraction. This study tested the hypothesis that the blood pressure response to a controlled static contraction would be attenuated after unilateral cycling of the contralateral (opposite) leg, but preserved after cycling of the ipsilateral (same) leg. To test this, the blood pressure response to 90 s of isometric plantar flexion [50% maximal voluntary contraction (MVC)] was compared before and after 20 min of contralateral and ipsilateral single-leg cycling at 20% peak oxygen consumption and rest (control) in 10 healthy subjects (three males and seven females). The mean arterial pressure response was significantly attenuated after contralateral single-leg cycling (+9.8 ± 7.5% ∆mmHg vs. +6.7 ± 6.6% ∆mmHg pre and postexercise, respectively, P = 0.04) and rest (+9.0 ± 7.5% ∆mmHg vs. +6.6 ± 5.2% ∆mmHg pre and postexercise, respectively, P = 0.03). In contrast, the pressor response nonsignificantly increased following ipsilateral single-leg cycling (+5.5 ± 5.2% ∆mmHg vs. +8.9 ± 7.2% ∆mmHg pre and postexercise, respectively, P = 0.08). The heart rate, leg blood flow, and leg conductance responses to plantar flexion were not affected by any condition (P ≥ 0.12). These results are consistent with the notion that peripheral, but not central mechanisms promote exercise pressor reflex sensitivity after exercise.

Endurance training attenuates the increase in peripheral chemoreflex sensitivity with intermittent hypoxia.

Patients with heart failure and sleep apnea have greater chemoreflex sensitivity, presumably due to intermittent hypoxia (IH), and this is predictive of mortality. We hypothesized that endurance training would attenuate the effect of IH on peripheral chemoreflex sensitivity in healthy humans. Fifteen young healthy subjects (9 female, 26 ± 1 yr) participated. Between visits, 11 subjects underwent 8 wk of endurance training that included running four times/wk at 80% predicted maximum heart rate and interval training, and four control subjects did not change activity. Chemoreflex sensitivity (the slope of ventilation responses to serial oxygen desaturations), blood pressure, heart rate, and muscle sympathetic nerve activity (MSNA) were assessed before and after 30 min of IH. Endurance training decreased resting systolic blood pressure (119 ± 3 to 113 ± 3 mmHg; P = 0.027) and heart rate (67 ± 3 to 61 ± 2 beats/min; P = 0.004) but did not alter respiratory parameters at rest (P > 0.2). Endurance training attenuated the IH-induced increase in chemoreflex sensitivity (pretraining: Δ 0.045 ± 0.026 vs. posttraining: Δ -0.028 ± 0.040 l·min-1·% O2 desaturation-1; P = 0.045). Furthermore, IH increased mean blood pressure and MSNA burst rate before training (P < 0.05), but IH did not alter these measures after training (P > 0.2). All measurements were similar in the control subjects at both visits (P > 0.05). Endurance training attenuates chemoreflex sensitization to IH, which may partially explain the beneficial effects of exercise training in patients with cardiovascular disease.

Coronary Exercise Hyperemia Is Impaired in Patients with Peripheral Arterial Disease.

BACKGROUND: Peripheral arterial disease (PAD) is an atherosclerotic vascular disease that affects over 200 million people worldwide. The hallmark of PAD is ischemic leg pain and this condition is also associated with an augmented blood pressure response to exercise, impaired vascular function, and high risk of myocardial infarction and cardiovascular mortality. In this study, we tested the hypothesis that coronary exercise hyperemia is impaired in PAD. METHODS: Twelve patients with PAD and no overt coronary disease (65 ± 2 years, 7 men) and 15 healthy control subjects (64 ± 2 years, 9 men) performed supine plantar flexion exercise (30 contractions/min, increasing workload). A subset of subjects (n = 7 PAD, n = 8 healthy) also performed isometric handgrip exercise (40% of maximum voluntary contraction to fatigue). Coronary blood velocity in the left anterior descending artery was measured by transthoracic Doppler echocardiography; blood pressure and heart rate were monitored continuously. RESULTS: Coronary blood velocity responses to 4 min of plantar flexion exercise (PAD: Δ2.4 ± 1.2, healthy: Δ6.0 ± 1.6 cm/sec, P = 0.039) and isometric handgrip exercise (PAD: Δ8.3 ± 4.2, healthy: Δ16.9 ± 3.6, P = 0.033) were attenuated in PAD patients. CONCLUSION: These data indicate that coronary exercise hyperemia is impaired in PAD, which may predispose these patients to myocardial ischemia.

Muscle oxygenation during dynamic plantar flexion exercise: combining BOLD MRI with traditional physiological measurements.

Blood-oxygen-level-dependent magnetic resonance imaging (BOLD MRI) has the potential to quantify skeletal muscle oxygenation with high temporal and high spatial resolution. The purpose of this study was to characterize skeletal muscle BOLD responses during steady-state plantar flexion exercise (i.e., during the brief rest periods between muscle contraction). We used three different imaging modalities (ultrasound of the popliteal artery, BOLD MRI, and near-infrared spectroscopy [NIRS]) and two different exercise intensities (2 and 6 kg). Six healthy men underwent three separate protocols of dynamic plantar flexion exercise on separate days and acute physiological responses were measured. Ultrasound studies showed the percent change in popliteal velocity from baseline to the end of exercise was 151 ± 24% during 2 kg and 589 ± 145% during 6 kg. MRI studies showed an abrupt decrease in BOLD signal intensity at the onset of 2 kg exercise, indicating deoxygenation. The BOLD signal was further reduced during 6 kg exercise (compared to 2 kg) at 1 min (-4.3 ± 0.7 vs. -1.2 ± 0.4%, P < 0.001). Similarly, the change in the NIRS muscle oxygen saturation in the medial gastrocnemius was -11 ± 4% at 2 kg and -38 ± 11% with 6 kg (P = 0.041). In conclusion, we demonstrate that BOLD signal intensity decreases during plantar flexion and this effect is augmented at higher exercise workloads.

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

Prostanoids are produced during skeletal muscle contraction and subsequently stimulate muscle afferent nerves, thereby contributing to the exercise pressor reflex. Humans with peripheral arterial disease (PAD) have an augmented exercise pressor reflex, but the metabolite(s) responsible for this augmented response is not known. We tested the hypothesis that intravenous injection of ketorolac, which blocks the activity of cyclooxygenase, would attenuate the rise in mean arterial blood pressure (MAP) and heart rate (HR) evoked by plantar flexion exercise. Seven PAD patients underwent 4 min of single-leg dynamic plantar flexion (30 contractions/min) in the supine posture (workload: 0.5-2.0 kg). MAP and HR were measured on a beat-by-beat basis; changes from baseline in response to exercise were determined. Ketorolac did not affect MAP or HR at rest. During the first 20 s of exercise with the most symptomatic leg, ΔMAP was significantly attenuated by ketorolac (2 ± 2 mmHg) compared with control (8 ± 2 mmHg, P = 0.005), but ΔHR was similar (6 ± 2 vs. 5 ± 1 beats/min). Importantly, patients rated the exercise bout as "very light" to "fairly light," and average pain ratings were 1 of 10. Ketorolac had no effect on perceived exertion or pain ratings. Ketorolac also had no effect on MAP or HR in seven age- and sex-matched healthy subjects who performed a similar but longer plantar flexion protocol (workload: 0.5-7.0 kg). These data suggest that prostanoids contribute to the augmented exercise pressor reflex in patients with PAD.