Muller MD, Drew RC, Ross AJ, Blaha CA, Cauffman AE, Kaufman MP, Sinoway LI. Inhibition of cyclooxygenase attenuates the blood pressure response to plantar flexion exercise in peripheral arterial disease. Am J Physiol Heart Circ Physiol 309: H523-H528, 2015. First published June 8, 2015 doi:10.1152/ajpheart.00267.2015.-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, ⌬MAP was significantly attenuated by ketorolac (2 Ϯ 2 mmHg) compared with control (8 Ϯ 2 mmHg, P ϭ 0.005), but ⌬HR was similar (6 Ϯ 2 vs. 5 Ϯ 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. PERIPHERAL ARTERIAL DISEASE (PAD) is a form of atherosclerosis that preferentially affects the lower extremity. Because leg blood flow is impaired in PAD, it is not surprising that dynamic exercise, such as walking, provokes pain in the calf, thigh, or buttocks, termed "intermittent claudication." Clinical exercise testing (e.g., the Bruce treadmill protocol) also causes a large increase in blood pressure (BP) in PAD patients, and studies (10, 11) have linked this augmented pressor response to cardiovascular morbidity and mortality. In recent years, our laboratory has focused on BP control in patients with PAD. Specifically, we found that 1) the BP response to single-leg dynamic plantar flexion exercise was augmented in PAD patients compared with healthy control subjects; 2) the pressor response occurred at very low workloads and before the onset of pain; 3) the pressor response correlated with the anklebrachial index (ABI), suggesting that disease severity plays a role; and 4) intravenous infusion of ascorbic acid lowered the pressor response to exercise in PAD (13,28). To date, the mechanisms for these findings are largely unknown. Understanding BP regulation during exercise in PAD ...

Peripheral artery disease (PAD) is an atherosclerotic vascular disease that affects 200 million people worldwide. Although PAD primarily affects large arteries, it is also associated with microvascular dysfunction, an exaggerated blood pressure (BP) response to exercise, and high cardiovascular mortality. We hypothesized that fatiguing plantar flexion exercise that evokes claudication elicits a greater reduction in skeletal muscle oxygenation (SmO) and a higher rise in BP in PAD compared with age-matched healthy subjects, but low-intensity steady-state plantar flexion elicits similar responses between groups. In the first experiment, eight patients with PAD and eight healthy controls performed fatiguing plantar flexion exercise (from 0.5 to 7 kg for up to 14 min). In the second experiment, seven patients with PAD and seven healthy controls performed low-intensity plantar flexion exercise (2.0 kg for 14 min). BP, heart rate (HR), and SmO were measured continuously using near-infrared spectroscopy (NIRS). SmO is the ratio of oxygenated hemoglobin to total hemoglobin, expressed as a percent. At fatigue, patients with PAD had a greater increase in mean arterial BP (18 ± 2 vs. vs. 10 ± 2 mmHg, = 0.029) and HR (14 ± 2 vs. 6 ± 2 beats/min, = 0.033) and a greater reduction in SmO (-54 ± 10 vs. -12 ± 4%, = 0.001). However, both groups had similar physiological responses to low-intensity, nonpainful plantar flexion exercise. These data suggest that patients with PAD have altered oxygen uptake and/or utilization during fatiguing exercise coincident with an augmented BP response. In this laboratory study, patients with peripheral artery disease performed plantar flexion exercise in the supine posture until symptoms of claudication occurred. Relative to age- and sex-matched healthy subjects we found that patients had a higher blood pressure response, a higher heart rate response, and a greater reduction in skeletal muscle oxygenation as determined by near-infrared spectroscopy. Our data suggest that muscle ischemia contributes to the augmented exercise pressor reflex in peripheral artery disease.

The purpose of this study was to investigate blood pressure (BP) and leg skeletal muscle oxygen saturation (Smo) during treadmill walking in patients with peripheral artery disease (PAD) and healthy subjects. Eight PAD patients (66 ± 8 yr, 1 woman) and eight healthy subjects (65 ± 7 yr, 1 woman) walked on a treadmill at 2 mph (0.89 m/s). The incline increased by 2% every 2 min, from 0 to 15% or until maximal discomfort. BP was measured every 2 min with an auscultatory cuff. Heart rate (HR) was recorded continuously with an ECG. Smo in the gastrocnemius muscle was measured on each leg using near-infrared spectroscopy. The change in systolic BP from seated to peak walking time (PWT) was greater in PAD (healthy: 23 ± 9 vs. PAD: 44 ± 19 mmHg, = 0.007). HR was greater in PAD patients compared with controls at PWT ( = 0.011). The reduction in Smo (PWT - seated) was greater in PAD (healthy: 15 ± 12 vs. PAD: 49 ± 5%, < 0.001) in the most affected leg and in the least affected leg (healthy: 12 ± 11 vs. PAD: 32 ± 18%, = 0.003). PAD patients have an exaggerated decline in leg Smo during walking compared with healthy subjects, which may elicit the exaggerated rise in BP and HR during walking in PAD. This is the first study to simultaneously measure skeletal muscle oxygen saturation and blood pressure (BP) during treadmill exercise in patients with peripheral arterial disease. We found that BP and leg deoxygenation responses to slow-paced, graded treadmill walking are greater in patients with peripheral arterial disease compared with healthy subjects. These data may help explain the high cardiovascular risk in patients with peripheral arterial disease.

During exercise, β-adrenergic receptors are activated throughout the body. In healthy humans, the net effect of β-adrenergic stimulation is an increase in coronary blood flow. However, the role of vascular β1 vs. β2 receptors in coronary exercise hyperemia is not clear. In this study, we simultaneously measured noninvasive indexes of myocardial oxygen supply (i.e., blood velocity in the left anterior descending coronary artery; Doppler echocardiography) and demand [i.e., rate pressure product (RPP) = heart rate × systolic blood pressure) and tested the hypothesis that β1 blockade with esmolol improves coronary exercise hyperemia compared with nonselective β-blockade with propranolol. Eight healthy young men received intravenous infusions of esmolol, propranolol, and saline on three separate days in a single-blind, randomized, crossover design. During each infusion, subjects performed isometric handgrip exercise until fatigue. Blood pressure, heart rate, and coronary blood velocity (CBV) were measured continuously, and RPP was calculated. Changes in parameters from baseline were compared with paired -tests. Esmolol (Δ = 3296 ± 1204) and propranolol (Δ = 2997 ± 699) caused similar reductions in peak RPP compared with saline (Δ = 5384 ± 1865). In support of our hypothesis, ΔCBV with esmolol was significantly greater than with propranolol (7.3 ± 2.4 vs. 4.5 ± 1.6 cm/s; = 0.002). This effect was also evident when normalizing ΔCBV to ΔRPP. In summary, not only does selective β1 blockade reduce myocardial oxygen demand during exercise, but it also unveils β2-receptor-mediated coronary exercise hyperemia. In this study, we evaluated the role of vascular β1 vs. β2 receptors in coronary exercise hyperemia in a single-blind, randomized, crossover study in healthy men. In response to isometric handgrip exercise, blood flow velocity in the left anterior descending coronary artery was significantly greater with esmolol compared with propranolol. These findings increase our understanding of the individual and combined roles of coronary β1 and β2 adrenergic receptors in humans.