UW-Madison Department of Kinesiology - Bill Schrage

Publications

• Blain, G.M., Limberg, J.K., Mortenson, G.F., & Schrage, W.G. (2012). Rapid onset vasodilation is blunted in obese humans. Acta Physiologica. pp. 1408-1416.
  Abstract: Aim: Conduit artery function in obese humans is frequently assessed at rest, but very little is known about resistance artery function in response to muscle contraction. We tested the hypothesis that obese adults will exhibit reduced contraction-induced rapid onset vasodilatation. Single and brief forearm contractions were used to isolate the local effects of muscle contraction on the forearm vasodilatory response, independent of systemic haemodynamic and sympathetic neural influence. Methods: We measured forearm blood flow (Doppler ultrasound), blood pressure (finger photoplethysmography) and heart rate (electrocardiogram) on a beat-by-beat basis in 14 obese (body mass index = 36.2 1.7 kg m)2) and 14 lean (body mass index = 21.6 0.7 kg m)2) young (18–40 years) adults. Percent changes from baseline in forearm vascular conductance (FVC%) were calculated in response to single, brief forearm contractions performed in random order at 15, 20, 25, 30, 40 and 50% of maximal voluntary contraction (MVC). Results: In both groups, each single contraction evoked a significant (P < 0.05), immediate (within one cardiac cycle) and graded FVC% increase from one up to six cardiac cycles post-contraction. Immediate (20–50% MVC), peak (15–50% MVC) and total (area under the curve, 20–50% MVC) vasodilatory responses were reduced with obesity. The degree of impaired vasodilatation increased with increasing workloads. Conclusions: These novel findings demonstrate a blunted contraction-induced rapid onset vasodilatation with obesity that is exercise intensity dependent. Impaired rapid onset vasodilatation may negatively impact haemodynamic responses to everyday intermittent activities performed by obese humans. Keywords
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• Limberg, J.K., & Schrage, W.G. (2011). Hypoxia: Just say NO? Journal of Physiology. 589(9), 2111-12.
• Limberg, J.K., Eldridge, M.W., Proctor, L.T., Sebranek, J.J., & Schrage, W.G. (2010). Alpha-adrenergic control of blood flow during exercise: effect of sex and menstrual phase. J. Appl Physiology. 109(5), 1360-68.
  Abstract: Sex differences exist in autonomic control of the cardiovascular system. This study was designed to directly test sex or female menstrual phase-related differences in α-adrenergic control of blood flow during exercise. We hypothesized that women would exhibit reduced α-adrenergic vasoconstriction compared with men during exercise; in addition, women would constrict less during the early luteal than the early follicular phase of the female menses. Young men (n = 10) were studied once and women (n = 9) studied twice, once during the early follicular phase and once during the early luteal phase of female menses. We measured forearm blood flow (FBF; Doppler ultrasound of the brachial artery) during rest and steady-state dynamic exercise (15 and 30% of maximal voluntary contraction, 20 contractions/min). A brachial artery catheter was inserted for the local administration of α-adrenergic agonists [phenylephrine (PE; α(1)) or clonidine (CL; α(2))]. Blood flow responses to exercise [forearm vascular conductance (FVC)] were similar between all groups. At rest, infusion of PE or CL decreased FVC in all groups (40-60% reduction). Vasoconstriction to PE was abolished in all groups at 15 and 30% exercise intensity. Vasoconstriction to CL was reduced at 15% and abolished at 30% intensity in all groups; women had less CL-induced constriction during the early luteal than early follicular phase (P < 0.017, 15% intensity). These results indicate that vasodilator responses to forearm exercise are comparable between men and women and are achieved through similar paths of α-adrenergic vascular control at moderate intensities; this control may differ at low intensities specific to the female menstrual phase.
• Schrage, W.G., Wilkins, B.W., Johnson, C.P., Eisenach, J.H., Limberg, J.K., Dietz, N.M., Curry, T.B., & Joyner, M.J. (2010). Roles of nitric oxide synthase and cyclooxygenase in leg vasodilation and oxygen consumption during prolonged low-intensity exercise in untrained humans. J. Appl Physiology. 109(3), 768-77.
  Abstract: The vasodilator signals regulating muscle blood flow during exercise are unclear. We tested the hypothesis that in young adults leg muscle vasodilation during steady-state exercise would be reduced independently by sequential pharmacological inhibition of nitric oxide synthase (NOS) and cyclooxygenase (COX) with NG-nitro-L-arginine methyl ester (L-NAME) and ketorolac, respectively. We tested a second hypothesis that NOS and COX inhibition would increase leg oxygen consumption (VO2) based on the reported inhibition of mitochondrial respiration by nitric oxide. In 13 young adults, we measured heart rate (ECG), blood pressure (femoral venous and arterial catheters), blood gases, and venous oxygen saturation (indwelling femoral venous oximeter) during prolonged (25 min) steady-state dynamic knee extension exercise (60 kick/min, 19 W). Leg blood flow (LBF) was determined by Doppler ultrasound of the femoral artery. Whole body VO2 was measured, and leg VO2 was calculated from blood gases and LBF. Resting intra-arterial infusions of acetylcholine (ACh) and nitroprusside (NTP) tested inhibitor efficacy. Leg vascular conductance (LVC) to ACh was reduced up to 53±4% by L-NAME+ketorolac infusion, and the LVC responses to NTP were unaltered. Exercise increased LVC from 4±1 to 33.1±2 ml.min(-1).mmHg(-1) and tended to decrease after L-NAME infusion (31±2 ml.min(-1).mmHg(-1), P=0.09). With subsequent administration of ketorolac LVC decreased to 29.6±2 ml.min(-1).mmHg(-1) (P=0.02; n=9). While exercise continued, LVC returned to control values (33±2 ml.min(-1).mmHg(-1)) within 3 min, suggesting involvement of additional vasodilator mechanisms. In four additional subjects, LVC tended to decrease with L-NAME infusion alone (P=0.08) but did not demonstrate the transient recovery. Whole body and leg VO2 increased with exercise but were not altered by L-NAME or L-NAME+ketorolac. These data indicate a modest role for NOS- and COX-mediated vasodilation in the leg of exercising humans during prolonged steady-state exercise, which can be restored acutely. Furthermore, NOS and COX do not appear to influence muscle VO2 in untrained healthy young adults
• Limberg, J.K., DeVita, M.D., Blain, G.M., & Schrage, W.G. (2010). Muscle blood flow responses to dynamic exercise in young obese humans. J. Appl Physiology. 108(2), 349-55.
  Abstract: Exercise is a common nonpharmacological way to combat obesity; however, no studies have systematically tested whether obese humans exhibit reduced skeletal muscle blood flow during dynamic exercise. We hypothesized that exercise-induced blood flow to skeletal muscle would be lower in young healthy obese subjects (body mass index of >30 kg/m(2)) compared with lean subjects (body mass index of <25 kg/m(2)). We measured blood flow (Doppler Ultrasound of the brachial and femoral arteries), blood pressure (auscultation, Finapress), and heart rate (ECG) during rest and two forms of single-limb, steady-state dynamic exercise: forearm exercise (20 contractions/min at 4, 8, and 12 kg) and leg exercise (40 kicks/min at 7 and 14 W). Forearm exercise increased forearm blood flow (FBF) similarly in both groups (P > 0.05; obese subjects n = 9, lean subjects n = 9). When FBF was normalized for perfusion pressure, forearm vascular conductance was not different between groups at increasing workloads (P > 0.05). Leg exercise increased leg blood flow (LBF) similarly in both groups (P > 0.05; obese subjects n = 10, lean subjects n = 12). When LBF was normalized for perfusion pressure, leg vascular conductance was not different between groups at increasing workloads (P > 0.05). These results were confirmed when relative blood flow was expressed at average relative workloads. In conclusion, our results show that obese subjects exhibited preserved FBF and LBF during dynamic exercise
• Kirby, B.S., Voyles, W.F., Simpson, C.B., Carlson, R.E., Schrage, W.G., & Dinenno, F.A. (2009). Endothelium-dependent vasodilatation and exercise hyperaemia in ageing humans: impact of acute ascorbic acid administration. J. Physiology. 587(9), 1989-03.
  Abstract: Age-related increases in oxidative stress impair endothelium-dependent vasodilatation in humans, leading to the speculation that endothelial dysfunction contributes to impaired muscle blood flow and vascular control during exercise in older adults. We directly tested this hypothesis in 14 young (22 +/- 1 years) and 14 healthy older men and women (65 +/- 2 years). We measured forearm blood flow (FBF; Doppler ultrasound) and calculated vascular conductance (FVC) responses to single muscle contractions at 10, 20 and 40% maximum voluntary contraction (MVC) before and during ascorbic acid (AA) infusion, and we also determined the effects of AA on muscle blood flow during mild (10% MVC) continuous rhythmic handgrip exercise. For single contractions, the peak rapid hyperaemic responses to all contraction intensities were impaired approximately 45% in the older adults (all P < 0.05), and AA infusion did not impact the responses in either age group. For the rhythmic exercise trial, FBF (approximately 28%) and FVC (approximately 31%) were lower (P = 0.06 and 0.05) in older versus young adults after 5 min of steady-state exercise with saline. Subsequently, AA was infused via brachial artery catheter for 10 min during continued exercise. AA administration did not significantly influence FBF or FVC in young adults (1-3%; P = 0.24-0.59), whereas FBF increased 34 +/- 7% in older adults at end-exercise, and this was due to an increase in FVC (32 +/- 7%; both P < 0.05). This increase in FBF and FVC during exercise in older adults was associated with improvements in vasodilator responses to acetylcholine (ACh; endothelium dependent) but not sodium nitroprusside (SNP; endothelium independent). AA had no effect on ACh or SNP responses in the young. We conclude that acute AA administration does not impact the observed age-related impairment in the rapid hyperaemic response to brief muscle contractions in humans; however, it does significantly increase muscle blood flow during continuous dynamic exercise in older adults, and this is probably due (in part) to an improvement in endothelium-dependent vasodilatation
• Ji, L., Diffee, G.M., & Schrage, W.G. (2008). Challenges in Exercise Physiology Research and Education. Quest. 60, 13-18.
• Schrage, W.G., Eisenach, J.H., & Joyner, M.J. (2007). Aging reduces nitric oxide and prostaglandin mediated vasodilation during exercise. Journal of Physiology. 579(1), 227-236.
  Abstract: PMID:17138603 In older humans, infusions of endothelial agonists suggest endothelial dysfunction, due in part to less nitric oxide (NO)- and prostaglandin (PG)-mediated vasodilatation, and a shift toward PG-mediated vasoconstriction. Ageing can also be associated with lower exercise blood flow (exercise hyperaemia), but the vascular mechanisms mediating this remain unknown. Notably, in young adults, inhibition of NO and PGs during exercise decreases exercise hyperaemia by approximately 20 and approximately 12%, respectively. We tested our first hypothesis that in older humans inhibition of NO would decrease hyperaemia, but that inhibition of PGs would increase hyperaemia by blocking vasoconstrictor PGs. Fifteen older subjects (65 +/- 3 years) performed dynamic forearm exercise for 20 min (20 contractions min(-1)). Forearm blood flow (FBF) was measured beat-to-beat with Doppler ultrasound, while saline or drugs were infused sequentially via brachial artery catheter in the exercising forearm. After achieving steady-state exercise, L-NAME (25 mg) was infused over 5 min to inhibit NO synthase. After a further 2 min of exercise (saline), ketorolac (6 mg) was infused over 5 min to inhibit PGs, followed by a further 3 min of exercise with saline. Drug order was reversed in seven subjects. L-NAME reduced steady-state exercise hyperaemia by 12 +/- 3% in older subjects (P<0.01), whereas ketorolac had no net effect on blood flow (3 +/- 6%, P>0.4). The effects of l-NAME and ketorolac were independent of drug order. By comparing these results with our previous results in young adults, we tested our second hypothesis that in older humans inhibition of NO or PGs would have less impact on exercise hyperaemia due to less vasodilatation from these signals. Our results suggest that, compared with young adults, in older humans the relative contribution of NO to exercise hyperaemia is reduced approximately 45% (22 +/- 4 versus 12 +/- 3%), but the role of PG in mediating vasodilatation is lost in ageing human skeletal muscle. Lower exercise hyperaemia in older humans may be mediated in part by less NO- and PG-mediated vasodilatation during exercise.
• Schrage, W.G., Joyner, M.J., & Dinenno, F.A. (2004). Local inhibition of nitric oxide and prostaglandins independently reduces forearm exercise hyperaemia in humans. Journal of Physiology. 557(2), 599-611.