Phenylephrine decreases frontal lobe oxygenation at rest but not during moderately intense exercise

J Appl Physiol 108: 1472 1478, 2010. First published March 11, 2010; doi:10.1152/japplphysiol.01206.2009. Phenylephrine decreases frontal lobe oxygenation at rest but not during moderately intense exercise Patrice Brassard, Thomas Seifert, Mads Wissenberg, Peter M. Jensen, Christian K. Hansen, and Niels H. Secher Department of Anesthesia, The Copenhagen Muscle Research Center, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark Submitted 23 October 2009; accepted in final form 5 March 2010 Brassard P, Seifert T, Wissenberg M, Jensen PM, Hansen CK, Secher NH. Phenylephrine decreases frontal lobe oxygenation at rest but not during moderately intense exercise. J Appl Physiol 108: 1472 1478, 2010. First published March 11, 2010; doi:10.1152/japplphysiol.01206.2009. Whether sympathetic activity influences cerebral blood flow (CBF) and oxygenation remains controversial. The influence of sympathetic activity on CBF and oxygenation was evaluated by the effect of phenylephrine on middle cerebral artery (MCA) mean flow velocity (V mean ) and the nearinfrared spectroscopy-derived frontal lobe oxygenation (Sc O2 ) at rest and during exercise. At rest, nine healthy male subjects received bolus injections of phenylephrine (0.1, 0.25, and 0.4 mg), and changes in mean arterial pressure (MAP), MCA V mean, internal jugular venous O 2 saturation (Sjv O2 ), Sc O2, and arterial PCO 2 (Pa CO2 ) were measured and the cerebral metabolic rate for O 2 (CMR O2 ) was calculated. In randomized order, a bolus of saline or 0.3 mg of phenylephrine was then injected during semisupine cycling, eliciting a low ( 110 beats/ min) or a high ( 150 beats/min) heart rate. At rest, MAP and MCA V mean increased 20% (P 0.001) and 10% (P 0.001 for 0.25 mg of phenylephrine and P 0.05 for 0.4 mg of phenylephrine), respectively. Sc O2 then decreased 7% (P 0.001). Phenylephrine had no effect on Sjv O2,Pa CO2,orCMR O2. MAP increased after the administration of phenylephrine during low-intensity exercise ( 15%), but this was attenuated ( 10%) during high-intensity exercise (P 0.001). The reduction in Sc O2 after administration of phenylephrine was attenuated during low-intensity exercise ( 5%, P 0.001) and abolished during high-intensity exercise ( 3%, P not significant), where Pa CO2 decreased 7% (P 0.05) and CMR O2 increased 17% (P 0.05). These results suggest that the administration of phenylephrine reduced Sc O2 but that the increased cerebral metabolism needed for moderately intense exercise eliminated that effect. cerebral oxygenation; sympathetic activity; exercise ARTERIAL PRESSURE, METABOLIC activity of the brain, and arterial gas tensions are determinants of cerebral blood flow (CBF), but whether sympathetic activity also influences CBF and cerebral oxygenation remains debated (45, 48). The cerebral circulation is richly supplied by perivascular adrenergic nerves (12), and smooth muscle cells in the arterioles have - and -adrenergic receptors (11). Sympathetic nerve stimulation constricts cerebral arteries, arterioles, and veins (2, 13, 50) and may protect the brain during acute increases in arterial pressure (3, 14). For example, cerebral sympathetic activity increases during rapid eye movement sleep, when surges of arterial pressure are observed (7). Biochemical evidence suggests that sympathetic nerve activity influences CBF in humans (30), but it exerts only Address for reprint requests and other correspondence: P. Brassard, Division of Kinesiology, Department of Social and Preventive Medicine, PEPS-Université Laval, 2300 rue de la Terasse, local 2122, Québec, Qc, Canada GIV OA6 (e-mail: patrice.brassard@kin.msp.ulaval.ca). a minor influence on CBF compared with its role on many other regions of the circulation. While evaluating the impact of arterial pressure changes on CBF velocity and cerebral oxygenation, Lucas et al. (27) reported an increase of middle cerebral artery (MCA) mean flow velocity (V mean ) but a lowering of near-infrared spectroscopy (NIRS)-derived frontal lobe oxygenation (Sc O2 ) with stepwise increase in arterial pressure. As demonstrated for skeletal muscles, flow is balanced by the metabolic demand of the tissue and sympathetic activity (41). Thus, vasodilatation induced by the high metabolic rate of the brain might counteract the ability of sympathetic nerves to elicit vasoconstriction and reduce CBF and Sc O2. Phenylephrine and norepinephrine bind to -adrenergic receptors, leading to an increase in mean arterial pressure (MAP) through an elevation in total peripheral resistance (TPR), and cardiac output (CO) is usually lowered or does not increase (4, 31). However, these drugs are reported to have no impact on CBF (33, 38) or to induce only a small reduction in CBF (24). Yet continuous infusion of increasing doses of norepinephrine reduces MCA V mean and cerebral oxygenation, characterized by Sc O2 and internal jugular venous O 2 saturation (Sjv O2 ) (4). In addition, the utilization of phenylephrine to correct anesthesia-induced hypotension (MAP 60 mmhg) reduces Sc O2 (31). On the other hand, ephedrine, which stimulates - and -adrenergic receptors directly and indirectly by promoting endogenous release of norepinephrine, maintains Sc O2, apparently through an increase in CO (31). According to the available literature, the influence of sympathetic nervous activation with phenylephrine on MCA V mean and Sc O2 is unclear. While increasing arterial pressure with phenylephrine does not seem to reduce CBF (9, 23, 26, 39, 40, 46), others report an increase in MCA V mean combined with a reduction in Sc O2 (27). Although the high metabolic rate of the brain may influence the capacity of the sympathetic nerves to induce vasoconstriction, cerebral metabolic rate for O 2 (CMR O2 ) has not been evaluated in these studies. Also, no data are available on the impact of stimulating the sympathetic nervous system on MCA V mean and Sc O2 during exercise, a condition associated with increased CMR O2 (42). Within this context, this study evaluated whether phenylephrine affects MCA V mean and Sc O2 at rest and whether the response is attenuated or eliminated during exercise of increasing intensity as the CMR O2 increases (42). METHODS Nine healthy male subjects (mean SD: 23 5 yr, 1.84 0.09 m, and 77 6 kg) participated in the study after providing written informed consent as approved by the regional ethics committee (H-A-2008-056) according to the principles established in the Declara- 1472 8750-7587/10 Copyright 2010 the American Physiological Society http://www.jap.org

PHENYLEPHRINE AND FRONTAL LOBE OXYGENATION 1473 tion of Helsinki. The subjects did not suffer from any medical conditions, nor were they taking any medications. No restriction on physical activity prior to the study was imposed on the subjects, but they were asked to have a light breakfast before visiting the laboratory. Catheterization. Upon arrival to the laboratory, the subjects were placed on a hospital bed tilted slightly head-down. Under local anesthesia (2% lidocaine) and guided by ultrasound, a catheter (1.6 mm; model ES-04706, Arrow International) was inserted retrograde in the right internal jugular vein and advanced to its bulb. A second catheter (1.1 mm) was inserted in the left brachial artery and a third catheter (0.7 mm) in the left subclavian vein through an arm vein for the administration of phenylephrine. After catheterization, the subjects were placed supine, and they rested for 1 h to offset the nociceptive stimuli associated with catheterization. Measurements. Sc O2 was monitored by NIRS (INVOS Cerebral Oximeter, Somanetics, Troy, MI), since changes in Sc O2 parallel those in Sjv O2 and MCA V mean (44). The NIRS-derived Sc O2 is based on the absorption of light in the spectrum for oxygenated and deoxygenated hemoglobin and reports Sc O2 as a percentage of light absorbed by oxygenated hemoglobin to light absorbed by total hemoglobin. An emitter generates light at 733 and 808 nm, and the reflection is registered by two sensors placed 3 and 4 cm from the emitter. This placement of the optodes allows for the subtraction of reflections derived from superficial tissues of the scalp and the skull for Sc O2 (17). With increasing distance between the emitter and the optodes, light penetrates deeper into the tissues, and with evaluation of absorption at two distances (spatial resolution), absorption in deep tissue, i.e., in the brain, is recorded. Values reported for Sc O2 account predominantly for hemoglobin oxygenation in the frontal cortex, and the NIRS-derived cerebral oxygenation follows the estimated cerebral capillary O 2 saturation (36). The optodes were attached as high as possible on the forehead to avoid the frontal sinuses, and they were covered for protection from external light. MCA V mean was monitored through the posterior temporal ultrasound window with transcranial Doppler sonography (Multidop X, DWL, Sipplingen, Germany) using a 2-MHz probe at a depth of 45 55 mm (1). After the optimal signal-to-noise ratio was obtained, the probe was fixed by adhesive ultrasonic gel (Tensive, Parker Laboratories, Orange, NJ) and secured by a headband. MCA V mean was calculated from the integral of the maximal-frequency Doppler shifts over one heartbeat by the same operator, and at rest and during exercise, determination of MCA V mean has a coefficient of variation of 5% (34). Hemodynamic monitoring included recording of MAP, heart rate (HR), stroke volume (SV), and thus CO. MAP was measured through a transducer (Edwards Life Sciences, Irvine, CA) placed at the level of the heart and connected to a monitor (Dialogue-2000, IBC-Danica Electronic) with sampling at 100 Hz (Di-720, Dataq) for offline analysis of HR and CO. Beat-to-beat SV was estimated from the arterial pressure wave according to the Modelflow method (52). Integrating the aortic flow waveform per beat provides left ventricular SV (Beatscope, FMS, Amsterdam, The Netherlands). This derived CO has been successfully validated against a thermodilution estimate of CO during a deliberate reduction in central blood volume induced by head-up tilt and the upright position in healthy subjects (18), during cardiac surgery and liver transplantation (21, 31), and in intensive care medicine (22), as well as against Doppler echocardiography during exercise (47). Arterial and internal jugular venous blood samples were obtained simultaneously at baseline and 1, 2, and 15 min after bolus injection of saline or phenylephrine at rest and 1, 2, and 10 min after bolus injection of saline or phenylephrine during exercise. Blood samples were purged of any air bubbles and immediately analyzed for O 2, Sjv O2, and arterial PCO 2 (Pa CO2 ) using a blood gas analyzer (ABL 725, Radiometer, Copenhagen, Denmark). Rest. After 1hofrecovery from catheterization, subjects received an intravenous bolus injection of saline ( 5 ml) and three 5-ml doses of phenylephrine (0.1, 0.25, and 0.4 mg) separated by 20 min, and variables were monitored for 15 min. Arterial and internal jugular venous catheterization provided concentration differences for O 2. CMR O2 was derived from the arterial-venous difference for O 2 with a resting global CBF taken as 46 ml 100 g 1 min 1 (29) adjusted to changes in MCA V mean, with the assumption of a constant vessel diameter (43). O 2, Sjv O2, and Pa CO2 were measured at baseline and 1, 2, and 15 min after the bolus of saline or phenylephrine. The periods of interest for which data are presented are as follows: 1) at baseline, 2) at the highest MAP after drug administration, 3) at the lowest Sc O2 within 10 min following the highest MAP, and 4) upon return of Sc O2 to baseline. Exercise. At 30 min following the experimental protocol at rest, a bolus of saline or 0.3 mg of phenylephrine was injected, in a randomized order, during semisupine cycling at a low (HR 110 beats/min) or a high (HR 150 beats/min) exercise intensity. CMR O2 is unchanged during low-intensity exercise but increases when the workload is moderately intense (42). The subjects cycled for 5 min to reach the target steady-state HR. Thereafter, saline or phenylephrine was administered, and the subjects continued to cycle for 10 min. The parameters determined at rest were evaluated during exercise, and data are similarly presented. Each variable represents the mean of the last 3 5 s for each period of interest. Statistical analysis. A two-way ANOVA on repeated measures at rest [time condition (saline or phenylephrine)] and three-way ANOVA with repeated measures during exercise [time condition (saline or phenylephrine) mode (exercise at 110 beats/min vs. exercise at 150 beats/min)] were performed. Results are presented as means SD for data normally distributed or as medians (range), and P 0.05 was considered statistically significant by using Sigmastat (SPSS, Chicago, IL) and SAS version 9.1 (SAS Institute, Cary, NC). Table 1. Changes in systemic hemodynamics and MCA V mean with increasing doses of phenylephrine at rest Phenylephrine Saline 0.1 mg 0.25 mg 0.4 mg MAP, mmhg Baseline 84 5 85 6 87 5 88 6 Bolus 89 5 100 7* 104 5* 108 7* Pulse pressure, mmhg Baseline 62 8 61 6 60 7 58 10 Bolus 63 6 61 6 61 6 64 7 HR, beats/min Baseline 61 10 61 10 61 11 64 9 Bolus 62 12 49 10* 47 13* 51 13* SV, ml Baseline 105 11 106 10 105 10 107 12 Bolus 105 9 100 15 99 15 101 15 CO, l/min Baseline 7.0 (2.8) 6.4 (3.8) 6.0 (3.7) 6.4 (4.1) Bolus 6.6 (4.0) 4.3 (3.5)* 4.1 (4.6)* 4.6 (5.6)* TPR, Torr min l 1 Baseline 13.4 2.6 14.0 3.1 14.2 3.2 13.3 2.7 Bolus 14.4 3.4 21.5 4.9* 23.8 5.2* 22.6 5.4* MCA V mean, cm/s Baseline 66.6 9.4 68.1 11.6 65.2 9.0 64.4 10.8 Bolus 67.5 9.8 69.8 11.5 71.4 12.9* 70.5 10.7 Frontal lobe oxygenation, % Baseline 82 6 84 5 84 5 84 5 Bolus 83 5 84 5 83 5 81 5 Lowest 82 5* 79 5* 77 6* 75 6* Values are means SD or median (range). MAP, mean arterial pressure; HR, heart rate; SV, stroke volume; CO, cardiac output; TPR, total peripheral resistance; MCA V mean, middle cerebral artery mean flow velocity. Bolus represents the highest data recorded or calculated at the maximal impact of the drug. *P 0.001 vs. baseline. P 0.05 vs. baseline. P 0.001 vs. saline. P 0.05 vs. saline.

1474 PHENYLEPHRINE AND FRONTAL LOBE OXYGENATION RESULTS Rest. At rest, MAP increased 20% with augmenting doses of phenylephrine, which was greater than the changes observed with the bolus of saline (P 0.001). The highest MAP achieved with the administration of the drug was reached after 32 9, 42 22, and 45 14 s for 0.1, 0.25, and 0.4 mg of phenylephrine, respectively. The increase in MAP was accounted for by an elevation in TPR (by 60%, P 0.001) as CO was decreased (Table 1, Fig. 1). The reduction in CO was the consequence of a lowering in HR, phenylephrine having no impact on SV, although pulse pressure increased with the highest dose of the drug (P 0.05). At the maximal impact of the drug, MCA V mean increased by 10% with 0.25 and 0.4 mg of phenylephrine (P 0.001 for 0.25 mg and P 0.05 for 0.4 mg), but Sc O2 was decreased by 7% with increasing doses (P 0.001). The lowest Sc O2 was observed 108 37, 167 65, and 180 49 s following the three doses of phenylephrine. Phenylephrine did not affect Sjv O2,Pa CO2,orCMR O2 (Table 2). Exercise. Compared with saline, MAP also increased after the administration of phenylephrine during low-intensity exercise ( 15%), but this was attenuated (to 10%) during highintensity exercise (P 0.001; Table 3, Fig. 2). Since CO was reduced by phenylephrine (P 0.05), TPR increased by 34% during low-intensity exercise and by 24% during high-intensity Fig. 1. Changes in mean arterial pressure (MAP), cardiac output (CO), total peripheral resistance (TPR), middle cerebral artery (MCA) mean flow velocity (V mean), and frontal lobe oxygenation (Sc O2 ) following a bolus of saline or increasing doses of phenylephrine (PHE). Left: kinetic changes. *P 0.001 vs. baseline, P 0.05 vs. saline. Right: absolute changes at specific periods of interest. MAP: for highest MAP, *P 0.001 vs. baseline for all doses of phenylephrine, P 0.05 vs. baseline for saline, P 0.001 vs. saline for all doses of phenylephrine; for lowest Sc O2, *P 0.001 vs. baseline for 0.25 mg of phenylephrine, P 0.05 vs. baseline for 0.1 mg of phenylephrine; for baseline Sc O2, P 0.05 vs. baseline for 0.1 mg of phenylephrine, P 0.001 vs. saline for all doses of phenylephrine. CO: for highest MAP, *P 0.001 vs. baseline for all doses of phenylephrine, P 0.001 vs. saline for all doses of phenylephrine; for lowest Sc O2, P 0.05 vs. saline for 0.1 and 0.25 mg of phenylephrine. TPR: for highest MAP, *P 0.001 vs. saline for all doses of phenylephrine, P 0.001 vs. saline for all doses of phenylephrine; for lowest Sc O2, P 0.05 vs. baseline for 0.4 mg of phenylephrine, P 0.05 vs. saline for 0.25 and 0.4 mg of phenylephrine. MCA V mean: for highest MAP, *P 0.001 vs. baseline for 0.25 and 0.4 mg of phenylephrine, P 0.05 vs. baseline for 0.4 mg of phenylephrine; for baseline Sc O2, P 0.05 vs. baseline for 0.25 mg of phenylephrine, P 0.05 vs. saline for 0.4 mg of phenylephrine. Sc O2 : for lowest Sc O2, *P 0.001 vs. baseline for all doses of phenylephrine, P 0.001 vs. saline for 0.25 and 0.4 mg of phenylephrine, P 0.05 vs. saline for 0.1 mg of phenylephrine.

PHENYLEPHRINE AND FRONTAL LOBE OXYGENATION Table 2. Changes in arterial O 2, CMRo 2, arterial Pco 2, and internal jugular venous So 2 with increasing doses of phenylephrine at rest and at different intensities of exercise with phenylephrine vs. saline 1475 Rest Exercise Phenylephrine 110 Beats/min 150 Beats/min Saline 0.1 mg 0.25 mg 0.4 mg Saline Phenylephrine Saline Phenylephrine Arterial O 2,mM Baseline 8.7 0.3 8.7 0.3 8.7 0.3 8.8 0.3 8.8 0.2 8.8 0.2 8.9 0.2 9.0 0.3 Bolus 8.7 0.3 8.8 0.3 8.8 0.3 8.9 0.2 9.0 0.2 9.1 0.2 9.4 0.2* 9.5 0.2* CMRo 2, 1 mol 100 g 1 min Baseline 182 38 188 52 182 32 181 37 207 31 211 35 207 42 215 48 Bolus 183 27 181 35 179 26 185 30 198 30 188 37 217 51 206 39 Arterial Pco 2, kpa Baseline 5.4 0.2 5.5 0.2 5.5 0.3 5.6 0.2 5.1 0.2 5.2 0.3 5.2 0.3 5.3 0.3 Bolus 5.5 0.2 5.6 0.3 5.6 0.2 5.5 0.1 5.3 0.2 5.5 0.3 5.0 0.4 4.9 0.4* Internal jugular venous So 2,% Baseline 69.1 2.9 69.3 4.4 67.3 3.2 69.4 5.0 62.4 2.5 62.9 3.5 64.7 3.3 63.6 4.0 Bolus 68.2 3.9 69.3 3.5 69.0 3.1 68.2 3.3 64.6 4.0 66.8 3.2 63.3 5.6 65.3 4.5 Values are means SD. CMRo 2, cerebral metabolic rate for O 2;So 2,O 2 saturation. *P 0.05 vs. baseline. P 0.05 vs. exercise at 110 beats/min. P 0.05 vs. rest. exercise (P 0.05). HR was also reduced by phenylephrine compared with saline at both exercise intensities, but the reduction in HR was attenuated during high-intensity exercise ( 10% vs. 2%, P 0.01). The reduction in Sc O2 following phenylephrine administration during low-intensity exercise ( 5%, P 0.001 vs. saline) was lost during high-intensity exercise ( 3%, P not significant vs. saline). There were no differences in pulse pressure, SV, or MCA V mean after the administration of phenylephrine compared with saline during exercise. Phenylephrine had no influence on Sjv O2 or CMR O2, and while the latter remained unaffected by low-intensity exercise, it increased by 17% (P 0.05) during high-intensity exercise. Phenylephrine also had no influence on Pa CO2 during low-intensity exercise but reduced Pa CO2 by 7% during high-intensity exercise (P 0.05). DISCUSSION Stimulation of sympathetic activity by the administration of phenylephrine decreased Sc O2 in healthy subjects, but exercise of increasing intensity abolished the extent of these changes in regional cerebral oxygenation, possibly as the result of an Table 3. Changes in systemic hemodynamics, MCA V mean and frontal lobe oxygenation at different intensities of exercise with phenylephrine vs. saline Exercise at 110 Beats/min Exercise at 150 Beats/min Saline Phenylephrine Saline Phenylephrine MAP, mmhg Baseline 92 14 94 8 108 15 112 11 Bolus 98 13 b 109 12 a,d 113 15 b 123 11 a,d Pulse pressure, mmhg Baseline 76 16 78 11 107 19 118 22 Bolus 76 14 80 10 103 17 118 19 HR, beats/min Baseline 112 4 113 5 149 8 155 7 Bolus 114 4 102 5 a,c 154 3 152 9 a,c,e SV, ml Baseline 116 11 122 15 145 21 134 21 Bolus 110 8 115 11 133 17 125 24 CO, l/min Baseline 13.0 1.3 13.6 1.4 21.6 3.3 20.9 3.8 Bolus 12.5 1.2 11.7 1.0 a 20.5 2.6 b 19.1 4.4 b TPR, Torr min l 1 Baseline 7.2 1.6 7.0 1.0 5.0 1.1 5.5 1.3 Bolus 8.1 1.6 b 9.4 1.8 b,d 5.5 1.1 6.8 2.0 b,d MCA V mean, cm/s Baseline 65.5 12.8 65.8 12.7 68.7 14.6 67.6 12.9 Bolus 67.2 12.2 69.9 12.4 70.4 16.6 71.5 15.6 Frontal lobe oxygenation, % Baseline 82 5 83 6 83 8 83 6 Bolus 82 6 85 5 83 8 84 5 Lowest 80 6 78 6 a 82 7 81 5 Values are means SD. a P 0.001 vs. baseline. b P 0.05 vs. baseline. c P 0.001 vs. exercise of the same intensity with saline. d P 0.05 vs. exercise of the same intensity with saline. e P 0.01 vs. Exercise at 110 beats/min phenylephrine.

1476 PHENYLEPHRINE AND FRONTAL LOBE OXYGENATION Fig. 2. Changes in MAP, CO, TPR, MCA V mean, and Sc O2 after administration of 0.3 mg of phenylephrine at low-intensity exercise [110 beats/min (EX110)] and high-intensity exercise [150 beats/min (EX150)] compared with a bolus of saline. Left: kinetic changes. *P 0.001 vs. baseline, P 0.05 vs. saline. Right: changes at specific periods of interest. MAP: **P 0.001 EX110 vs. EX150; highest MAP, *P 0.001 vs. baseline for EX110 phenylephrine and EX150 phenylephrine, P 0.05 vs. baseline for EX110 and EX150, P 0.05 vs. saline for EX110 phenylephrine and EX150 phenylephrine; lowest Sc O2, *P 0.001 vs. baseline for EX110, EX110 phenylephrine, EX150, and EX150 phenylephrine, P 0.05 vs. saline for EX110 phenylephrine and EX150 phenylephrine; baseline Sc O2, P 0.05 vs. baseline for EX150 and EX150 phenylephrine. CO: **P 0.001 for EX110 vs. EX150; highest MAP, *P 0.001 vs. baseline for EX110 phenylephrine, P 0.05 vs. baseline for EX150 and EX150 phenylephrine. TPR: **P 0.001 for EX110 vs. EX150; highest MAP, P 0.05 vs. baseline for EX110, EX110 phenylephrine, and EX150 phenylephrine, P 0.05 vs. saline for EX110 phenylephrine and EX150 phenylephrine. Sc O2 : lowest Sc O2, *P 0.001 vs. baseline for EX110 phenylephrine. increase in CMR O2. This was the case, although there was a reduction in Pa CO2 with administration of phenylephrine at the highest workload. These data support the hypothesis that cerebral oxygenation is influenced by sympathetic activity but that this influence is attenuated or lost as CMR O2 increases during exercise. Stimulation of -adrenergic activity by phenylephrine has not been associated with a reduction in CBF (9, 23, 26, 39, 40, 46). However, CMR O2 was not evaluated in these studies, and no exercise data are available. Lucas et al. (27) recently reported an increase in MCA V mean and a lowering of Sc O2 with a phenylephrine-induced stepwise increase in arterial pressure, which support the present findings. The are several possible explanations for the reduction of Sc O2 with phenylephrine. The administration of phenylephrine reduced CO (10, 15) as a consequence of a baroreflex-mediated reduction in HR induced by the increase in arterial pressure. An association seems to exist between changes in CO, CBF, and cerebral oxygenation with different physiological stimuli. For example, when CO is reduced in the upright position, both MCA V mean and Sc O2 decrease, although blood pressure at the level of the brain remains relatively constant (49). Also during exercise, there is a direct relationship between the increase in MCA V mean and CO in cardiac patients (20), and increases in CO and MCA V mean are attenuated during exercise following the administration of -adrenergic blocking agents (25); the attenuation of MCA V mean is eliminated by regional anesthesia of the sympathetic nerves to the brain (19). Furthermore, manipulation of CO by administration of albumin vs. lower body negative pressure during exercise is transmitted to a parallel change in MCA V mean (32).

PHENYLEPHRINE AND FRONTAL LOBE OXYGENATION Although there was a decrease in Sc O2 resulting from phenylephrine administration, a 10% increment in MCA V mean preceded the reduction in Sc O2. Zhang et al. (53) reported a similar increase in MCA V mean in response to continuous phenylephrine infusion (2 g kg 1 min 1 ). While Lucas et al. (27) also reported an elevation in MCA V mean with phenylephrine infusion, Sc O2 was lowered. We interpret the reduction in Sc O2 as a reflection of a reduction in regional cerebral perfusion and the increase in MCA V mean as a direct effect on the artery by the drug. The administration of phenylephrine may induce changes in small cerebral arterioles, i.e., vasoconstriction, transiently increasing MCA V mean (not CBF). However, this vasoconstriction may eventually reduce Sc O2 as in the present study. In addition, despite the fact that phenylephrine does not seem to cross an intact blood-brain barrier (33), pharmacologically induced hypertension may have affected the blood-brain barrier (28). The increase in arterial pressure induced by the bolus of phenylephrine may also have stimulated the superior cervical ganglia, leading to cerebral vasoconstriction (6). Thus the combination of a reduction in CO, a direct effect of phenylephrine on the vessels, and a cerebral response to an increase in perfusion pressure could contribute to restrain cerebral oxygenation. We used exercise to modulate the influence of phenylephrine on Sc O2. We were inspired by the finding that, for skeletal muscles, there is a metabolic restraint, sympatholysis, on the ability of the sympathetic system to cause vasoconstriction during exercise (37). Such sympatholysis was evidenced by an important effect of phenylephrine on TPR at rest but, to a lesser degree, during exercise. Similarly, the reduction in Sc O2 by phenylephrine at rest and during low-intensity exercise was abolished during moderately high-intensity exercise, apparently associated with an increase in CMR O2, but other manifestations associated with intense exercise should be considered. For example, increased body temperature is associated with an attenuated vasoconstrictor responsiveness to phenylephrine-induced elevation in arterial pressure in humans (8). Also, high-intensity exercise may be associated with a hyperventilation-induced reduction in Pa CO2, lowering CBF (51). Yet, even with a lowering of Pa CO2, phenylephrine was unable to affect Sc O2 at the highest exercise intensity. In the absence of a change in arterial O 2 content, hemoglobin concentration, and CMR O2, a reduction in Sjv O2 would represent a reduction in global cerebral oxygenation. Our data showed no influence of phenylephrine on Sjv O2. However, we sampled blood at 1 and 2 min after the bolus of phenylephrine and not at the maximal effect of the drug or the lowest Sc O2 encountered after the highest MAP. Although it might be that phenylephrine does not influence global cerebral oxygenation, the absence of a reduction in Sjv O2 may represent a sampling problem. Furthermore, the acute exposure to phenylephrine we used may have been insufficient to influence global cerebral oxygenation. Infusion of norepinephrine decreases Sc O2, Sjv O2, and MCA V mean in healthy subjects (4), suggesting that an infusion, rather than a bolus injection, is needed to affect Sjv O2. The reduction in Sc O2 could also be related to decreased skin blood flow measured in the frontal area by NIRS with phenylephrine. However, if that were the case, we would expect a similar effect during exercise. Furthermore, we used spatially resolved NIRS, i.e., two detecting optodes were placed at different distances from the transmitting optodes, such that the signal reflects cerebral, rather than skin and bone, hemoglobin saturation (16, 36). Nevertheless, an evaluation of CBF by positron emission tomography or magnetic resonance is needed to confirm an effect of phenylephrine on CBF (5, 35). Finally, CMR O2 may be overestimated, should MCA diameter be directly or indirectly reduced by phenylephrine. Conclusion. The administration of phenylephrine reduced Sc O2, but increasing CMR O2 during moderately intense exercise may have abolished that effect, despite Pa CO2 being lowered. We interpret the lack of an effect of phenylephrine on Sc O2 during exercise as supporting a balance between cerebral metabolism and a sympathetic restraint on blood flow. A restraint in cerebral oxygenation by phenylephrine could be established directly through a pharmacological effect or a reflex increase in cerebral vascular resistance triggered by the elevation in arterial pressure, eventually supported by a lowered CO. ACKNOWLEDGMENTS The authors thank Denis R. Joanisse for review of the manuscript. GRANTS P. Brassard is the recipient of a postdoctoral fellowship from the Fonds de la Recherche en Santé du Québec. REFERENCES 1477 1. Aaslid R, Markwalder TM, Nornes H. Noninvasive transcranial Doppler ultrasound recording of flow velocity in basal cerebral arteries. J Neurosurg 57: 769 774, 1982. 2. Auer LM, Edvinsson L, Johansson BB. Effect of sympathetic nerve stimulation and adrenoceptor blockade on pial arterial and venous calibre and on intracranial pressure in the cat. Acta Physiol Scand 119: 213 217, 1983. 3. Bill A, Linder J. Sympathetic control of cerebral blood flow in acute arterial hypertension. Acta Physiol Scand 96: 114 121, 1976. 4. 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