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Wilson LC, Cotter JD, Fan JL, Lucas RA, Thomas KN, Ainslie PN. Cerebrovascular reactivity and dynamic autoregulation in tetraplegia. Am J Physiol Regul Integr Comp Physiol 298: R1035-R1042, 2010. First published January 20, 2010; doi: 10.1152/ajpregu.00815.2009.--Humans with spinal cord injury have impaired cardiovascular function proportional to the level and completeness of the lesion. The effect on cerebrovascular function is unclear, especially for high-level lesions. The purpose of this study was to evaluate the integrity of dynamic cerebral autoregulation (CA) and the cerebrovascular reactivity in chronic tetraplegia (Tetra). After baseline, steady-state hypercapnia (5% C[O.sub.2]) and hypocapnia (controlled hyperventilation) were used to assess cerebrovascular reactivity in 6 men with Tetra (C5-C7 lesion) and 14 men without [able-bodied (AB)]. Middle cerebral artery blood flow velocity (MCAv), cerebral oxygenation, arterial blood pressure (BP), heart rate (HR), cardiac output (Q; model flow), partial pressure of end-tidal C[O.sub.2] ([MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII.]), and plasma catecholamines were measured. Dynamic CA was assessed by transfer function analysis of spontaneous fluctuations in BP and MCAv. MCAv pulsatility index (MCAv PI) was calculated as ([MCAv.sub.systolic]--[MCAv.sub.diastolic][MCAv.sub.mean] and standardized by dividing by mean arterial pressure (MAP). Resting BP, total peripheral resistance, and catecholamines were lower in Tetra (P < 0.05), and standardized MCAv PI was ~36% higher in Tetra (P = 0.003). Resting MCAv, cerebral oxygenation, HR, and PET[CO.sub.2] were similar between groups (P > 0.05). Although phase and transfer function gain relationships in dynamic CA were maintained with Tetra (P > 0.05), coherence in the very low-frequency range (0.02-0.07 Hz) was ~21% lower in Tetra (P = 0.006). Full (hypo- and hypercapnic) cerebrovascular reactivity to C[O.sub.2] was unchanged with Tetra (P > 0.05). During hypercapnia, standardized MCAv PI reactivity was enhanced by ~78% in Tetra (P = 0.016). Despite impaired cardiovascular function, chronic Tetra involves subtle changes in dynamic CA and cerebrovascular reactivity to C[O.sub.2]. Changes are evident in coherence at baseline and MCAv PI during baseline and hypercapnic states in chronic Tetra, which may be indicative of cerebrovascular adaptation. spinal cord injury; cerebral autoregulation; reliability doi: 10.1152/ajpregu.00815.2009.

DeRuisseau LR, Recca DM, Mogle JA, Zoccolillo M, DeRuisseau KC. Metallothionein deficiency leads to soleus muscle contractile dysfunction following acute spinal cord injury in mice. Am J Physiol Regul Integr Comp Physiol 297: R1795-R1802, 2009. First published October 14, 2009; doi: 10.1152/ajpregu.00263.2009.--Metallothionein (MT) is a small molecular weight protein possessing metal binding and free radical scavenging properties. We hypothesized that MT-1/MT-2 null ([MT.sup.-/-]) mice would display exacerbated soleus muscle atrophy, oxidative injury, and contractile dysfunction compared with the response of wild-type (WT) mice following acute spinal cord transection (SCT). Four groups of mice were studied: WT laminectomy, WT transection, [MT.sup.-/-] laminectomy ([MT.sup.-/-] lami), and [MT.sup.-/-] transection ([MT.sup.-/-] trans). Laminectomy animals served as surgical controls. Mice in SCT groups experienced similar percent body mass (BM) losses at 7 days postinjury. Soleus muscle mass (MM) and MM-to-BM ratio were lower at 7 days postinjury in SCT vs. laminectomy mice, with no differences observed between strains. However, soleus muscles from [MT.sup.-/-] trans mice showed reduced maximal specific tension compared with [MT.sup.-/-] lami animals. Mean cross-sectional area ([[micro]m.sup.2]) of type I and type IIa fibers decreased similarly in SCT groups compared with laminectomy controls, and no difference in fiber distribution was observed. Lipid peroxidation (4-hydroxynoneal) was greater in [MT.sup.-/-] trans vs. [MT.sup.-/-] lami mice, but protein oxidation (protein carbonyls) was not altered by MT deficiency or SCT. Expression of key antioxidant proteins (catalase, manganese, and copper-zinc superoxide dismutase) was similar between the groups. In summary, MT deficiency did not impact soleus MM loss, but resulted in contractile dysfunction and increased lipid peroxidation following acute SCT. These findings suggest a role of MT in mediating protective adaptations in skeletal muscle following disuse mediated by spinal cord injury. muscle atrophy; oxidative stress; spinal cord transection; antioxidant; stress protein doi: 10.1152/ajpregu.00263.2009

The primary afferent neurotransmitter triggering the spinal micturition reflex after complete spinal cord injury (SCI) in the rat is unknown. Substance P detected immunohistochemically in the sacral parasympathetic nucleus was significantly higher in 12 SCI rats than in 12 spinally intact rats (P = 0.008), suggesting substance P as a plausible candidate for the primary afferent neurotransmitter. The effects of the tachykinin NK1 receptor antagonist L-733060 on the spinal micturition reflex were then determined by performing conscious cystometry in an additional 14 intact rats and 14 SCI rats with L-733060 (0.1-100 [micro]g) administered intrathecally at L6-S1. L-733060 was without effect in intact rats, but blocked the spinal micturition reflex in 10 of 14 SCI rats and increased the intermicturition interval in 2 of 4 others at doses ranging from 10 to 100 [micro]g. Both phasic and nonphasic voiding contractions, differentiated according to the presence of phasic external urethral sphincter (EUS) activity, were present in most SCI rats. Both types of contractions were blocked by high doses of L-733060. Interestingly, there was a relative decline in phasic voiding contractions at high doses as well as a decline in contraction amplitude in nonphasic voiding contractions. In other respects, cystometric variables were largely unaffected in either spinally intact or SCI rats. L-733060 did not affect tonic EUS activity at any dose except when the spinal micturition reflex was blocked and tonic activity was consequently lost. These experiments show that tachykinin action at spinal NK1 receptors plays a major role in the spinal micturition reflex in SCI rats. spinal cord injury; bladder; tachykinins; external urethral sphincter

We investigated the effects of intrathecal application of [GABA.sub.A]- or [GABA.sub.B]-receptor agonists on detrusor-sphincter dyssynergia (DSD) in spinal cord transection (SCT) rats. Adult female Sprague-Dawley rats were used. At 4 wk after [Th.sub.9-10] SCT, simultaneous recordings of intravesical pressure and urethral pressure were performed under an awake condition to examine the effect of intrathecal application of [GABA.sub.A] and [GABA.sub.B] agonists (muscimol and baclofen, respectively) or [GABA.sub.A] and [GABA.sub.B] antagonists (bicuculline and saclofen, respectively) at the level of [L.sub.6]-[S.sub.1] spinal cord. In spinal-intact rats, the effects of bicuculline and saclofen on bladder and urethral activity were also examined. During urethral pressure measurements, DSD characterized by urethral pressure increases during isovolumetric bladder contractions were observed in 95% of SCT rats. However, after intrathecal application of muscimol or baclofen, urethral pressure showed urethral relaxation during isovolumetric bladder contractions. The effective dose to induce inhibition of urethral activity was lower compared with the dose that inhibited bladder contractions. The effect of muscimol and baclofen was antagonized by intrathecal bicuculline and saclofen, respectively. In spinal-intact rats, intrathecal application of bicuculline induced DSD-like changes. These results indicate that [GABA.sub.A]and [GABA.sub.B]-receptor activation in the spinal cord exerts the inhibitory effects on DSD after SCT. Decreased activation of [GABA.sub.A] receptors due to hypofunction of GABAergic mechanisms in the spinal cord might be responsible, at least in part, for the development of DSD after SCT. bladder; urethra; spinal cord; [gamma]-aminobutyric acid; detrusor-sphincter dyssynergia

Autonomic dysreflexia (AD) is a debilitating disorder producing episodes of extreme hypertension in patients with high-level spinal cord injury (SCI). Factors leading to AD include loss of vasomotor baroreflex control to regions below injury level, changes in spinal circuitry, and peripheral changes. The present study tested for peripheral changes below and above injury level 6 wk after a transection at the fourth thoracic spinal level. Changes in vascular conductance were recorded in the femoral, renal, brachial, and carotid arteries in response to intravenous injections of two [alpha]t-adrenergic agonists, phenylephrine (PE; 0.03-100 [micro]g/kg) and methoxamine (Meth; 1-300 [micro]g/kg). Unlike PE, Meth is not subject to neuronal reuptake. Ganglionic blockade (0.6 mg/kg chlorisondamine) was used to eliminate the central component of the cardiovascular response. After ganglionic blockade, SCI animals exhibited prolonged vasoconstriction in response to PE in all blood vessels measured compared with those in intact animals (all, P < 0.035). However, the PE dose-response curves obtained after ganglionic blockade revealed no significant difference in the potency between the two groups (all, P > 0.06), indicating that the prolonged vasoconstriction was not due to supersensitivity to PE. In contrast to PE, vascular responses to Meth did not vary between intact and SCI groups (all P > 0.108). These results show the development of a widespread peripheral change producing prolonged vasoconstriction in response to PE, but not Meth, possibly due to reduced neuronal reuptake of PE after SCI. This is the first study to report such a change in blood vessels not only below but also above injury level. Interventions to correct this reduced reuptake may help limit the development of AD. autonomic dysreflexia; spinal cord transection; phenylephrine; methoxamine

Spinal cord injury (SCI) has profound effects on cardiovascular autonomic function due to injury to descending autonomic pathways, and cardiovascular diseases are the leading causes of morbidity and mortality after SCI. Evaluation of cardiovascular autonomic dysfunction after SCI and appraisal of simple noninvasive autonomic assessments that are clinically meaningful would be useful to SCI clinicians and researchers. We aimed to assess supine and upright cardiovascular autonomic function from frequency analyses of heart rate and blood pressure variability (HRV and BPV) after SCI. We studied 26 subjects with chronic cervical or thoracic SCI and 17 able-bodied controls. We continuously recorded R-R interval (RRI, by ECG) and beat-to-beat blood pressure (by Finometer) in supine and seated positions. Cardiovascular control was assessed from spectral analysis of RRI and blood pressure time series. Cardiac baroreflex control was assessed from cross-spectral analyses of low-frequency spectra. Supine and upright low-frequency HRV and BPV were reduced in cervical SCI subjects, as were total BPV and HRV. Supine high-frequency HRV was reduced in thoracic SCI subjects. Cardiac baroreflex delay was increased in cervical SCI subjects. Supine frequency domain indexes were correlated with sympathetic skin responses, orthostatic cardiovascular responses, and plasma catecholamine levels. SCI results in reduced sympathetic drive to the heart and vasculature and increased baroreflex delay in cervical SCI subjects and reduced cardiac vagal tone in thoracic SCI subjects. Frequency analyses of autonomic function are related to clinical measures of autonomic control after SCI and provide useful noninvasive clinical tools with which to assess autonomic completeness of injury following SCI. baroreceptor reflex; autonomic nervous system; spectral analysis

Direct effects of vasoactive substances on blood pressure can be examined in individuals with tetraplegia due to disruption of descending spinal pathways to sympathetic preganglionic neurons, as cervical lesions interfere with baroreceptor reflex buffering of sympathetic outflow. In this study, we assessed effects of the nitric oxide synthase inhibitor nitro-L-arginine methyl ester (L-NAME) on mean arterial pressure, heart rate, and plasma norepinephrine concentrations in individuals with tetraplegia vs. effects shown in a neurologically intact control group. Seven individuals with tetraplegia and seven age-matched controls received, on separate visits and in the following order, placebo (30 ml normal saline) and 0.5, 1, 2, and 4 mg/kg L-NAME intravenously over 60 min. Supine hemodynamic data were collected, and blood was sampled at the end of each infusion and at 120, 180, and 240 min thereafter. L-NAME increased mean arterial pressure, and the relative increase was greater in the tetraplegia group than in the control group. Heart rate was reduced after L-NAME administration in both groups. L-NAME decreased plasma norepinephrine in the control group but not in the group with tetraplegia. These findings suggest that reflexive sympathoinhibition normally buffers the pressor response to nitric oxide synthase inhibition, an effect that is not evident in individuals with tetraplegia as a result of decentralized sympathetic vasomotor control. spinal cord injury; nitro-L-arginine methyl ester; norepinephrine; sympathetic nervous system

The inability to maintain body weight within prescribed ranges occurs in a significant portion of the human spinal cord injury (SCI) population. Using a rodent model of long-term high thoracic (spinal level T3) spinal cord transection (TX), we aimed to identify derangements in body weight, body composition, plasma insulin, glucose tolerance, and metabolic function, as measured by uncoupling protein 1 (UCP1) expression in interscapular brown adipose tissue (IBAT). Sixteen weeks after SCI, body weights of injured female rats stabilized and were significantly lower than surgical control animals. At the same time point, SCI rats had a significantly lower whole body fat:lean tissue mass ratio than controls, as measured indirectly by NMR. Despite lower body weight and fat mass, the cumulative consumption of standard laboratory chow (4.0 kcal/g) and mean energy intake (kcal*[day.sup.-1]*100 g body [wt.sup.-1]) of chronic SCI rats was significantly more than controls. Glucose tolerance tests indicated a significant enhancement in glucose handling in 16-wk SCI rats, which were coupled with lower serum insulin levels. The post mortem weight of gonadal and retroperitoneal fat pads was significantly reduced after SCI and IBAT displayed significantly lower real-time PCR expression of UCP1 mRNA. The reduced fat mass and IBAT UCP1 mRNA expression are contraindicative of the cumulative caloric intake by the SCI rats. The prolonged postinjury loss of body weight, including fat mass, is not due to hypophagia but possibly to permanent changes in gastrointestinal transit and absorption, as well as whole body homeostatic mechanisms. metabolic syndrome; fat mass; lean body mass; weight loss; energy balance

Sympathetic preganglionic neurons and interneurons are closely apposed (presumably synapsed upon) by corticospinal tract (CST) axons. Sprouting of the thoracic CST rostral to lumbar spinal cord injuries (SCI) substantially increases the incidence of these appositions. To test our hypothesis that these additional synapses would increase CST control of sympathetic activity after SCI, we measured the effects of electrical stimulation of the CST on renal sympathetic nerve activity (RSNA) and arterial pressure (AP) in [alpha]-chloralose-anesthetized rats with either chronically intact or chronically lesioned spinal cords. Stimuli were delivered to the CST at intensities between 25-150 [micro]A and frequencies between 25 and 75 Hz. Stimulation of the CST at the midcervical level decreased RSNA and AP. These decreases were not mediated by direct projections of the CST to the thoracic spinal cord because we could still elicit them by midcervical stimulation after acute lesions of the CST at caudal cervical levels. In contrast, caudal thoracic CST stimulation increased RSNA and AP. Neither the responses to cervical nor thoracic stimulation were affected by chronic lumbar SCI. These data show that the CST mediates decreases in RSNA via a cervical spinal system but excites spinal sympathetic neurons at caudal thoracic levels. Because chronic lumber spinal cord injury affected responses evoked from neither the cervical nor thoracic CST, we conclude that lesion-induced or regeneration-induced formation of new synapses between the CST and sympathetic neurons may not affect cardiovascular regulation. sympathetic preganglionic neurons; sympathetic interneurons; spinal cord injury; cardiovascular regulation doi:10.1152/ajpregu.00044.2007

We recently demonstrated that treatment with the 5-H[T.sub.1A/7] receptor agonist [(R)-(+)-8-hydroxy-2-di-n-propylamino]tetralin (8-OH-DPAT) increases bladder capacity in chloralose-anesthetized female cats with chronic spinal cord injury. In the current study, we investigated the effects of 8-OH-DPAT on bladder capacity and external urethral sphincter (EUS) activity in urethane-anesthetized female rats (initial body mass 175-200 g) with chronic spinal cord injury (transsection at T10). Cystometric study took place 8-12 wk posttranssection. Intravesical pressure was monitored in urethane-anesthetized rats with a transvesical catheter, and EUS activity was assessed electromyographically. Spinal cord injury disrupts phasic activity of the EUS, resulting in decreased voiding efficiency and increased residual volume. 8-OH-DPAT induced a dose-dependent decrease in bladder capacity (the opposite of its effect in chronic spinal cord-injured cats) with an increase in micturition volume and decrease in residual volume resulting from improvement in voiding efficiency. The unexpected improvement in voiding efficiency can be explained by the 8-OH-DPAT-induced emergence of phasic EUS relaxation. Phasic EUS relaxation was also altered by 8-OH-DPAT in spinally intact rats, whereas the 5-H[T.sub.1A] receptor antagonist N-tert-butyl-3-[4-(2-methoxyphenyl)-piperazin-1-yl]-2-phenylpropanamide (WAY-100635), on its own, was without effect. It remains to be determined when phasic relaxation is restored after spinal cord injury, and indeed whether it is ever truly lost or is only temporarily separated from excitatory input. bladder; micturition; neurogenic voiding; detrusor; urethra

This study was conducted to examine reflex mechanisms that mediate urinary bladder and external urethral sphincter (EUS) coordination in urethane-anesthetized female Sprague-Dawley rats. We investigated the properties of EUS reflexes elicited by electrical stimulation of pelvic nerve afferent axons (pelvic-EUS reflex). The changes in the reflexes induced by bladder distension and administration of agonists or antagonists for glutamatergic or serotonergic receptors were examined. The reflexes consisted of an early response (ER, 18- to 22-ms latency) and a late, long-duration (> 100-ms latency) response (LR), which consisted of bursts of activity at 20- to 160-ms interburst intervals. In a few experiments, a reflex with an intermediate (40- to 70-ms) latency was also identified. With the bladder empty, the ER, but not the LR, was detected in the majority of experiments. The LR was markedly enhanced when the bladder was distended. The ER remained, but the LR was abolished, after spinal cord transection at [T.sub.8]-[T.sub.9]). The LR and LR were significantly decreased 75 and 35%, respectively, by the N-methyl-D-aspartate receptor antagonist MK-801 (0.3 mg/kg iv), but only decreased 18 and 14%, respectively, by the [alpha]-amino-5-methylisoxazole-4-propionate receptor antagonist LY-215490 (3 mg/kg iv). The serotonin (5-H[T.sub.1A]) receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (1 mg/kg iv) enhanced spontaneous EUS activity and the pelvic-EUS reflex. WAY-100635 (0.1-1 mg/kg iv), a 5-H[T.sub.1A] antagonist, reversed the effect of 8-hydroxy -2-(di-n-propylamino)-tetralin and suppressed EUS activity and the pelvic-EUS reflex. These results indicate that glutamatergic and serotonergic mechanisms are important in the reflex pathways underlying bladder-sphincter coordination in rats. pelvic nerve; bladder distension; bursting activity; spinal cord injury

The aim of the study was to assess endothelial function, measured by flow-mediated dilation (FMD), in an inactive extremity (leg) and chronically active extremity (arm) within one subject. Eleven male spinal cord-injured (SCI) individuals and eleven male controls (C) were included. Echo Doppler measurements were performed to measure FMD responses after 10 and 5 min of arterial occlusion of the leg (superficial femoral artery, SFA) and the arm (brachial artery, BA), respectively. A nitroglycerine spray was administered to determine the endothelium independent vasodilatation in the SFA. In the SFA, relative changes in FMD were significantly enhanced in SCI compared with C (SCI: 14.1 [+ or -] 1.3%; C: 9.2 [+ or -] 2.3%), whereas no differences were found in the BA (SCI: 12.5 [+ or -] 2.9%: C: 14.2 [+ or -] 3.3%). Because the FMD response is directly proportional to the magnitude of the stimulus, the FMD response was also expressed relative to the shear rate. No differences between the groups were found for the FMD-to-shear rate ratio in the SFA (SCI:0.061 [+ or -] 0.023%/[s.sup.-1]; C: 0.049 [+ or -] 0.024%/[s.sup.-1]), whereas the FMD-to-shear rate ratio was significantly decreased in the BA of SCI individuals (SCI: 0.037 [+ or -] 0.01%/[s.sup.-1]; C: 0.061 [+ or -] 0.027%/[s.sup.-1]). The relative dilatory response to nitroglycerine did not differ between the groups. (SCI: 15.6 [+ or -] 2.0%; C: 13.4 [+ or -] 2.3%). In conclusion, our results indicate that SCI individuals have a preserved endothelial function in the inactive legs and possibly an attenuated endothelial function in the active arms compared with controls. vascular endothelial function; deconditioning; ultrasound

Research was conducted to study the long-term effects of electrically stimulated leg cycling (ESLC) on oxygen-transporting organs and body composition of spinal cord-injured patients. Individual changes in core and skin temperature were determined during continuous ESLC in the subjects. Results indicated that body composition in patients with long-standing tetraplegia improved after eight weeks of ESLC. Increased medium density was also evident in most of the stimulated muscle groups.

Wecht, Jill M., Ronald E. De Meersman, Joseph P. Weir, William A. Bauman, and David R. Grimm. Effects of autonomic disruption and inactivity on venous vascular function. Am. J. Physiol. Heart Circ. Physiol. 278: H515-H520, 2000.--The effects of autonomic disruption and inactivity were studied on the venous vascular system. Forty-eight subjects, 24 with spinal cord injury (SCI) and 12 sedentary and 12 active able-bodied controls, participated in this study. Peripheral autonomic data were obtained to estimate sympathetic vasomotor control [low-frequency component of systolic blood pressure ([LF.sub.SBP])]. Vascular parameters were determined using strain-gauge venous occlusion plethysmography: venous capacitance (VC), venous emptying rate (VER), and total venous outflow (VO.sub.t). An additional vascular parameter was calculated: venous compliance [(VC/occlusion pressure) x 100]. VC and [VO.sub.t] were significantly different (SCI [is less than] sedentary [is less than] active). VER adjusted for VC was not different for any group comparison, whereas venous compliance was significantly lower in the SCI group than in the able-bodied groups and in the sedentary group compared with the active group. Regression analysis for the total group revealed a significant relationship between [LF.sub.SBP] and venous compliance (r = 0.64, P [is less than] 0.0001). After controlling for [LF.sub.SBP] through analysis of covariance, we found that mean differences for all venous vascular parameters did not change from unadjusted mean values. Our findings suggest that in subjects with SCI, the loss of sympathetic vasomotor tone contributes more than inactivity to reductions in venous vascular function. Heightened VC, [VO.sub.t], vasomotor tone, and venous compliance in the active group compared with the sedentary group imply that regular endurance training contributes to optimal venous vascular function and peripheral autonomic integrity. spinal cord injury; vasomotor tone; venous occlusion plethysmography; autonomic nervous system

Fatty acid kinetics and carbohydrate metabolism during electrical exercise in spinal cord-injured humans. Am J Physiol Regulatory Integrative Comp Physiol 281: R1492-R1498, 2001.--Motor center activity and reflexes from contracting muscle have been shown to be important for mobilization of free fatty acids (FFA) during exercise. We studied FFA metabolism in the absence of these mechanisms: during involuntary, electrically induced leg cycling in individuals with complete spinal cord injury (SCI). Healthy subjects performing voluntary cycling served as controls (C). Ten SCI (level of injury: [C.sub.5]-[T.sub.7]) and six C exercised for 30 min at comparable oxygen uptake rates (~1 l/min), and [1-[sup.14]C]palmitate was infused continuously to estimate FFA turnover. From femoral arteriovenous differences, blood flow, muscle biopsies, and indirect calorimetry, leg substrate balances as well as concentrations of intramuscular substrates were determined. Leg oxygen uptake was similar in the two groups during exercise. In SCI, but not in C, plasma FFA and FFA appearance rate fell during exercise, and plasma glycerol increased less than in C (P < 0.05). Fractional uptake of FFA across the working legs decreased from rest to exercise in all individuals (P < 0.05) but was always lower in SCI than in C (P < 0.05). From rest to exercise, leg FFA uptake increased less in SCI than in C subjects (14 [+ or -] 3 to 57 [+ or -] 20 vs. 41 [+ or -] 13 to 170 [+ or -] 57 [micro]mol * [min.sup.-1] * [leg.sup.-1]; P < 0.05). Muscle glycogen breakdown, leg glucose uptake, carbohydrate oxidation, and lactate release were higher (P < 0.05) in SCI than in C during exercise. Counterregulatory hormonal changes were more pronounced in SCI vs. C, whereas insulin decreased only in C. In conclusion, FFA mobilization, delivery, and fractional uptake are lower and muscle glycogen breakdown and glucose uptake are higher in SCI patients during electrically induced leg exercise compared with healthy subjects performing voluntary exercise. Apparently, blood-borne mechanisms are not sufficient to elicit a normal increase in fatty acid mobilization during exercise. Furthermore, in exercising muscle, FFA delivery enhances FFA uptake and inhibits carbohydrate metabolism, while carbohydrate metabolism inhibits FFA uptake. radiolabeled palmitate; free fatty acids; glycerol; lipid metabolism; epinephrine; norepinephrine; lipolysis; insulin; growth hormone; skeletal muscle; lactate; physical activity