Acute antioxidant supplementation and skeletal muscle vascular conductance in aged rats: role of exercise and fiber type

Age-related increases in oxidative stress contribute to impaired skeletal muscle vascular control. However, recent evidence indicates that antioxidant treatment with tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl) attenuates flow-mediated vasodilation in isolated arterioles from the highly oxidative soleus muscle of aged rats. Whether antioxidant treatment with tempol evokes similar responses in vivo at rest and during exercise in senescent individuals and whether this effect varies based on muscle fiber type composition are unknown. We tested the hypothesis that redox modulation via acute systemic tempol administration decreases vascular conductance (VC) primarily in oxidative hindlimb locomotor muscles at rest and during submaximal whole body exercise (treadmill running at 20 m/min, 5% grade) in aged rats. Eighteen old (25-26 mo) male Fischer 344 x Brown Norway rats were assigned to either rest (n = 8) or exercise (n = 10) groups. Regional VC was determined via radiolabeled microspheres before and after intra-arterial administration of tempol (302 μmol/kg). Tempol decreased mean arterial pressure significantly by 9% at rest and 16% during exercise. At rest, similar VC in 26 out of 28 individual hindlimb muscles or muscle parts following tempol administration compared with control resulted in unchanged total hindlimb muscle VC (control: 0.18 ± 0.02; tempol: 0.17 ± 0.05 ml·min(-1)·100 g(-1)·mmHg(-1); P > 0.05). During exercise, all individual hindlimb muscles or muscle parts irrespective of fiber type composition exhibited either an increase or no change in VC with tempol (i.e., ↑11 and ?17 muscles or muscle parts), such that total hindlimb VC increased by 25% (control: 0.93 ± 0.04; tempol: 1.15 ± 0.09 ml·min(-1)·100 g(-1)·mmHg(-1); P ≤ 0.05). These results demonstrate that acute systemic administration of the antioxidant tempol significantly impacts the control of regional vascular tone in vivo presumably via redox modulation and improves skeletal muscle vasodilation independently of fiber type composition during submaximal whole body exercise in aged rats.     

Contribution of adenosine to compensatory dilation in hypoperfused contracting human muscles is independent of nitric oxide

We previously demonstrated that nitric oxide (NO) contributes to compensatory vasodilation in the contracting human forearm subjected to acute hypoperfusion. We examined the potential role of an adenosine-NO interaction to this response in 17 male subjects (25 ± 2 yr). In separate protocols subjects performed rhythmic forearm exercise (20% of maximum) while hypoperfusion was evoked by balloon inflation in the brachial artery above the elbow. Each trial included exercise before inflation, exercise with inflation, and exercise after deflation (3 min each). Forearm blood flow (FBF; ultrasound) and local [brachial artery catheter pressure (BAP)] and systemic [mean arterial pressure (MAP); Finometer] arterial pressure were measured. In protocol 1 (n = 10), exercise was repeated during nitric oxide synthase inhibition [N(G)-monomethyl-L-arginine (L-NMMA)] alone and during L-NMMA-aminophylline (adenosine receptor blockade) administration. In protocol 2, exercise was repeated during aminophylline alone and during aminophylline-L-NMMA. Forearm vascular conductance (FVC; ml·min(-1)·100 mmHg(-1)) was calculated from blood flow (ml/min) and BAP (mmHg). Percent recovery in FVC during inflation was calculated as (steady-state inflation + exercise value - nadir)/[steady-state exercise (control) value - nadir]. In protocol 1, percent recovery in FVC was 108 ± 8% during the control (no drug) trial. Percent recovery in FVC was attenuated with inhibition of NO formation alone (78 ± 9%; P < 0.01 vs. control) and was attenuated further with combined inhibition of NO and adenosine (58 ± 9%; P < 0.01 vs. L-NMMA). In protocol 2, percent recovery was reduced with adenosine receptor blockade (74 ± 11% vs. 113 ± 6%, P < 0.01) compared with control drug trials. Percent recovery in FVC was attenuated further with combined inhibition of adenosine and NO (48 ± 11%; P < 0.05 vs. aminophylline). Our data indicate that adenosine contributes to compensatory vasodilation in an NO-independent manner during exercise with acute hypoperfusion.     

Prostaglandins do not contribute to the nitric oxide-mediated compensatory vasodilation in hypoperfused exercising muscle

We tested the hypothesis that 1) prostaglandins (PGs) contribute to compensatory vasodilation in contracting human forearm subjected to acute hypoperfusion, and 2) the combined inhibition of PGs and nitric oxide would attenuate the compensatory vasodilation more than PG inhibition alone. In separate protocols, subjects performed forearm exercise (20% of maximum) during hypoperfusion evoked by intra-arterial balloon inflation. Each trial included baseline, exercise before inflation, exercise with inflation, and exercise after deflation. Forearm blood flow (FBF; ultrasound) and local (brachial artery) and systemic arterial pressure [mean arterial pressure (MAP); Finometer] were measured. In protocol 1 (n = 8), exercise was repeated during cyclooxygenase (COX) inhibition (Ketorolac) alone and during Ketorolac-NOS inhibition [N(G)-monomethyl-l-arginine (l-NMMA)]. In protocol 2 (n = 8), exercise was repeated during l-NMMA alone and during l-NMMA-Ketorolac. Forearm vascular conductance (FVC; ml·min(-1)·100 mmHg(-1)) was calculated from FBF (ml/min) and local MAP (mmHg). The percent recovery in FVC during inflation was calculated as (steady-state inflation + exercise value - nadir)/[steady-state exercise (control) value - nadir] × 100. In protocol 1, COX inhibition alone did not reduce the %FVC recovery compared with the control (no drug) trial (92 ± 11 vs. 100 ± 10%, P = 0.83). However, combined COX-nitric oxide synthase (NOS) inhibition caused a substantial reduction in %FVC recovery (54 ± 8%, P < 0.05 vs. Ketorolac alone). In protocol 2, the percent recovery in FVC was attenuated with NOS inhibition alone (69 ± 9 vs. 107 ± 10%, P < 0.01) but not attenuated further during combined NOS-COX inhibition (62 ± 10%, P = 0.74 vs. l-NMMA alone). Our data indicate that PGs are not obligatory to the compensatory dilation observed during forearm exercise with hypoperfusion.     

Regional hemodynamics during postexercise hypotension. I. Splanchnic and renal circulations.

Moderate exercise elicits a relative postexercise hypotension that is caused by an increase in systemic vascular conductance. Previous studies have shown that skeletal muscle vascular conductance is increased postexercise. It is unclear whether these hemodynamic changes are limited to skeletal muscle vascular beds. The aim of this study was to determine whether the splanchnic and/or renal vascular beds also contribute to the rise in systemic vascular conductance during postexercise hypotension. A companion study aims to determine whether the cutaneous vascular bed is involved in postexercise hypotension (Wilkins BW, Minson CT, and Halliwill JR. J Appl Physiol 97: 2071-2076, 2004). Heart rate, arterial pressure, cardiac output, leg blood flow, splanchnic blood flow, and renal blood flow were measured in 13 men and 3 women before and through 120 min after a 60-min bout of exercise at 60% of peak oxygen uptake. Vascular conductances of leg, splanchnic, and renal vascular beds were calculated. One hour postexercise, mean arterial pressure was reduced (79.1 +/- 1.7 vs. 83.4 +/- 1.8 mmHg; P < 0.05), systemic vascular conductance was increased by approximately 10%, leg vascular conductance was increased by approximately 65%, whereas splanchnic (16.0 +/- 1.8 vs. 18.5 +/- 2.4 ml.min(-1).mmHg(-1); P = 0.13) and renal (20.4 +/- 3.3 vs. 17.6 +/- 2.6 ml.min(-1).mmHg(-1); P = 0.14) vascular conductances were unchanged compared with preexercise. This suggests there is neither vasoconstriction nor vasodilation in the splanchnic and renal vasculature during postexercise hypotension. Thus the splanchnic and renal vascular beds neither directly contribute to nor attenuate postexercise hypotension.     

Glycerol-induced fluid shifts attenuate the vestibulosympathetic reflex in humans

The glycerol dehydration test (GDT) has been used to test for the presence of Ménière's disease and elicits acute alterations in vestibular reflexes in both normal and pathological states. Activation of the vestibulosympathetic reflex (VSR) increases muscle sympathetic nerve activity (MSNA) and peripheral vascular resistance. We hypothesized that the GDT would attenuate the VSR through fluid shifts of the inner ear. Sixteen male subjects (26 ± 1 yr) were randomly assigned to be administered either glycerol mixed with cranberry juice (97 ± 3 ml glycerol + equal portion of cranberry juice; n = 9) or a placebo control [water + cranberry juice (100 ml each); n = 7]. Subjects in both groups performed head-down rotation (HDR), which engages the VSR, before and after administration of either the glycerol or placebo. MSNA (microneurography), arterial blood pressure, and leg blood flow (venous occlusion plethysmography) were measured during HDR. Before glycerol administration, HDR significantly increased MSNA burst frequency (Δ8 ± 1 bursts/min; P < 0.01) and total activity (Δ77 ± 18%; P < 0.01) and decreased calf vascular conductance (-Δ20 ± 3%; P < 0.01). However, HDR performed postadministration of glycerol resulted in an attenuated MSNA increase (Δ3 ± 1 bursts/min, Δ22 ± 3% total activity) and decrease in calf vascular conductance (-Δ7 ± 4%). HDR significantly increased MSNA burst frequency (Δ5 ± 1 and Δ5 ± 2 bursts/min) and total activity (Δ58 ± 13% and Δ52 ± 18%) in the placebo group before and after placebo, respectively (P < 0.01). Likewise, decreases in calf vascular conductance during HDR before and after placebo were not different (-Δ13 ± 4% and -Δ14 ± 2%, respectively; P < 0.01). These results suggest that fluid shifts of the inner ear via glycerol dehydration attenuate the VSR. These data provide support that inner ear fluid dynamics can have a significant impact on blood pressure regulation via the VSR in humans.     

Systemic alpha-adrenergic and nitric oxide inhibition on basal limb blood flow: effects of endurance training in middle-aged and older adults

Endurance training improves endothelium-dependent vasodilation, yet it does not increase basal blood flow in the legs. We determined the effects of a 3-mo aerobic exercise intervention on basal leg blood flow and alpha-adrenergic vasoconstriction and nitric oxide (NO) release in seven apparently healthy middle-aged and older adults (60 +/- 3 yr). Basal femoral artery blood flow (via Doppler ultrasound) (pretraining: 354 +/- 29; posttraining: 335 +/- 34 ml/min) and vascular conductance did not change significantly with the exercise training. Before the exercise intervention, femoral artery blood flow increased 32 +/- 16% with systemic alpha-adrenergic blockade (with phentolamine) (P < 0.05), and the addition of nitric oxide synthase (NOS) inhibition using N(G)-monomethyl-L-arginine (L-NMMA) did not affect femoral artery blood flow. After training was completed, femoral artery blood flow increased 47 +/- 7% with alpha-adrenergic blockade (P < 0.01) and then decreased 18 +/- 7% with the subsequent administration of L-NMMA (P < 0.05). Leg vascular conductance showed a greater alpha-adrenergic blockade-induced vasodilation (+1.7 +/- 0.5 to +3.0 +/- 0.5 units, P < 0.05) as well as NOS inhibition-induced vasoconstriction (-0.8 +/- 0.4 to -2.7 +/- 0.7 units, P < 0.05) after the exercise intervention. Resting plasma norepinephrine concentration significantly increased after the training. These results suggest that regular aerobic exercise training enhances NO bioavailability in middle-aged and older adults and that basal limb blood flow does not change with exercise training because of the contrasting influences of sympathetic nervous system activity and endothelium-derived vasodilation on the vasculature.     

Erythropoietin for the Treatment of Subarachnoid Hemorrhage: A Feasible Ingredient for a Successful Medical Recipe

Subarachnoid hemorrhage (SAH) following aneurysm bleeding accounts for 6% to 8% of all cerebrovascular accidents. Although an aneurysm can be effectively managed by surgery or endovascular therapy, delayed cerebral ischemia is diagnosed in a high percentage of patients resulting in significant morbidity and mortality. Cerebral vasospasm occurs in more than half of all patients after aneurysm rupture and is recognized as the leading cause of delayed cerebral ischemia after SAH. Hemodynamic strategies and endovascular procedures may be considered for the treatment of cerebral vasospasm. In recent years, the mechanisms contributing to the development of vasospasm, abnormal reactivity of cerebral arteries and cerebral ischemia following SAH, have been investigated intensively. A number of pathological processes have been identified in the pathogenesis of vasospasm, including endothelial injury, smooth muscle cell contraction from spasmogenic substances produced by the subarachnoid blood clots, changes in vascular responsiveness and inflammatory response of the vascular endothelium. To date, the current therapeutic interventions remain ineffective as they are limited to the manipulation of systemic blood pressure, variation of blood volume and viscosity and control of arterial carbon dioxide tension. In this scenario, the hormone erythropoietin (EPO) has been found to exert neuroprotective action during experimental SAH when its recombinant form (rHuEPO) is administered systemically. However, recent translation of experimental data into clinical trials has suggested an unclear role of recombinant human EPO in the setting of SAH. In this context, the aim of the current review is to present current evidence on the potential role of EPO in cerebrovascular dysfunction following aneurysmal subarachnoid hemorrhage.     

Effects of hyperglycemia on the cerebrovascular response to rhythmic handgrip exercise

Dynamic cerebral autoregulation (CA) is challenged by exercise and may become less effective when exercise is exhaustive. Exercise may increase arterial glucose concentration, and we evaluated whether the cerebrovascular response to exercise is affected by hyperglycemia. The effects of a hyperinsulinemic euglycemic clamp (EU) and hyperglycemic clamp (HY) on the cerebrovascular (CVRI) and systemic vascular resistance index (SVRI) responses were evaluated in seven healthy subjects at rest and during rhythmic handgrip exercise. Transfer function analysis of the dynamic relationship between beat-to-beat changes in mean arterial pressure and middle cerebral artery (MCA) mean blood flow velocity (V(mean)) was used to assess dynamic CA. At rest, SVRI decreased with HY and EU (P < 0.01). CVRI was maintained with EU but became reduced with HY [11% (SD 3); P < 0.01], and MCA V(mean) increased (P < 0.05), whereas brain catecholamine uptake and arterial Pco(2) did not change significantly. HY did not affect the normalized low-frequency gain between mean arterial pressure and MCA V(mean) or the phase shift, indicating maintained dynamic CA. With HY, the increase in CVRI associated with exercise was enhanced (19 +/- 7% vs. 9 +/- 7%; P < 0.05), concomitant with a larger increase in heart rate and cardiac output and a larger reduction in SVRI (22 +/- 4% vs. 14 +/- 2%; P < 0.05). Thus hyperglycemia lowered cerebral vascular tone independently of CA capacity at rest, whereas dynamic CA remained able to modulate cerebral blood flow around the exercise-induced increase in MCA V(mean). These findings suggest that elevated blood glucose does not explain that dynamic CA is affected during intense exercise.     

Melatonin differentially affects vascular blood flow in humans

Melatonin is synthesized and released into the circulation by the pineal gland in a circadian rhythm. Melatonin has been demonstrated to differentially alter blood flow to assorted vascular beds by the activation of different melatonin receptors in animal models. The purpose of the present study was to determine the effect of melatonin on blood flow to various vascular beds in humans. Renal (Doppler ultrasound), forearm (venous occlusion plethysmography), and cerebral blood flow (transcranial Doppler), arterial blood pressure, and heart rate were measured in 10 healthy subjects (29±1 yr; 5 men and 5 women) in the supine position for 3 min. The protocol began 45 min after the ingestion of either melatonin (3 mg) or placebo (sucrose). Subjects returned at least 2 days later at the same time of day to repeat the trial after ingesting the other substance. Melatonin did not alter heart rate and mean arterial pressure. Renal blood flow velocity (RBFV) and renal vascular conductance (RVC) were lower during the melatonin trial compared with placebo (RBFV, 40.5±2.9 vs. 45.4±1.5 cm/s; and RVC, 0.47±0.02 vs. 0.54±0.01 cm·s(-1)·mmHg(-1), respectively). In contrast, forearm blood flow (FBF) and forearm vascular conductance (FVC) were greater with melatonin compared with placebo (FBF, 2.4±0.2 vs. 1.9±0.1 ml·100 ml(-1)·min(-1); and FVC, 0.029±0.003 vs. 0.023±0.002 arbitrary units, respectively). Melatonin did not alter cerebral blood flow measurements compared with placebo. Additionally, phentolamine (5-mg bolus) after melatonin reversed the decrease in RVC, suggesting that melatonin increases sympathetic outflow to the kidney to mediate renal vasoconstriction. In summary, exogenous melatonin differentially alters vascular blood flow in humans. These data suggest the complex nature of melatonin on the vasculature in humans.     

THE COMBINATION OF α-LIPOIC ACID INTAKE WITH ECCENTRIC EXERCISE MODULATES ERYTHROPOIETIN RELEASE

The generation of reactive nitrogen/oxygen species (RN/OS) represents an important mechanism in erythropoietin (EPO) expression and skeletal muscle adaptation to physical and metabolic stress. RN/OS generation can be modulated by intense exercise and nutrition supplements such as α-lipoic acid, which demonstrates both anti- and pro-oxidative action. The study was designed to show the changes in the haematological response through the combination of α-lipoic acid intake with running eccentric exercise. Sixteen healthy young males participated in the randomised and placebo-controlled study. The exercise trial involved a 90-min run followed by a 15-min eccentric phase at 65% VO₂max (-10% gradient). It significantly increased serum concentrations of nitric oxide (NO), hydrogen peroxide (H₂O₂) and pro-oxidative products such as 8-isoprostanes (8-iso), lipid peroxides (LPO) and protein carbonyls (PC). α-Lipoic acid intake (Thiogamma: 1200 mg daily for 10 days prior to exercise) resulted in a 2-fold elevation of serum H₂O₂ concentration before exercise, but it prevented the generation of NO, 8-iso, LPO and PC at 20 min, 24 h, and 48 h after exercise. α-Lipoic acid also elevated serum EPO level, which highly correlated with NO/H₂O₂ ratio (r = 0.718, P < 0.01). Serum total creatine kinase (CK) activity, as a marker of muscle damage, reached a peak at 24 h after exercise (placebo 732 ± 207 IU · L^-1, α-lipoic acid 481 ± 103 IU · L^-1), and correlated with EPO (r = 0.478, P < 0.01) in the α-lipoic acid group. In conclusion, the intake of high α-lipoic acid modulates RN/OS generation, enhances EPO release and reduces muscle damage after running eccentric exercise.     

Systemic Administration of Erythropoietin Inhibits Retinopathy in RCS Rats

Objective

Royal College of Surgeons (RCS) rats develop vasculopathy as photoreceptors degenerate. The aim of this study was to examine the effect of erythropoietin (EPO) on retinopathy in RCS rats.

Methods

Fluorescein angiography was used to monitor retinal vascular changes over time. Changes in retinal glia and vasculature were studied by immunostaining. To study the effects of EPO on retinal pathology, EPO (5000 IU/kg) was injected intraperitoneally in 14 week old normal and RCS rats twice a week for 4 weeks. Changes in the retinal vasculature, glia and microglia, photoreceptor apoptosis, differential expression of p75 neurotrophin receptor (p75^NTR), pro-neurotrophin 3 (pro-NT3), tumour necrosis factor-α (TNFα), pigment epithelium derived factor (PEDF) and vascular endothelial growth factor-A (VEGF-A), the production of CD34⁺ cells and mobilization of CD34⁺/VEGF-R2⁺ cells as well as recruitment of CD34⁺ cells into the retina were examined after EPO treatment.

Results

RCS rats developed progressive capillary dropout and subretinal neovascularization which were accompanied by retinal gliosis. Systemic administration of EPO stabilized the retinal vasculature and inhibited the development of focal vascular lesions. Further studies showed that EPO modulated retinal gliosis, attenuated photoreceptor apoptosis and p75^NTR and pro-NT3 upregulation, promoted the infiltration of ramified microglia and stimulated VEGF-A expression but had little effect on TNFα and PEDF expression. EPO stimulated the production of red and white blood cells and CD34⁺ cells along with effective mobilization of CD34⁺/VEGF-R2⁺ cells. Immunofluorescence study demonstrated that EPO enhanced the recruitment of CD34⁺ cells into the retina.

Conclusions

Our results suggest that EPO has therapeutic potentials in treatment of neuronal and vascular pathology in retinal disease. The protective effects of EPO on photoreceptors and the retinal vasculature may involve multiple mechanisms including regulation of retinal glia and microglia, inhibition of p75^NTR-pro-NT3 signaling together with stimulation of production and mobilization of bone marrow derived cells.     

Effects of ATP-induced leg vasodilation on VO2 peak and leg O2 extraction during maximal exercise in humans

During maximal whole body exercise VO2 peak is limited by O2 delivery. In turn, it is though that blood flow at near-maximal exercise must be restrained by the sympathetic nervous system to maintain mean arterial pressure. To determine whether enhancing vasodilation across the leg results in higher O2 delivery and leg VO2 during near-maximal and maximal exercise in humans, seven men performed two maximal incremental exercise tests on the cycle ergometer. In random order, one test was performed with and one without (control exercise) infusion of ATP (8 mg in 1 ml of isotonic saline solution) into the right femoral artery at a rate of 80 microg.kg body mass-1.min-1. During near-maximal exercise (92% of VO2 peak), the infusion of ATP increased leg vascular conductance (+43%, P<0.05), leg blood flow (+20%, 1.7 l/min, P<0.05), and leg O2 delivery (+20%, 0.3 l/min, P<0.05). No effects were observed on leg or systemic VO2. Leg O2 fractional extraction was decreased from 85+/-3 (control) to 78+/-4% (ATP) in the infused leg (P<0.05), while it remained unchanged in the left leg (84+/-2 and 83+/-2%; control and ATP; n=3). ATP infusion at maximal exercise increased leg vascular conductance by 17% (P<0.05), while leg blood flow tended to be elevated by 0.8 l/min (P=0.08). However, neither systemic nor leg peak VO2 values where enhanced due to a reduction of O2 extraction from 84+/-4 to 76+/-4%, in the control and ATP conditions, respectively (P<0.05). In summary, the VO2 of the skeletal muscles of the lower extremities is not enhanced by limb vasodilation at near-maximal or maximal exercise in humans. The fact that ATP infusion resulted in a reduction of O2 extraction across the exercising leg suggests a vasodilating effect of ATP on less-active muscle fibers and other noncontracting tissues and that under normal conditions these regions are under high vasoconstrictor influence to ensure the most efficient flow distribution of the available cardiac output to the most active muscle fibers of the exercising limb.     

High dose Erythropoietin increases brain tissue oxygen tension in Severe Vasospasm after Subarachnoid Hemorrhage

ABSTRACT: BACKGROUND: Vasospasm-related delayed cerebral ischemia (DCI) significantly impacts on outcome after aneurysmal subarachnoid hemorrhage (SAH). Erythropoietin (EPO) may reduce the severity of cerebral vasospasm and improve outcome, however, underlying mechanisms are incompletely understood. In this study, the authors aimed to investigate the effect of EPO on cerebral metabolism and brain tissue oxygen tension (PbtO2). METHODS: Seven consecutive poor grade SAH patients with multimodal neuromonitoring (MM) received systemic EPO therapy (30.000 IU per day for 3 consecutive days) for severe cerebral vasospasm. Cerebral perfusion pressure (CPP), mean arterial blood pressure (MAP), intracranial pressure (ICP), PbtO2 and brain metabolic changes were analyzed during the next 24 hours after each dose given. Statistical analysis was performed with a mixed effects model. RESULTS: A total of 22 interventions were analyzed. Median age was 47 years (32-68) and 86% were female. Three patients (38%) developed DCI. MAP slightly decreased 2 hours after intervention (P<0.04) without significantly affecting CPP and ICP. PbtO2 significantly increased over time (P<0.05) to a maximum of 7+/-4mmHg increase 16 hours after infusion. Brain metabolic parameters did not change over time. CONCLUSIONS: EPO increases PbtO2 in poor grade SAH patients with severe cerebral vasospasm. The effect on outcome needs further investigation.     

Cardiopulmonary baroreflex is reset during dynamic exercise.

The purpose of this study was to examine the hypothesis that the operating point of the cardiopulmonary baroreflex resets to the higher cardiac filling pressure of exercise associated with the increased cardiac filling volumes. Eight men (age 26 +/- 1 yr; height 180 +/- 3 cm; weight 86 +/- 6 kg; means +/- SE) participated in the present study. Lower body negative pressure (LBNP) was applied at 8 and 16 Torr to decrease central venous pressure (CVP) at rest and during steady-state leg cycling at 50% peak oxygen uptake (104 +/- 20 W). Subsequently, two discrete infusions of 25% human serum albumin solution were administered until CVP was increased by 1.8 +/- 0.6 and 2.4 +/- 0.4 mmHg at rest and 2.9 +/- 0.9 and 4.6 +/- 0.9 mmHg during exercise. During all protocols, heart rate, arterial blood pressure, and CVP were recorded continuously. At each stage of LBNP or albumin infusion, forearm blood flow and cardiac output were measured. During exercise, forearm vascular conductance increased from 7.5 +/- 0.5 to 8.7 +/- 0.6 U (P = 0.024) and total systemic vascular conductance from 7.2 +/- 0.2 to 13.5 +/- 0.9 l.min(-1).mmHg(-1) (P < 0.001). However, there was no significant difference in the responses of both forearm vascular conductance and total systemic vascular conductance to LBNP and the infusion of albumin between rest and exercise. These data indicate that the cardiopulmonary baroreflex had been reset during exercise to the new operating point associated with the exercise-induced change in cardiac filling volume.     

Leg vasoconstriction during dynamic exercise with reduced cardiac output.

We evaluated whether a reduction in cardiac output during dynamic exercise results in vasoconstriction of active skeletal muscle vasculature. Nine subjects performed four 8-min bouts of cycling exercise at 71 +/- 12 to 145 +/- 13 W (40-84% maximal oxygen uptake). Exercise was repeated after cardioselective (beta 1) adrenergic blockade (0.2 mg/kg metoprolol iv). Leg blood flow and cardiac output were determined with bolus injections of indocyanine green. Femoral arterial and venous pressures were monitored for measurement of heart rate, mean arterial pressure, and calculation of systemic and leg vascular conductance. Leg norepinephrine spillover was used as an index of regional sympathetic activity. During control, the highest heart rate and cardiac output were 171 +/- 3 beats/min and 18.9 +/- 0.9 l/min, respectively. beta 1-Blockade reduced these values to 147 +/- 6 beats/min and 15.3 +/- 0.9 l/min, respectively (P < 0.001). Mean arterial pressure was lower than control during light exercise with beta 1-blockade but did not differ from control with greater exercise intensities. At the highest work rate in the control condition, leg blood flow and vascular conductance were 5.4 +/- 0.3 l/min and 5.2 +/- 0.3 cl.min-1.mmHg-1, respectively, and were reduced during beta 1-blockade to 4.8 +/- 0.4 l/min (P < 0.01) and 4.6 +/- 0.4 cl.min-1.mmHg-1 (P < 0.05). During the same exercise condition leg norepinephrine spillover increased from a control value of 2.64 +/- 1.16 to 5.62 +/- 2.13 nM/min with beta 1-blockade (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparative study of C-Reactive Protein and other biochemical parameters in patients with hepatitis B and malaria in Calabar, Nigeria

Serum levels of C-reactive proteins (CRP), Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), total protein, albumin and globulins were investigated using high sensitivity Immunoturbidometric and colorimetric techniques in individuals with hepatitis (n=50), Malaria (n=50) and 40 control subjects in age range of 30 to 65 years. The hepatitis patients had a significantly higher (P < 0.01) level of aminotransferases when compared to malaria patients and control subjects. The mean value of ALT was 103.50 ± 71.4 IU/L and 46.72 ±17.48 IU/L for hepatitis and malaria respectively. The values for AST were 116.76 ± 63.27 IU/L and 57.74 IU/L ± 15.18 IU/L for hepatitis and malaria respectively while the values for control were 34.75 ± 14.64 and 35.25 ± 15.56 IU/L for AST and ALT respectively. The malaria patients showed a significantly higher level (P < 0.01) of aminotransferases when compared to the control. The mean serum CRP levels were 0.71 ± 0.11 mg/dL and 0.78 ± 0.13 mg/dL for hepatitis and malaria respectively. These values were significantly higher (P < 0.01) than those of the controls which was 0.32 ± 0.12 mg/dL. The values of CRP in malaria were significantly higher (P< 0.05) when compared with hepatitis. In malaria, AST correlated with CRP (r = 0.58). The mean serum proteins of hepatitis patients were significantly lower (P < 0.05) than those of the control and malaria while there were no significant differences between the total protein in malaria when compared with control. Albumin levels in both patients were significantly lower (P > 0.05) than those of the controls. The mean values were 33.40 ± 3.40g/L and 34.47 ± 3.56g/L for hepatitis and malaria respectively and 37.00 ± 3.43 g/L for the control. C-reactive protein correlated negatively with albumin in malaria (r = -0.26) while albumin had a negative correlation with globulin(r = -0.36). Also albumin-globulin ratio were significantly (P < 0.05) decreased in both patients when compared with controls. This result suggests that a systemic acute phase response is present in hepatitis and malaria patients hence measurement of C-reactive proteins may be helpful in the diagnosis and management of hepatitis and malaria; especially in the malaria endemic region such as Nigeria. Keywords: Hepatitis B, Malaria, C-reactive protein, Liver function tests.     

Cerebral autoregulation dynamics in endurance-trained individuals

Aerobic fitness may be associated with reduced orthostatic tolerance. To investigate whether trained individuals have less effective regulation of cerebral vascular resistance, we studied the middle cerebral artery (MCA) mean blood velocity (V(mean)) response to a sudden drop in mean arterial pressure (MAP) after 2.5 min of leg ischemia in endurance athletes and untrained subjects (maximal O(2) uptake: 69 ± 7 vs. 42 ± 5 ml O(2)·min(-1)·kg(-1); n = 9 for both, means ± SE). After cuff release when seated, endurance athletes had larger drops in MAP (94 ± 6 to 62 ± 5 mmHg, -39%, vs. 99 ± 5 to 73 ± 4 mmHg, -26%) and MCA V(mean) (53 ± 3 to 37 ± 2 cm/s, -30%, vs. 58 ± 3 to 43 ± 2 cm/s, -25%). The athletes also had a slower recovery to baseline of both MAP (25 ± 2 vs. 16 ± 1 s, P < 0.01) and MCA V(mean) (15 ± 1 vs. 11 ± 1 s, P < 0.05). The onset of autoregulation, determined by the time point of increase in the cerebrovascular conductance index (CVCi = MCA V(mean)/MAP) appeared later in the athletes (3.9 ± 0.4 vs. 2.7 ± 0.4s, P = 0.01). Spectral analysis revealed a normal MAP-to-MCA V(mean) phase in both groups but ~40% higher normalized MAP to MCA V(mean) low-frequency transfer function gain in the trained subjects. No significant differences were detected in the rates of recovery of MAP and MCA V(mean) and the rate of CVCi regulation (18 ± 4 vs. 24 ± 7%/s, P = 0.2). In highly trained endurance athletes, a drop in blood pressure after the release of resting leg ischemia was more pronounced than in untrained subjects and was associated with parallel changes in indexes of cerebral blood flow. Once initiated, the autoregulatory response was similar between the groups. A delayed onset of autoregulation with a larger normalized transfer gain conforms with a less effective dampening of MAP oscillations, indicating that athletes may be more prone to instances of symptomatic cerebral hypoperfusion when MAP declines.     

Effects of dehydration on cerebrovascular control during standing after heavy resistance exercise

We tested the hypothesis that dehydration exacerbates reductions of middle cerebral artery blood velocity (MCAv) and alters cerebrovascular control during standing after heavy resistance exercise. Ten males participated in two trials under 1) euhydration (EUH) and 2) dehydration (DEH; fluid restriction + 40 mg furosemide). We recorded finger photoplethysmographic arterial pressure and MCAv (transcranial Doppler) during 10 min of standing immediately after high-intensity leg press exercise. Symptoms (e.g., lightheadedness) were ranked by subjects during standing (1-5 scale). Low-frequency (LF) oscillations of mean arterial pressure (MAP) and mean MCAv were calculated as indicators of cerebrovascular control. DEH reduced plasma volume by 11% (P = 0.002; calculated from hemoglobin and hematocrit). During the first 30 s of standing after exercise, subjects reported greater symptoms during DEH vs. EUH (P = 0.05), but these were mild and resolved at 60 s. While MAP decreased similarly between conditions immediately after standing, MCAv decreased more with DEH than EUH (P = 0.02). With prolonged standing under DEH, mean MCAv remained below baseline (P ≤ 0.01), and below EUH values (P ≤ 0.05). LF oscillations of MAP were higher for DEH at baseline and during the entire 10 min of stand after exercise (P ≤ 0.057), while LF oscillations in mean MCAv were distinguishable only at baseline and 5 min following stand (P = 0.05). Our results suggest that mean MCAv falls below a "symptomatic threshold" in the acute phase of standing after exercise during DEH, although symptoms were mild and transient. During the prolonged phase of standing, increases in LF MAP and mean MCAv oscillations with DEH may help to maintain cerebral perfusion despite absolute MCAv remaining below the symptomatic threshold.     

Effects of the menstrual cycle and sex on postexercise hemodynamics

Factors associated with the menstrual cycle, such as the endogenous hormones estrogen and progesterone, have dramatic effects on cardiovascular regulation. It is unknown how this affects postexercise hemodynamics. Therefore, we examined the effects of the menstrual cycle and sex on postexercise hemodynamics. We studied 14 normally menstruating women [24.0 (4.2) yr; SD] and 14 men [22.5 (3.5) yr] before and through 90 min after cycling at 60% .VO2(peak) for 60 min. Women were studied during their early follicular, ovulatory, and mid-luteal phases; men were studied once. In men and women during all phases studied, mean arterial pressure was decreased after exercise throughout 60 min (P < 0.001) postexercise and returned to preexercise values at 90 min (P = 0.089) postexercise. Systemic vascular conductance was increased following exercise in both sexes throughout 60 min (P = 0.005) postexercise and tended to be elevated at 90 min postexercise (P = 0.052), and femoral vascular conductance was increased following exercise throughout 90 min (P < 0.001) postexercise. Menstrual phase and sex had no effect on the percent reduction in arterial pressure (P = 0.360), the percent rise in systemic vascular conductance (P = 0.573), and the percent rise in femoral vascular conductance (P = 0.828) from before to after exercise, nor did the pattern of these responses differ across recovery with phase or sex. This suggests that postexercise hemodynamics are largely unaffected by sex or factors associated with the menstrual cycle.     

H2-receptor-mediated vasodilation contributes to postexercise hypotension.

The early (approximately 30 min) postexercise hypotension response after a session of aerobic exercise is due in part to H1-receptor-mediated vasodilation. The purpose of this study was to determine the potential contribution of H2-receptor-mediated vasodilation to postexercise hypotension. We studied 10 healthy normotensive men and women (ages 23.7 +/- 3.4 yr) before and through 90 min after a 60-min bout of cycling at 60% peak O2 uptake on randomized control and H2-receptor antagonist days (300 mg oral ranitidine). Arterial pressure (automated auscultation), cardiac output (acetylene washin) and femoral blood flow (Doppler ultrasound) were measured. Vascular conductance was calculated as flow/mean arterial pressure. Sixty minutes postexercise on the control day, femoral (delta62.3 +/- 15.6%, where Delta is change; P < 0.01) and systemic (delta13.8 +/- 5.3%; P = 0.01) vascular conductances were increased, whereas mean arterial pressure was reduced (Delta-6.7 +/- 1.1 mmHg; P < 0.01). Conversely, 60 min postexercise with ranitidine, femoral (delta9.4 +/- 9.2%; P = 0.34) and systemic (delta-2.8 +/- 4.8%; P = 0.35) vascular conductances were not elevated and mean arterial pressure was not reduced (delta-2.2 +/- 1.3 mmHg; P = 0.12). Furthermore, postexercise femoral and systemic vascular conductances were lower (P < 0.05) and mean arterial pressure was higher (P = 0.01) on the ranitidine day compared with control. Ingestion of ranitidine markedly reduces vasodilation after exercise and blunts postexercise hypotension, suggesting H2-receptor-mediated vasodilation contributes to postexercise hypotension.