Decrease in cardiac output and muscle sympathetic activity during vasovagal syncope

The importance of cardiac output (CO) to blood pressure level during vasovagal syncope is unknown. We measured thermodilution CO, mean blood pressure (MBP), and leg muscle mean sympathetic nerve activity (MSNA) each minute during 60 degrees head-up tilt in 26 patients with recurrent syncope. Eight patients tolerated tilt (TT) for 45 min (mean age 60 +/- 5 yr) and 15 patients developed syncope during tilt (TS) (mean age 58 +/- 4 yr, mean tilt time 15.4 +/- 2 min). In TT patients, CO decreased during the first minute of tilt (from 3.2 +/- 0.2 to 2.5 +/- 0.3 l x min(-1) x m(-2), P = 0.001) and thereafter remained stable between 2.5 +/- 0.3 (P = 0.001) and 2.4 +/- 0.2 l x min(-1) x m(-2) (P = 0.004) at 5 and 45 min, respectively. In TS patients, CO decreased during the first minute (from 3.3 +/- 0.2 to 2.7 +/- 0.1 l x min(-1) x m(-2), P = 0.02) and was stable until 7 min before syncope, falling to 2.0 +/- 0.2 at syncope (P = 0.001). Regression slopes for CO versus time during tilt were -0.01 min(-1) in TT versus -0.1 l x min(-1) x m(-2) x min(-1) in TS (P = 0.001). However, MBP was more closely correlated to total peripheral resistance (R = 0.56, P = 0.001) and MSNA (R = 0.58, P = 0.001) than CO (R = 0.32, P = 0.001). In vasovagal reactions, a progressive decline in CO may contribute to hypotension some minutes before syncope occurs.     

Hemodynamic effects of nicotine in canine skeletal muscle.

Studies were conducted in 36 artificially ventilated, anesthetized dogs to clarify hemodynamic effects of nicotine in resting gracilis muscle. In Series 1, effects of intravenous nicotine (36 micrograms/kg/min) were evaluated in (i) intact muscles (Condition 1), (ii) denervated muscles (Condition 2), (iii) denervated muscles following local alpha-adrenergic blockade (Condition 3), (iv) denervated muscles following combined local alpha- and beta-adrenergic blockade (Condition 4), and (v) intact muscles with aortic pressure maintained constant (Condition 5). In Series 2, nicotine was infused directly into the gracilis artery at a rate of 3.6 micrograms/kg/min. Muscle blood flow was obtained with an electromagnetic flowmeter and used to calculate vascular resistance and oxygen consumption (Fick equation). Plasma catecholamine levels were determined with a radioenzymatic method. Intravenous nicotine doubled mean aortic pressure under Conditions 1-4. In intact and denervated muscles (Conditions 1 and 2) proportional increases in vascular resistance, reflective of vasoconstriction, held blood flow constant. Muscle oxygen consumption was unchanged. alpha-Adrenergic blockade with phenoxybenzamine following denervation (Condition 3) converted muscle vasoconstriction to vasodilation during nicotine infusion. Additional beta-adrenergic blockade (Condition 4) restored muscle vasoconstriction. Nicotine-induced muscle vasoconstriction was maintained under controlled pressure (Condition 5). Intravenous nicotine significantly increased plasma catecholamine levels. Intra-arterial infusions of nicotine (Series 2) caused no hemodynamic changes in muscle. In conclusion, intravenous nicotine caused vasoconstriction in muscle, which was not due to reduced metabolic demand, pressure-flow autoregulation, or a direct [corrected] effect on vascular smooth muscle, but to stimulation of alpha-adrenergic receptors. Following denervation, this vasoconstriction was maintained by elevated plasma catecholamines. alpha-Adrenergic blockade unmasked nicotine-induced vasodilation mediated by beta-adrenergic receptors, whereas combined alpha- and beta-adrenergic blockade unmasked nicotine-induced vasoconstriction by a nonadrenergic mechanism.     

Leg crossing, muscle tensing, squatting, and the crash position are effective against vasovagal reactions solely through increases in cardiac output.

Tensing of lower body muscles without or with leg crossing (LBMT, LCMT), whole body tensing (WBT), squatting, and sitting with the head bent between the knees ("crash position", HBK) are believed to abort vasovagal reactions. The underlying mechanisms are unknown. To study these interventions in patients with a clinical history of vasovagal syncope and a vasovagal reaction during routine tilt table testing, we measured blood pressure (BP) continuously with Finapres and derived heart rate, stroke volume, cardiac output (CO), and total peripheral resistance using Modelflow. In series A (n = 12) we compared LBMT to LCMT. In series B (n = 9), WBT was compared with LCMT. In series C (n = 14) and D (n = 9), we tested squatting and HBK. All maneuvers caused an increase in BP, varying from a systolic rise from 77 +/- 8 to 104 +/- 18 mmHg (P < 0.05) in series A during LBMT to a rise from 70 +/- 10 to 123 +/- 9 mmHg (P < 0.05) in series B during LCMT. In each maneuver, the BP increase started within 3-5 s from start of the maneuver. In all maneuvers, there was an increase in CO varying from 54 +/- 12% of baseline to 94 +/- 21% in WBT to a rise from 65 +/- 17% to 110 +/- 22% in LCMT in series A. No maneuver caused significant change in total peripheral resistance. We conclude that the mechanism underlying the effects of these maneuvers is exclusively an increase in CO.     

Sympathetic withdrawal and forearm vasodilation during vasovagal syncope in humans

Dietz, Niki M., John R. Halliwill, John M. Spielmann, LoriA. Lawler, Bettina G. Papouchado, Tamara J. Eickhoff, and Michael J. Joyner. Sympathetic withdrawal and forearm vasodilation duringvasovagal syncope in humans. J. Appl.Physiol. 82(6): 1785-1793, 1997.Our aim was todetermine whether sympathetic withdrawal alone can account for theprofound forearm vasodilation that occurs during syncope in humans. Wealso determined whether either vasodilating ₂-adrenergic receptors ornitric oxide (NO) contributes to this dilation. Forearm blood flow wasmeasured bilaterally in healthy volunteers(n = 10) by using plethysmographyduring two bouts of graded lower body negative pressure (LBNP) tosyncope. In one forearm, drugs were infused via a brachial arterycatheter while the other forearm served as a control. In the controlarm, forearm vascular resistance (FVR) increased from 77 ± 7 unitsat baseline to 191 ± 36 units with 40 mmHg of LBNP(P < 0.05). Mean arterial pressurefell from 94 ± 2 to 47 ± 4 mmHg just before syncope, and allsubjects demonstrated sudden bradycardia at the time of syncope. At theonset of syncope, there was sudden vasodilation and FVR fell to 26 ± 6 units (P < 0.05 vs. baseline). When the experimental forearm was treated withbretylium, phentolamine, and propranolol, baseline FVR fell to 26 ± 2 units, the vasoconstriction during LBNP was absent, and FVR fellfurther to 16 ± 1 units at syncope(P < 0.05 vs. baseline). During thesecond trial of LBNP, mean arterial pressure again fell to 47 ± 4 mmHg and bradycardia was again observed. Treatment of the experimentalforearm with the NO synthase inhibitorN^G-monomethyl-L-arginine in additionto bretylium, phentolamine, and propranolol significantly increasedbaseline FVR to 65 ± 5 units but did not prevent the marked forearmvasodilation during syncope (FVR = 24 ± 4 vs. 29 ± 8 units inthe control forearm). These data suggest that the profound vasodilationobserved in the human forearm during syncope is not mediated solely bysympathetic withdrawal and also suggest that neither₂-adrenergic-receptor-mediated vasodilation nor NO is essential to observe this response.

     

Effect of long-term bedrest on lower leg muscle activation patterns during quiet standing

It has been well known that balance instabilities after long-term exposure to microgravity (e.g., Anderson et al. 1986) or bedrest (BR) can be related to alterations and/or adaptations to postural control strategies. Little is known, however, how the reduced muscular activity affects the activation pattern of the lower limb muscles during quiet standing (QS). The purpose of this study was to investigate whether or not any changes in the lower limb muscle activation patterns during QS would occur after BR.     

Response of plasma renin activity to postural change in vasovagal syncope in children, with observations on syncope

37 children aged 7-14 years with a history of repetitive fainting (vasovagal syncope) were studied. Plasma renin activity (PRA), blood pressure and heart rate were measured before and after standing for 15 min. Standing PRA was significantly higher in cases of fainting (n = 14) than in cases of nonfainting (n = 23). A significant positive correlation was observed between PRA and fall in systolic blood pressure on standing in cases of fainting, but not in cases of nonfainting. These findings suggest that the renin-angiotensin system may respond to the fall in blood pressure in children subject to fainting, unlike their adult counterparts previously reported.     

Changes in force and stiffness during stretch of skeletal muscle fibers, effects of hypertonicity.

Slow stretch ramps (velocity: 0.17 fiber lengths s-1) were imposed during fused tetanic contractions of intact muscle fibers of the frog (1.4-3.0 degrees C; sarcomere length: 2.12-2.21 microns). Instantaneous force-extension relations were derived both under isometric conditions and during slow stretch by applying fast (0.2 ms) length steps to the fiber. An increase in tonicity (98 mM sucrose added to control Ringer solution) led to significant reduction of the maximum isometric tension but at the same time to marked increase in the force enhancement during slow stretch. The maximum force level reached during the stretch was affected very little. Experiments on relaxed fibers showed that recruitment of passive parallel elastic components were of no relevance for these effects. Hypertonicity slightly increased the instantaneous stiffness of the active fiber both in the presence and in the absence of stretch. The total extension of the undamped fiber elasticity was considerably reduced by increased tonicity under isometric conditions but was only slightly affected during slow stretch. The change in length of the undamped cross-bride elasticity upon stretch was thus greater in the hypertonic than in the normotonic solution suggesting a greater increase in force per cross-bridge in the hypertonic medium. The contractile effects are consistent with the assumptions that hypertonicity reduces the capability of the individual cross-bridge to produce active force and, furthermore, that hypertonicity has only minor effects on the number of attached cross-bridges and the maximum load-bearing capacity of the individual bridge.     

Resting myoplasmic free calcium in frog skeletal muscle fibers estimated with fluo-3.

Fluo-3 is an unusual tetracarboxylate Ca2+ indicator. For recent lots supplied by Molecular Probes Inc. (Eugene, OR), FMAX, the fluorescence intensity of the indicator in its Ca(2+)-bound form, is approximately 200 times that of FMIN, the fluorescence intensity of the indicator in its Ca(2+)-free form. (For earlier lots, impurities may account for the smaller reported values of FMAX/FMIN, 36-40). We have injected fluo-3 from a high-purity lot into intact single fibers from frog muscle and measured the indicator's absorbance and fluorescence signals at rest (A and F, respectively) and changes in absorbance and fluorescence following action potential stimulation (delta A and delta F signals substantially lagged behind that of the myoplasmic free Ca2+ transient. Our analysis of fluo-3's signals from myoplasm therefore focused on information about the level of resting myoplasmic free [Ca2+] ([Ca2+]r). From A, delta A, and in vitro estimates of fluo-3's molar extinction coefficients, the change in the fraction of fluo-3 in the Ca(2+)-bound form during activity (delta f) was estimated. From delta f, delta F, and F, the fraction of the indicator in the Ca(2+)-bound form in the resting fiber (fr) was estimated by fr = (delta f x F/delta F) + (1-FMAX/FMIN)-1. Since FMAX/FMIN is large, the contribution of the second term to the estimate of fr is small. At 16 degrees C, the mean value (mean +/- S.E.) of fr was 0.086 +/- 0.004 (N = 15). From two estimates of the apparent dissociation constant of fluo-3 for Ca2+ in the myoplasm, 1.09 and 2.57 microM, the average value of [Ca2+]r is calculated to be 0.10 and 0.24 microM, respectively. The smaller of these estimates lies near the upper end of the range of values for [Ca2+]r in frog fibers (0.02-0.12 microM) estimated by others with aequorin and Ca(2+)-selective electrodes. The larger of the estimates lies within the range of values (0.2-0.3 microM) previously estimated in this laboratory with fura red. We conclude that [Ca2+]r in frog fibers is at least 0.1 microM and possibly as large as 0.3 microM.     

Reactive oxygen in skeletal muscle. II. Extracellular release of free radicals.

We have tested the hypothesis that diaphragm muscle fibers release superoxide anion radicals (O2-.) into the extracellular space. Fiber bundles were isolated from rat diaphragm and incubated in Krebs-Ringer solution containing cytochrome c (10(-5) M), a standard assay for O2-.. Bundles were either passive or active, i.e., directly stimulated to contract rhythmically. After 1 h, absorbance of reduced cytochrome c in the incubation medium was measured at 550 nm. Absorbance was greater in medium exposed to passive muscle than in medium without muscle (P < 0.01), indicating O2-. release by passive muscle. Absorbance was greater in medium exposed to active muscle than in that exposed to passive muscle (P < 0.01), an increase inhibited by superoxide dismutase (10(3) U/ml). Active bundles fatigued; bundles developing the lowest final stresses produced the greatest absorbance increases (P < 0.001), suggesting that the magnitude of fatigue was inversely related to O2-. release. We conclude that O2-. is released by diaphragm myocytes into the interstitium and surrounding medium, a process accelerated by fatiguing muscular contractions.     

Involuntary leg movements affect interstitial nutrient gradients and blood flow in rat skeletal muscle.

To evaluate the effect of passive muscle shortening and lengthening (PSL) on the transcapillary exchange of glucose, lactate, and insulin in the insulin-stimulated state, microdialysis was performed in rat quadriceps muscle. Electrical pulsatile stimulation (0.1 ms, 0.3-0.6 V, 1 Hz) was performed on the sciatic nerve in one leg to induce passive tension on the quadriceps during a hyperinsulinemic-euglycemic clamp (10 mU x kg(-1) x min(-1)). In the non-insulin-stimulated (basal) state, the muscle arterial-interstitial (A-I) concentration difference of glucose was 1.6 +/- 0.3 mM (P < 0.01). During insulin infusion, it remained unaltered in resting muscle (1.3 +/- 0.3 mM) but diminished during PSL. In the basal state there was no A-I concentration difference of lactate, whereas in the insulin infusion state it increased significantly and was significantly greater in moving (2.8 +/- 0.5 mM, P < 0.01) than in resting muscle (0.7 +/- 0.4 mM). The A-I concentration difference of insulin was equal in resting and moving muscle: 86 +/- 7 and 100 +/- 8 microU/ml, respectively. Muscle blood flow estimated by use of radiolabeled microspheres increased during PSL from 17 +/- 4 to 34 +/- 6 ml x 100 g(-1) x min(-1) (P < 0.05). These results confirm that diffusion over the capillary wall is partly rate limiting for the exchange of insulin and glucose and lactate in resting muscle. PSL, in addition to insulin stimulation, increases blood flow and capillary permeability and, as a result, diminishes the A-I concentration gradient of glucose but not that of insulin or lactate.     

Cholinergic sites in skeletal muscle. I. Denervation effects.

Cholinergic interactions in systems derived from rat skeletal mixed muscle are detailed. The isotherms of the binding of [125I]diiodo-alpha-bungarotoxin over the range of 10(-10)-10(-5) M toxin have been separated into a "nonspecific" component exclusive to the toxin and a "specific" component that binds both the toxin and d-tubocurarine. The "specific" component appears to reflect two independent sets of binding sites. One of the sets has an affinity constant on the order of 10(9) M-1. Following denervation, the number of sites in this high-affinity set begins to increase after 3 days, reaches a peak (28-fold higher than normal) on the 8th day, and begins to decline. Similar results are obtained when sensitivity of this set to an antibody derived from patients with myasthenia gravis is examined. This sensitivity is reflected by the inhibition of the alpha-bungarotoxin binding by the myasthenic IgG fraction. Following denervation, sensitivity first appears on day 3 progresses coincidentally with the increase in new sites in the set. The charcteristics of this set suggest that it represents the acetylcholine receptor and that the new sites appearing during the course of denervation are extrajunctional receptor sites. The interaction with the myasthenic IgG indicates an antigenic difference between junctional and extrajunctional receptors. The second set of specific binding sites has an affinity constant on the order of 10(5) M-1. The number of sites in this set increases only fivefold as a result of denervation. The increase also begins between days 2 and 3. The definition of this low affinity set of sites is not presently clear.     

The mechanical behavior of activated skeletal muscle during stretch: effects of muscle unloading and MyHC isoform shifts.

The response of activated skeletal muscle to a ramp stretch is complex. Force rises rapidly above the isometric plateau during the initial phase of stretch. However, after a strain of approximately 1-2%, force yields and continues to rise but with a slower slope. The resistance to stretch during the initial phase can be characterized by the stiffness of the muscle and/or the preyield modulus (E(pre)). Similarly, a measure of modulus also can be used to characterize the postyield modulus response (E(post)). This study examined the effects of muscle atrophy and altered myosin heavy chain (MyHC) isoform composition on both E(pre) and E(post). Female Sprague-Dawley rats were assigned to 1) control group, 2) a hypothyroid group, 3) a hyperthyroid group, 4) a hindlimb suspension group, and 5) a hindlimb suspension + hyperthyroid group. These interventions were used either to alter the MyHC isoform composition of the muscle or to induce atrophy. Soleus muscles were stretched at strain rates that ranged from approximately 0.15 to 1.25 muscle length/s. The findings of this study demonstrate that 4 wk of hindlimb suspension can produce a large (i.e., 40-60%) reduction in E(pre). Hindlimb suspension did not produce a proportional change in E(post). Analyses of the E(pre)-strain rate relationship demonstrated that there was little dependence on MyHC isoform composition. In summary, the disproportionate decrease in E(pre) of atrophied muscle has important implications with respect to issues related to joint stability, especially under dynamic conditions and conditions where the static joint stabilizers (i.e., ligaments) have been compromised by injury.     

Hemodynamic and metabolic responses to moderate asphyxia in brain and skeletal muscle of late-gestation fetal sheep.

The purpose of this study was to investigate metabolic and hemodynamic responses in two fetal tissues, hindlimb muscle and brain, to an episode of acute moderate asphyxia. Near-infrared spectroscopy was used to measure changes in total hemoglobin concentration ([tHb]) and the redox state of cytochrome oxidase (COX) simultaneously in the brain and hindlimb of near-term unanesthetized fetal sheep in utero. Oxygen delivery (DO(2)) to, and consumption (VO(2)) by, each tissue was derived from the arteriovenous difference in oxygen content and blood flow, measured by implanted flow probes. One hour of moderate asphyxia (n = 11), caused by occlusion of the maternal common internal iliac artery, led to a significant fall in DO(2) to both tissues and to a significant drop in VO(2) by the head. This was associated with an initial fall in redox state COX in the leg but an increase in the brain. [tHb], and therefore blood volume, fell in the leg and increased in the brain. These data suggest the presence of a fetal metabolic response to hypoxia, which, in the brain, occurs rapidly and could be neuroprotective.     

Aging and acute exercise enhance free radical generation in rat skeletal muscle.

Reactive oxygen species (ROS) are implicated in the mechanism of biological aging and exercise-induced oxidative damage. The present study examined the effect of an acute bout of exercise on intracellular ROS production, lipid and protein peroxidation, and GSH status in the skeletal muscle of young adult (8 mo, n = 24) and old (24 mo, n = 24) female Fischer 344 rats. Young rats ran on a treadmill at 25 m/min and 5% grade until exhaustion (55.4 +/- 2.7 min), whereas old rats ran at 15 m/min and 5% grade until exhaustion (58.0 +/- 2.7 min). Rate of dichlorofluorescin (DCFH) oxidation, an indication of ROS and other intracellular oxidants production in the homogenate of deep vastus lateralis, was 77% (P < 0.01) higher in rested old vs. young rats. Exercise increased DCFH oxidation by 38% (P < 0.09) and 50% (P < 0.01) in the young and old rats, respectively. DCFH oxidation in isolated deep vastus lateralis mitochondria with site 1 substrates was elevated by 57% (P < 0.01) in old vs. young rats but was unaltered with exercise. Significantly higher DCFH oxidation rate was also found in aged-muscle mitochondria (P < 0.01), but not in homogenates, when ADP, NADPH, and Fe(3+) were included in the assay medium without substrates. Lipid peroxidation in muscle measured by malondialdehyde content showed no age effect, but was increased by 20% (P < 0.05) with exercise in both young and old rats. Muscle protein carbonyl formation was unaffected by either age or exercise. Mitochondrial GSH/ GSSG ratio was significantly higher in aged vs. young rats (P < 0.05), whereas exercise increased GSSG content and decreased GSH/GSSG in both age groups (P < 0.05). These data provided direct evidence that oxidant production in skeletal muscle is increased in old age and during prolonged exercise, with both mitochondrial respiratory chain and NADPH oxidase as potential sources. The alterations of muscle lipid peroxidation and mitochondrial GSH status were consistent with these conclusions.     

Hemodynamic responses to heat stress in the resting and exercising human leg: insight into the effect of temperature on skeletal muscle blood flow

Heat stress increases limb blood flow and cardiac output (Q) in humans, presumably in sole response to an augmented thermoregulatory demand of the skin circulation. Here we tested the hypothesis that local hyperthermia also increases skeletal muscle blood flow at rest and during exercise. Hemodynamics, blood and tissue oxygenation, and muscle, skin, and core temperatures were measured at rest and during exercise in 11 males across four conditions of progressive whole body heat stress and at rest during isolated leg heat stress. During whole body heat stress, leg blood flow (LBF), Q, and leg (LVC) and systemic vascular conductance increased gradually with elevations in muscle temperature both at rest and during exercise (r(2) = 0.86-0.99; P < 0.05). Enhanced LBF and LVC were accompanied by reductions in leg arteriovenous oxygen (a-vO(2)) difference and increases in deep femoral venous O(2) content and quadriceps tissue oxygenation, reflecting elevations in muscle and skin perfusion. The increase in LVC occurred despite an augmented plasma norepinephrine (P < 0.05) and was associated with elevations in muscle temperature (r(2) = 0.85; P = 0.001) and arterial plasma ATP (r(2) = 0.87; P < 0.001). Isolated leg heat stress accounted for one-half of the increase in LBF with severe whole body heat stress. Our findings suggest that local hyperthermia also induces vasodilatation of the skeletal muscle microvasculature, thereby contributing to heat stress and exercise hyperemia. The increased limb muscle vasodilatation in these conditions of elevated muscle sympathetic vasoconstrictor activity is closely related to the rise in arterial plasma ATP and local tissue temperature.