Increase In Vascular Conductance Research Articles

Post-occlusive reactive hyperemia variables can be used to diagnose vascular dysfunction in hemorrhagic shock

IntroductionLaser doppler flowmetry (LDF) allows non-invasive assessment of microvascular functions. The combination of LDF with an occlusion functional test enables study of post-occlusive reactive hyperemia (PORH), providing additional information about vasomotor function, capillary blood flow reserve, and the overall reactivity of the microvascular system. AimTo identify early alterations of PORH variables in the skin of a rat in hemorrhagic shock (HS). Material and methodsMale Wistar rats (n = 14) weighing 400–450 g were anesthetized with a combination of tiletamine/zolazepam (20 mg/kg) and xylazine (5 mg/kg). The animals breathed on their own, and were placed on a heated platform in the supine position. A PE-50 catheter was inserted into the carotid artery to measure the mean arterial pressure (MAP). The optical probe of the Laser Doppler device was installed on the plantar surface of the hind limb of a rat; a pneumatic cuff was applied proximal to the same limb. The occlusion time was 3 min. The following physiological variables were measured at baseline and 30 min after blood loss: MAP, mmHg; mean cutaneous blood flow (M, PU); cutaneous vascular conductance (CVC = M/MAP); peak hyperemia (Mmax, PU) and maximum cutaneous vascular conductance (CVCmax) during PORH. In the HS group (n = 7), 30 % of the estimated blood volume was taken within 5 min. There was no blood loss in the group of sham-operated animals (Sham, n = 7). The results are presented as Me [25 %;75 %]. The U-Mann-Whitney criterion was used to evaluate intergroup differences. Differences were considered statistically significant at p < 0.05. ResultsThe groups did not differ at baseline. Blood loss led to a significant decrease in MAP (43 [31;46] vs. 94 [84;104] mmHg), M (11.5 [16.9;7.8] vs 16.7 [20.2;13.9]) and Mmax (18.1 [16.4;21.8] vs. 25.0 [23.0;26.2]) in the HS group compared to the Sham group, respectively. At the same time, both CVC (0.25 [0.23;0.30] vs. 0.16 [0.14;0.21]) and CVCmax (0.55 [0.38;0.49] vs 0.24 [0.23; 0.29]) increased after blood loss in the HS group compared to the Sham group. Arterial blood gas analysis revealed metabolic lactic acidosis in the HS group. ConclusionIn this rat model of HS, alterations in cutaneous blood flow are manifested by a decrease in perfusion (M) and the intensity of PORH (Mmax) with a simultaneous increase in vascular conductance (CVC and CVCmax).

Rapid Onset Vasodilation during Baroreceptor Loading and Unloading.

The purpose of these experiments was to determine if the increase in vascular conductance following a single muscle contraction (50% MVC) (6 male & 6 female subjects) was altered by baroceptor loading and unloading. Rapid onset vasodilation (ROV) was determined by measuring brachial artery blood flow (Doppler ultrasound), and blood pressure (Finapress). Brachial artery vascular conductance was calculated dividing blood flow by mean arterial pressure. ROV was described by the area under the ∆VC-time curve during the 30 s following muscle contraction. ROV was determined using chamber pressures of +20, +10, 0, -10, -20, & -40 mmHg chamber pressure (lower body positive and negative pressure, LBPP and LBNP) . We tested the hypothesis that the impact of baroreceptor loading and unloading produce a proportion change in ROV. The level of ROV following each contraction was proportional to the peak force ( r2 = 0.393, p = 0.0001). Peak force was therefore used as a covariate in further analysis. ROV during application of -40 mmHg LBNP (0.345 ± 0.229 ml • mmHg-1) was lower than during Control (0.532 ± 0.284 ml • mmHg-1, p=0.034) and +20 mmHg LBPP ( 0.658 ± 0.364 ml • mmHg-1, p=0.0008). ROV was linearly related to chamber pressure from -40 to +20 mmHg chamber pressure (r2 = 0.512, p = 0.022, n = 69) and from -20 to +10 mmHg chamber pressure (r2= 0.973, p < 0.0425, n=45), Overall, vasoconstrictor tone altered with physiologically relevant baroreceptor loading and unloading resulted in a proportion change in ROV.

Cerebrovascular reactivity is blunted in young adults with major depressive disorder: The influence of current depressive symptomology

BackgroundIn middle-aged adults with depression, cerebral vasodilatory reactivity is blunted; however, this has not been examined in treatment-naïve young adults with major depressive disorder (MDD). We tested the hypothesis that cerebrovascular reactivity would be blunted in young adults (18–30 yrs) with MDD compared to healthy non-depressed adults (HA) and would be attenuated to a greater extent in adults with symptomatic MDD (sMDD) compared to adults with MDD in remission (euthymic MDD; eMDD). MethodsSixteen adults with MDD [21±3yrs; n = 8 sMDD (6 women); n = 8 eMDD (5 women)] and 14 HA (22±3yrs; 9 women) participated. End-tidal carbon dioxide concentration (PETCO2; capnograph), beat-to-beat mean arterial pressure (MAP; finger photoplethysmography), middle cerebral artery blood velocity (MCAv; transcranial Doppler ultrasound), and internal carotid artery (ICA) diameter and blood velocity (Doppler ultrasound) were continuously measured during baseline and rebreathing-induced hypercapnia. Cerebrovascular reactivity was calculated as the relative increase in vascular conductance during hypercapnia. ResultsIn adults with MDD, cerebrovascular reactivity in the MCA (∆39±9 HA vs. ∆31±13% MDD, p = 0.04), but not the ICA (∆36±24 HA vs. ∆34±18% MDD, p = 0.84), was blunted compared to HA. In the MCA, cerebrovascular reactivity was reduced in adults with sMDD compared to adults with eMDD (∆36±11 eMDD vs. ∆25±13% sMDD, p = 0.02). LimitationsThe cross-sectional nature approach limits conclusions regarding the temporal nature of this link. ConclusionThese data indicate that MCA cerebrovascular reactivity is blunted in young adults with MDD and further modulated by current depressive symptomology, suggesting that the management of depressive symptomology may secondarily improve cerebrovascular health.

Greater post-contraction hyperaemia below vs. above heart level: the role of active vasodilatation vs. passive mechanical distension of arterioles.

The immediate increase in skeletal muscle blood flow following contraction is greater when the contracting muscle is below vs. above heart level. This has been attributed to muscle pump-mediated venous emptying and subsequent widening of the arterial to venous pressure gradient, which can occur below but not above heart level. However, alternative explanations could include greater rapid onset vasodilatation and/or transmural pressure-mediated mechanical distension of resistance vessels, but these remain unexplored. We demonstrate that active vasodilatation is not responsible for greater post-contraction hyperaemia below the heart. Instead, an increased transmural pressure-mediated mechanical distension of resistance vessels is a key mechanism responsible for this phenomenon. Our findings establish the importance of considering/accounting for local mechanical arteriolar distension effects when investigating exercise hyperaemia. They also inform the application of exercise for rehabilitative purposes and prompt investigation into whether arteriolar distension accompanying vasodilatation is reduced with diseases or ageing, thereby compromising exercising muscle perfusion. We tested the hypotheses that increased post-contraction hyperaemia in higher (H; below heart) vs. lower (L; above heart) transmural pressure conditions is due to (1) greater active vasodilatation or (2) greater transmural pressure-mediated arteriolar distension. Participants (n=20, 12 male, 8 female; combined mean age 24.5±2years) performed a 2s isometric handgrip contraction, where arm position was maintained within or changed between H and L during contraction, resulting in four starting-finishing arm position conditions (LL, HL, LH, HH). Post-contraction forearm blood flow (echo and Doppler ultrasound) was higher with contraction release in H vs. L environments (P<0.05). However, contraction initiated in H did not result in greater vasodilatation (forearm vascular conductance; FVC) than contraction initiated in L, regardless of contraction release condition (peak FVC: LL 217±104 vs. HL 204±92ml min-1 (100mmHg)-1 , P=0.313, LH 229±8 vs. HH 225±85ml min-1 (100mmHg)-1 , P=0.391; first post-contraction cardiac cycle FVC: same comparisons, both P=0.317). However, FVC of the first post-contraction cardiac cycle was greater for contractions released in H vs. L regardless of pre-contraction condition (LL 106±67 vs. LH 152±76ml min-1 (100mmHg)-1 , P<0.05; HL 80±51 vs. HH 119±58ml min-1 (100mmHg)-1 , P<0.05). These findings refute the hypothesis that greater hyperaemia following a single contraction in higher transmural pressure conditions is due to greater active vasodilatation. Instead, our findings reveal a key role for increased transmural pressure-mediated mechanical distension of arterioles in creating a greater increase in vascular conductance for a given active vasodilatation following skeletal muscle contraction.

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Muscle metaboreflex activation during dynamic exercise evokes epinephrine release resulting in β2-mediated vasodilation

Muscle metaboreflex-induced increases in mean arterial pressure (MAP) during submaximal dynamic exercise are mediated principally by increases in cardiac output. To what extent, if any, the peripheral vasculature contributes to this rise in MAP is debatable. In several studies, we observed that in response to muscle metaboreflex activation (MMA; induced by partial hindlimb ischemia) a small but significant increase in vascular conductance occurred within the nonischemic areas (calculated as cardiac output minus hindlimb blood flow and termed nonischemic vascular conductance; NIVC). We hypothesized that these increases in NIVC may stem from a metaboreflex-induced release of epinephrine, resulting in β2-mediated dilation. We measured NIVC and arterial plasma epinephrine levels in chronically instrumented dogs during rest, mild exercise (3.2 km/h), and MMA before and after β-blockade (propranolol; 2 mg/kg), α1-blockade (prazosin; 50 μg/kg), and α1 + β-blockade. Both epinephrine and NIVC increased significantly from exercise to MMA: 81.9 ± 18.6 to 141.3 ± 22.8 pg/ml and 33.8 ± 1.5 to 37.6 ± 1.6 ml·min(-1)·mmHg(-1), respectively. These metaboreflex-induced increases in NIVC were abolished after β-blockade (27.6 ± 1.8 to 27.5 ± 1.7 ml·min(-1)·mmHg(-1)) and potentiated after α1-blockade (36.6 ± 2.0 to 49.7 ± 2.9 ml·min(-1)·mmHg(-1)), while α1 + β-blockade also abolished any vasodilation (33.7 ± 2.9 to 30.4 ± 1.9 ml·min(-1)·mmHg(-1)). We conclude that MMA during mild dynamic exercise induces epinephrine release causing β2-mediated vasodilation.

Acute ingestion of dietary nitrate increases muscle blood flow via local vasodilation during exercise in young adults (705.9)

Dietary nitrate (NO3‐) supplementation with beetroot juice (BR) can reduce the O2 cost of submaximal exercise and increase exercise tolerance. NO3‐ is converted to nitrite and can be reduced to the vasodilator nitric oxide amid a low O2 environment and BR is observed to increase hindlimb blood flow in rats during treadmill exercise. We tested the hypothesis that BR increases forearm blood flow (FBF) via local vasodilation during handgrip exercise in young adults (n=7; 24±2 years). FBF (Doppler ultrasound) and blood pressure (finometer) were measured at rest and during graded handgrip exercise at 5, 15, and 25% maximal voluntary contraction (MVC) lasting 4 minutes each. During 25% MVC exercise, systemic hypoxia (80%SaO2) began and exercise continued for 3 additional minutes. Subjects then ingested concentrated BR (12.6 mmol nitrate) and repeated the exercise bout 2h post consumption. Compared to control, BR significantly increased FBF at 15% (183±29 vs. 165±21 ml/min), 25% (331±40 vs.293±43 ml/min), and 25% + hypoxia (393 ±59 vs. 357±49 ml/min; all P&lt;0.05), and this was due to increases in vascular conductance. Further, the increase in FBF from control was greatest at 25% MVC in normoxia and hypoxia (Δ~35‐40 ml/min) compared with 15% (Δ~18 ml/min) and 5% (Δ~5 ml/min). These findings may have important implications for aging and diseased populations that have impaired muscle perfusion and exercise intolerance.Grant Funding Source: Supported by HL095573

ASIC1a opposes exercise induced hyperemia and maximal exercise capacity

Acid Sensing Ion Channel 1a (ASIC1a) is an extracellular proton‐gated, cation‐selective channel in neurons and vascular smooth muscle cells (VSMC). It is unknown if ASIC1a contributes to vascular tone under conditions associated with extracellular acidosis, such as strenuous exercise. During exercise, vessel recruitment and dilation, mediated by the accumulation of extracellular protons, contribute to increases in blood flow to the exercising muscles. To determine if ASIC1a contributes to vascular responses during exercise, we measured femoral vascular conductance (FVC) during a step‐wise electrical stimulation (0.5 – 5.0 Hz at 3V for 60 sec) of the left major hindlimb muscle groups in anesthetized ASIC1a+/+ and ASIC1a−/− mice. Baseline hemodynamic parameters were similar. FVC increased to a greater extent in ASIC1a−/− versus ASIC1a+/+ mice (0.44 ± 0.03 vs. 0.30 ± 0.04 ml×min−1×100g hindlimb mass−1, n=5 each, p=0.0009) with stimulation. The enhanced FVC was associated with a greater peak oxygen (O2) uptake in conscious ASIC1a−/− mice during exhaustive treadmill running (9563 ± 120 vs. 8836 ± 276 ml×kg−1×hr−1, n=6–7, p=0.0082). Differences in peak O2 uptake were not due to differences in absolute or relative lean body mass. Our findings suggest ASIC1a activity may oppose increases in vascular conductance during strenuous exercise thus limiting peak exercise capacity. Supported by NHLBI 51971.

Assessment of voluntary rhythmic muscle contraction-induced exercising blood flow variability measured by Doppler ultrasound

Given recent technological developments, ultrasound Doppler can provide valuable measurements of blood velocity/flow in the conduit artery with high temporal resolution. In human-applied science such as exercise physiology, hemodynamic measurements in the conduit artery is commonly performed by blood flow feeding the exercising muscle, as the increase in oxygen uptake (calculated as a product of arterial blood flow to the exercising limb and the arterio-venous oxygen difference) is directly proportional to the work performed. The increased oxygen demand with physical activity is met through a central mechanism, an increase in cardiac output and blood pressure, as well as a peripheral mechanism, an increase in vascular conductance and oxygen extraction (a major part of the whole exercising muscles) from the blood. The increase in exercising muscle blood flow in relation to the target workload (quantitative response) may be one indicator in circulatory adjustment for the ac- tivity of muscle metabolism. Therefore, the determination of local blood flow dynamics (potential oxygen supply) feeding repeated (rhythmic) muscle contractions can contribute to the understanding of the factors limiting work capacity including, for instance, muscle metabolism, substance utilization and magnitude of vasodilatation in the exercising muscle. Using non-invasive measures of pulsed Doppler ultrasound, the validity of blood velocity/flow in the forearm or lower limb conduit artery feeding to the muscle has been previously demonstrated during rhythmic muscle exercise. For the evaluation of exercising blood flow, not only muscle contraction induced internal physiological variability, or fluctuations in the magnitude of blood velocity due to spontaneous muscle contraction and relaxation induced changes in force curve intensity, superimposed in cardiac beat-by-beat, but also the alterations in the blood velocity (external variability) due to a temporary sudden change in the achieved workload, compared to the target workload, should be considered. Furthermore, a small amount of inconsistency in the voluntary muscle contraction force at each kick seems to be unavoidable, and may influence exercising muscle blood flow, although subjects attempt to perform precisely similar repeated voluntary muscle contractions at target workload (muscle contraction force). This review presents the methodological considerations for the variability of exercising blood velocity/flow in the limb conduit artery during dynamic leg exercise assessed by pulsed Doppler ultrasound in relation to data previously reported in original research.

Elevated local skin temperature impairs cutaneous vasoconstrictor responses to a simulated haemorrhagic challenge while heat stressed

During a simulated haemorrhagic challenge, syncopal symptoms develop sooner when individuals are hyperthermic relative to normothermic. This is due, in part, to a large displacement of blood to the cutaneous circulation during hyperthermia, coupled with inadequate cutaneous vasoconstriction during the hypotensive challenge. The influence of local skin temperature on these cutaneous vasoconstrictor responses is unclear. This project tested the hypothesis that local skin temperature modulates cutaneous vasoconstriction during simulated haemorrhage in hyperthermic humans. Eight healthy participants (four men and four women; 32 ± 7 years old; 75.2 ± 10.8 kg) underwent lower-body negative pressure to presyncope while heat stressed via a water-perfused suit sufficiently to increase core temperature by 1.2 ± 0.2 °C. At forearm skin sites distal to the water-perfused suit, local skin temperature was either 35.2 ± 0.6 (mild heating) or 38.2 ± 0.2 °C (moderate heating) throughout heat stress and lower-body negative pressure, and remained at these temperatures until presyncope. The reduction in cutaneous vascular conductance during the final 90 s of lower-body negative pressure, relative to heat-stress baseline, was greatest at the mildly heated site (-10 ± 15% reduction) relative to the moderately heated site (-2 ± 12%; P = 0.05 for the magnitude of the reduction in cutaneous vascular conductance between sites), because vasoconstriction at the moderately heated site was either absent or negligible. In hyperthermic individuals, the extent of cutaneous vasoconstriction during a simulated haemorrhage can be modulated by local skin temperature. In situations where skin temperature is at least 38 °C, as is the case in soldiers operating in warm climatic conditions, a haemorrhagic insult is unlikely to be accompanied by cutaneous vasoconstriction.

The need for speed: Central command commanding vasodilation in human skeletal muscle?

muscular contractions lead to a large ([2][1]) and rapid ([14][2]) increase in muscle perfusion, providing a challenging field of research for over a century. A particular challenge has been deciphering the mechanism(s) that regulate the increase in vascular conductance that, in turn, enables the

Measurement of the exercising blood flow during rhythmical muscle contractions assessed by Doppler ultrasound: Methodological considerations

Given the recent technological developments, ultra-sound Doppler can provide valuable measurements of arterial blood flow with high temporal resolution. In a clinical setting, measurements of hemodynamics is used to monitor, diagnose and manage changes in blood velocity profile for cardiac valve disease, relatively large vessel stenosis and other cardiovascular diseases. In health science and preventive medicine for cardiovascular disease with exercise therapy, evaluation of cardiac and vascular function is a useful indicator not only at rest but also during exercise, leading to improved exercise tolerance as well as physical activity. During exercise, the increase in oxygen uptake (calculated as product of arterial blood flow to the exercising limb and the arteriovenous oxygen difference) is directly proportional to the work performed. The increased oxygen demand is met through a central mechanism, an increase in cardiac output and blood pressure, as well as a peripheral mechanism, an increase in vascular conductance and oxygen extraction (major part in the whole exercising muscles) from the blood. Therefore, the determination of the local blood flow dynamics (potential oxygen supply) feeding to rhythmic muscle contractions can contribute to the understanding of the factors limiting the work capacity including, for instance the muscle metabolism, substance utilization and vasodilatation in the exercising muscle. Using non-invasive measures of pulsed Doppler ultrasound the validity of evaluating blood velocity/flow in the fore- arm or lower limb conduit artery feeding to the mus- cle is demonstrated during rhythmic muscle exercise; however the exercising blood velocity profile (fast Fourier transformation) due to muscle contractions is always seen as a physiological variability or fluctuations in the magnitude in blood velocity due to the spontaneous muscle contraction and relaxation induced changes in force curve intensity. Considering the above mentioned variation in blood velocity in relation to muscle contractions may provide valuable information for evaluating the blood flow dynamics during exercise. This review presents the methodological concept that underlines the methodological considerations for determining the exercising blood velocity/flow in the limb conduit artery in relation the exercise model of dynamic leg exercise assessed by pulsed Doppler ultrasonography.

Human investigations into the exercise pressor reflex.

During exercise, neural input from skeletal muscles reflexly maintains or elevates blood pressure (BP) despite a maybe fivefold increase in vascular conductance. This exercise pressor reflex is illustrated by similar heart rate (HR) and BP responses to electrically induced and voluntary exercise. The importance of the exercise pressor reflex for tight cardiovascular regulation during dynamic exercise is supported by studies using pharmacological blockade of lower limb muscle afferent nerves. These experiments show attenuation of the increase in BP and cardiac output when exercise is performed with attenuated neural feedback. Additionally, there is no BP response to electrically induced exercise with paralysing epidural anaesthesia or when similar exercise is evoked in paraplegic patients. Furthermore, BP decreases when electrically induced exercise is carried out in tetraplegic patients. The lack of an increase in BP during exercise with paralysed legs manifests, although electrical stimulation of muscles enhances lactate release and reduces muscle glycogen. Thus, the exercise pressor reflex enhances sympathetic activity and maintains perfusion pressure by restraining abdominal blood flow, while brain, skin and muscle blood flow may also become affected because the reflex 'resets' arterial baroreceptor modulation of vascular conductance, making BP the primarily regulated cardiovascular variable during exercise.

Is tonic sympathetic vasoconstriction increased in the skeletal muscle vasculature of aged canines?

We tested the hypothesis that tonic adrenergic and nonadrenergic receptor-mediated sympathetic vasoconstriction would increase at rest and during exercise with advancing age. Young (n = 6; 22 ± 1 mo; means ± SE) and old (n = 6; 118 ± 9 mo) beagles were studied. Selective antagonists for alpha-1, alpha-2, neuropeptide Y (NPY), and purinergic (P(2x)) receptors were infused at rest and during treadmill running at 2.5 mph and 4 mph with 2.5% grade. Prazosin produced similar increases in vascular conductance in young and old beagles at rest (Young: 158 ± 34%; Old: 98 ± 19%) and during exercise at 2.5 mph (Young: 80 ± 10%; Old: 58 ± 12%) and 4 mph and 2.5% grade (Young: 57 ± 5%; Old: 26 ± 4%). Rauwolscine caused similar (P > 0.05) increases in vascular conductance in old compared with young dogs at rest (Young: 119 ± 25%; Old: 64 ± 22%) and at 2.5 mph (Young: 86 ± 13%; Old: 60 ± 7%) and 4 mph with 2.5% grade (Young: 61 ± 5%; Old: 43 ± 7%). N2-(diphenylacetyl)-N-[4-hydroxyphenyl)methyl]-d-arginine amide (BIBP) caused a smaller increase (P < 0.05) in vascular conductance in old compared with young dogs at rest (Young: 179 ± 44%; Old: 91 ± 22%), whereas similar increases (P > 0.05) of experimental limb vascular conductance in young and old dogs occurred following BIBP during exercise at 2.5 mph (Young: 56 ± 16%; Old: 50 ± 12%) and 4 mph and 2.5% grade (Young: 45 ± 10%; Old: 25 ± 7%). Pyridoxal-phosphate-6-azophenyl-2'-4'-disulfonic acid infusion produced a larger increase in vascular conductance in old compared with young beagles at rest (Young: 88 ± 14%; Old: 191 ± 58%), whereas similar increases were observed at 2.5 mph (Young: 47 ± 18%; Old: 31 ± 11%) and 4 mph with 2.5% grade (Young: 26 ± 13%; Old: -18 ± 8%). At rest, NPY receptor-mediated restraint of skeletal muscle blood flow was reduced with advancing age, whereas P(2x) receptor-mediated restraint of skeletal muscle blood flow was increased. During exercise, the magnitude of adrenergic and nonadrenergic sympathetic vasoconstriction was not different between young and old dogs. Overall, these data demonstrate that adrenergic receptor-mediated vasoconstriction was not elevated at rest, but nonadrenergic sympathetic vasoconstriction was altered under basal conditions in aged beagles.

Sympathetic cholinergic nerve contributes to increased muscle blood flow at the onset of voluntary static exercise in conscious cats

We examined whether a sympathetic cholinergic mechanism contributed to increased blood flow of the exercising muscle at the onset of voluntary static exercise in conscious cats. After six cats were operantly conditioned to perform static bar press exercise with a forelimb while maintaining a sitting posture, a Transonic or pulsed Doppler flow probe was implanted on the brachial artery of the exercising forelimb, and catheters were inserted into the left carotid artery and jugular vein. After the baseline brachial blood flow and vascular conductance decreased and became stable in progress of postoperative recovery, the static exercise experiments were started. Brachial blood flow and vascular conductance began to increase simultaneously with the onset of exercise. Their initial increases reached 52 +/- 8% and 40 +/- 6% at 3 s from the exercise onset, respectively. Both a sympathetic ganglionic blocker (hexamethonium bromide) and atropine sulfate or methyl nitrate blunted the increase in brachial vascular conductance at the onset of static exercise, whereas an inhibitor of nitric oxide synthesis (N(omega)-nitro-l-arginine methyl ester) did not alter the increase in brachial vascular resistance. Brachial blood flow and vascular conductance increased during natural grooming behavior with the forelimb in which the flow probe was implanted, whereas they decreased during grooming with the opposite forelimb and during eating behavior. Thus it is likely that the sympathetic cholinergic mechanism is capable of evoking muscle vasodilatation at the onset of voluntary static exercise in conscious cats.

α-Adrenergic receptor-mediated restraint of skeletal muscle blood flow during prolonged exercise

Sympathetic nervous system restraint of skeletal muscle blood flow during dynamic exercise has been well documented. However, whether sympathetic restraint of muscle blood flow persists and is constant throughout prolonged exercise has not been established. We hypothesized that both alpha1- and alpha2-adrenergic receptors would restrain skeletal muscle blood flow throughout prolonged constant-load exercise and that the restraint would increase as a function of exercise duration. Mongrel dogs were instrumented chronically with transit-time flow probes on the external iliac arteries and an indwelling catheter in a branch of the femoral artery. Flow-adjusted doses of selective alpha1- (prazosin) and alpha2-adrenergic receptor (rauwolscine) antagonists were infused after 5, 30, and 50 min of treadmill exercise at 3 and 6 miles/h. During mild-intensity exercise (3 miles/h), prazosin infusion resulted in a greater (P < 0.05) increase in vascular conductance (VC) after 5 [42% (SD 6)], compared with 30 [28% (SD 6)] and 50 [28% (SD 8)] min of running. In contrast, prazosin resulted in a similar increase in VC after 5 [29% (SD 10)], 30 [24% (SD 9)], and 50 [22% (SD 9)] min of moderate-intensity (6 miles/h) exercise. Rauwolscine infusion resulted in a greater (P < 0.05) increase in VC after 5 [39% (SD 14)] compared with 30 [26% (SD 9)] and 50 [22% (SD 4)] min of exercise at 3 miles/h. Rauwolscine infusion produced a similar increase in VC after 5 [19% (SD 3)], 30 [15% (SD 6)], and 50 [16% (SD 2)] min of exercise at 6 miles/h. These results suggest that the ability of alpha1- and alpha2-adrenergic receptors to produce vasoconstriction and restrain blood flow to active muscles may be influenced by both the intensity and duration of exercise.

Decreased muscle sympathetic nerve activity does not explain increased vascular conductance during contralateral isometric exercise in humans

At the onset of both electrically evoked (STIM) and voluntary (VOL) isometric calf exercise there is an increase in vascular conductance of the contralateral lower limb, suggesting withdrawal of muscle sympathetic nerve activity (MSNA). Seven subjects performed STIM or VOL ischaemic calf exercise at 30% maximum voluntary contraction in a seated position. Blood pressure, heart rate and peroneal MSNA in the resting contralateral lower limb were recorded. During both STIM and VOL exercise blood pressure increased (P < 0.05). Blood flow increased by 40 +/- 3 and 35 +/- 3% and conductance increased by 37 +/- 3 and 31 +/- 4% (P < 0.05) after 10 s of STIM and VOL, respectively, and thereafter declined. The time course and direction of these changes persisted with subjects in a semisupine position, confirming that the transient conductance changes were not an artefact of the dependent leg position. Thigh cuff inflation for 1 min without exercise caused a 47 +/- 7.5% (P < 0.05) reduction in MSNA, which recovered when the circulation was restored. However, when cuff inflation was followed by STIM or VOL exercise, MSNA did not fall further. These data suggest that the transient increase in vascular conductance at the onset of contralateral electrically evoked or voluntary lower limb exercise is unrelated to MSNA.

Arteriogenesis: role of nitric oxide.

Arteriogenesis is an important process for adapting the pre-existing circuit of vessels into functional collateral conduits for delivery of oxygen enriched blood to tissue distal to occlusion of a large, peripheral conduit artery. Recent evidence has shown that arteriogenesis is regulated by nitric oxide (NO), angiogenic factors and shear stress. NO significantly impacts vasomotor tone to enhance conductance of the newly recruited collateral arteries, and this effect is augmented by exercise training prior to arterial occlusion. NO-mediated increases in vascular conductance allows for greater collateral dependent blood flow to the tissue distal to occlusion. NO production is also critical to the efficacy of therapeutic arteriogenesis achieved by delivery of exogenous angiogenic growth factors (VEGF, FGF-2) or by exercise training. The critical role of NO in therapeutic arteriogenesis is independent of NO-mediated changes in vascular conductance and implies a central role in arteriogenic signaling events. Maintenance, or improvement, of NO production and signaling, such as with regular exercise, may improve endothelial cell function and thus may help preserve the arteriogenic potential of preexisting collateral networks.

Regional haemodynamic responses to activation of the medial prefrontal cortex depressor region

Electrical or chemical stimulation of the medial prefrontal cortex (MPFC) produces depressor and sympathoinhibitory responses. To characterise the MPFC depressor response more fully, we determined the regional haemodynamic changes which occurred in response to stimulation of the MPFC. In halothane-anaesthetised rats, we recorded arterial blood pressure and renal, superior mesenteric, and iliac arterial vascular conductance using miniaturised Doppler flow probes. Electrical stimulation of the MPFC (50–100 μA) was used to map the location of the depressor region. Increases in vascular conductance (or increases in blood flow) were recorded from the renal (+2.3±0.5 kHz/mmHg×10 3), mesenteric (+4.4±0.4 kHz/mmHg×10 3), and iliac (+8.3±1.0 kHz/mmHg×10 3) vascular beds in response to stimulation of the MPFC depressor region coinciding with the ventral infralimbic (IL) and dorsal peduncular (DP) cortical areas. Similar responses were obtained after microinjection of the chemical excitant l-glutamate ( n=3, 100 nl, 100 mM), indicating that the responses were due to excitation of cell bodies and not due to axons traversing the area. Administration of the nitric oxide synthesis inhibitor N G-nitro- l-arginine methyl ester ( l-NAME, 25 μmol/kg, i.v., n=5) significantly reduced the MPFC depressor response (51%, 12.5±1.2 to 6.1±2.5 mmHg). The increases in conductance in the hindquarter and mesenteric vascular beds were significantly reduced after l-NAME treatment (mesenteric by 77%, iliac by 70%), but there was no significant reduction of renal flow (35%). These observations indicate that the depressor region of the MPFC is localised to ventral regions (IL and DP) and that the depressor response is mediated by increased conductance in the hindquarters and mesenteric vascular beds. Furthermore, the depressor response may be mediated, in part, by release of nitric oxide in these vascular beds.

Vascular smooth muscle: integrator of vasoactive signals during exercise hyperemia.

The primary focus of this review is to discuss the importance of vascular smooth muscle function in mechanisms underlying exercise hyperemia in skeletal muscle. Important features of exercise hyperemia are presented and include: 1) the large magnitude of increase in blood flow, 2) the pattern of increased blood flow within and among skeletal muscle during exercise, 3) exercise hyperemia results from increases in vascular conductance produced by relaxation of vascular smooth muscle, 4) the increased blood flow is linked to the oxidative metabolism of the muscle, and 5) the increased blood flow occurs very rapidly with the initiation of exercise. A prevailing theme throughout this review is that vascular smooth muscle is a primary integrator of vasoactive signals that, in turn, regulate vascular resistance and muscle blood flow. Signal transduction pathways involved in vascular smooth muscle contraction and relaxation are discussed, with particular emphasis on the role of multiple and redundant signaling pathways for initiating a given contractile/relaxation response. We emphasize the concept that exercise hyperemia is a local phenomenon and that, during maximal exercise when most signals for vasoconstriction are still present, three primary control mechanisms are thought to regulate vasodilation and subsequent increases in vascular conductance: myogenic vascular control, metabolic vascular control, and endothelium-mediated vascular control. Experimental paradigms to test the relative importance of the predominant mechanisms thought to underlie exercise hyperemia are discussed and evaluated in light of the multiple and redundant control systems now known to contribute to control of blood flow in striated muscle tissue.