Insulin at physiological concentrations increases microvascular perfusion in human myocardium

Vascular endothelium regulates vascular tone and tissue perfusion in response to various physiological and pathological stimuli. Insulin and meal feeding increase microvascular perfusion and thus oxygen, nutrient, and hormone delivery to human skeletal muscle. Meal feeding also increases cardiac microvascular perfusion in healthy humans. To examine whether insulin at physiological concentrations increases microvascular perfusion in human myocardium, we studied 13 healthy, overnight-fasted, lean, young human volunteers by using myocardial contrast echocardiography (MCE) and insulin-clamp techniques. We measured cardiac microvascular blood volume (MBV), microvascular flow velocity (MFV), and microvascular blood flow (MBF) at baseline, 60 min, and 120 min after initiating insulin infusion at 1 mU.kg(-1).min(-1). MBF is the product of MBV and MFV and represents microvascular perfusion. Insulin increased myocardial MBV by 23% at 60 min (P < 0.01) and by 41% at 120 min (P = 0.001) without changing MFV. As a result, insulin-mediated myocardial MBF increased significantly at both 60 min (P < 0.01) and 120 min (P < 0.0005). Insulin also significantly increased brachial artery diameter, flow velocity, and total blood flow at 60 and 120 min (P < 0.05 for all). The changes in cardiac MBV correlated positively with quantitative insulin sensitivity check index (QUICKI) and negatively with body mass index but not with the steady-state glucose-infusion rates or the changes in brachial artery parameters. We conclude that insulin, at physiologically relevant concentrations, increases microvascular perfusion in human heart muscle by increasing cardiac MBV in healthy, insulin-sensitive adults. This insulin-mediated cardiac microvascular perfusion may play an important role in normal human myocardial oxygen and substrate physiology.     

Exercise hyperemia and vasoconstrictor responses in humans with cystic fibrosis.

ATP released from circulating erythrocytes is a potential signal regulating muscle blood flow during exercise (exercise hyperemia), and intravascular ATP appears to blunt sympathetic vasoconstriction during exercise. Erythrocytes from patients with cystic fibrosis (CF) do not release ATP. The goal of the present study was to determine whether increases in forearm blood flow during exercise are blunted in CF patients and whether CF patients exhibit greater vasoconstrictor responsiveness during exercise. Nine control subjects and 10 CF patients who were free of other disease complications (approximately 96% O2 saturation) performed incremental rhythmic forearm exercise at 5, 10, and 15% of maximum handgrip strength for 21 min (7 min at each workload). We used a cold pressor test to evoke sympathetic vasoconstriction under resting conditions and at each exercise workload. As a control, subjects performed a second exercise bout without the cold pressor test. Continuous brachial artery blood velocity was monitored beat-to-beat, and vessel diameter was assessed by Doppler ultrasound. Artery diameter, as well as blood pressure, heart rate, and O2 saturation, was measured at steady-state exercise and at 1 min into the cold pressor stimulus. Blood pressure and heart rate responses to the forearm exercise and each cold pressor test were similar in both groups (P > 0.05). Contrary to our hypothesis, forearm blood flow (P = 0.91) and forearm vascular conductance (P = 0.82) were similar at rest and at each level of exercise between CF patients and controls. Additionally, there was no difference in the degree of sympathetic vasoconstriction between groups at rest and at each level of exercise (P = 0.22). Our results suggest that ATP released from the deformation of erythrocytes is not an obligatory signal for exercise hyperemia in human skeletal muscle.     

Inhibiting NOS blocks microvascular recruitment and blunts muscle glucose uptake in response to insulin

We examined the effects of inhibiting nitric oxide synthase with Nomega-nitro-l-arginine-methyl ester (l-NAME) on total hindlimb blood flow, muscle microvascular recruitment, and hindlimb glucose uptake during euglycemic hyperinsulinemia in vivo in the rat. We used two independent methods to measure microvascular perfusion. In one group of animals, microvascular recruitment was measured using the metabolism of exogenously infused 1-methylxanthine (1-MX), and in a second group contrast-enhanced ultrasound (CEU) was used. Limb glucose uptake was measured by arterial-venous concentration differences after 2 h of insulin infusion. Saline alone did not alter femoral artery flow, glucose uptake, or 1-MX metabolism. Insulin (10 mU.min-1.kg-1) significantly increased hindlimb total blood flow (0.69 +/- 0.02 to 1.22 +/- 0.11 ml/min, P < 0.05), glucose uptake (0.27 +/- 0.05 to 0.95 +/- 0.08 micromol/min, P < 0.05), 1-MX uptake (5.0 +/- 0.5 to 8.5 +/- 1.0 nmol/min, P < 0.05), and skeletal muscle microvascular volume measured by CEU (10.0 +/- 1.6 to 15.0 +/- 1.2 video intensity units, P < 0.05). Addition of l-NAME to insulin completely blocked the effect of insulin on both total limb flow and microvascular recruitment (measured using either 1-MX or CEU) and blunted glucose uptake by 40% (P < 0.05). We conclude that insulin specifically recruits flow to the microvasculture in skeletal muscle via a nitric oxide-dependent pathway and that this may be important to insulin's overall action to regulate glucose disposal.     

Effect of cardiac pacing on forearm vascular responses and nitric oxide function

We examined the hypothesis that changes in heart rate at rest influence bioactivity of nitric oxide (NO) in humans by examining forearm blood flow responses during cardiac pacing in six subjects. Peak forearm and mean forearm blood flows across the cardiac cycle were continuously recorded at baseline and during pacing, with the use of high-resolution brachial artery ultrasound and Doppler flow velocity measurement. The brachial artery was cannulated to allow continuous infusion of saline or N(G)-monomethyl-L-arginine (L-NMMA). As heart rate increased, no changes in pulse pressure and mean or peak blood flow were evident. L-NMMA had no effect on brachial artery diameter, velocity, or flows compared with saline infusion. These results contrast with our recent findings that exercise involving the lower body, associated with increases in heart rate and pulse pressure, also increased forearm blood flow, the latter response being diminished by L-NMMA. These data suggest that changes in blood pressure, rather than pulse frequency, may be the stimulus for shear stress-mediated NO release in vivo.     

Exercise-mediated changes in conduit artery wall thickness in humans: role of shear stress

Episodic increases in shear stress have been proposed as a mechanism that induces training-induced adaptation in arterial wall remodeling in humans. To address this hypothesis in humans, we examined bilateral brachial artery wall thickness using high-resolution ultrasound in healthy men across an 8-wk period of bilateral handgrip training. Unilaterally, shear rate was attenuated by cuff inflation around the forearm to 60 mmHg. Grip strength, forearm volume, and girth improved similarly between the limbs. Acute bouts of handgrip exercise increased shear rate (P < 0.005) in the noncuffed limb, whereas cuff inflation successfully decreased exercise-induced increases in shear. Brachial blood pressure responses similarly increased during exercise in both the cuffed and noncuffed limbs. Handgrip training had no effect on baseline brachial artery diameter, blood flow, or shear rate but significantly decreased brachial artery wall thickness after 6 and 8 wk (ANOVA, P < 0.001) and wall-to-lumen ratio after week 8 (ANOVA, P = 0.005). The magnitude of decrease in brachial artery wall thickness and wall-to-lumen ratio after exercise training was similar in the noncuffed and cuffed arms. These results suggest that exercise-induced changes in shear rate are not obligatory for arterial wall remodeling during a period of 8 wk of exercise training in healthy humans.     

Effect of lower limb exercise on forearm vascular function: contribution of nitric oxide

We examined vascular function in an inactive muscle bed, the forearm, during lower limb exercise and determined the contribution of endothelium-derived nitric oxide (NO) to the hyperemic response. Eight young males were randomized to participate in two studies, each consisting of two bouts of lower limb exercise, separated by a 30-min recovery. Peak forearm blood flow (PFBF) and mean blood flow (MFBF) were continuously recorded at baseline and during exercise using continuous high-resolution vascular ultrasound and Doppler flow velocity measurement. During one session, the brachial artery was cannulated to allow continuous infusion of saline or N(G)-monomethyl-L-arginine (L-NMMA), an inhibitor of NO synthase. The alternate session was performed to control for possible effects of repeated exercise. At 60, 100, and 160 W, L-NMMA significantly decreased both PFBF and MFBF compared with the saline infusion. These results suggest that systemic production of NO occurs during exercise in resting vessel beds, which do not feed metabolically active tissue. This finding provides a plausible explanation for the antiatherogenic benefits of exercise.     

Flow-mediated dilation in human brachial artery after different circulatory occlusion conditions

Different magnitudes and durations of postocclusion reactive hyperemia were achieved by occluding different volumes of tissue with and without ischemic exercise to test the hypotheses that flow-mediated dilation (FMD) of the brachial artery would depend on the increase in peak flow rate or shear stress and that the position of the occlusion cuff would affect the response. The brachial artery FMD response was observed by high-frequency ultrasound imaging with curve fitting to minimize the effects of random measurement error in eight healthy, young, nonsmoking men. Reactive hyperemia was graded by 5-min occlusion distal to the measurement site at the wrist and the forearm and proximal to the site in the upper arm. Flow was further increased by exercise during occlusion at the wrist and forearm positions. For the two wrist occlusion conditions, flow increased eightfold and FMD was only 1 to 2% (P > 0.05). After the forearm and upper arm occlusions, blood flow was almost identical but FMD after forearm occlusions was 3.4% (P < 0.05), whereas it was significantly greater (6.6%, P < 0.05) and more prolonged after proximal occlusion. Forearm occlusion plus exercise caused a greater and more prolonged increase in blood flow, yet FMD (7.0%) was qualitatively and quantitatively similar to that after proximal occlusion. Overall, the magnitude of FMD was significantly correlated with peak forearm blood flow (r = 0.59, P < 0.001), peak shear rate (r = 0.49, P < 0.002), and total 5-min reactive hyperemia (r = 0.52, P < 0.001). The prolonged FMD after upper arm occlusion suggests that the mechanism for FMD differs with occlusion cuff position.     

Brachial artery adaptation to lower limb exercise training: role of shear stress

Lower limb exercise increases upper limb conduit artery blood flow and shear stress, and leg exercise training can enhance upper limb vascular function. We therefore examined the contribution of shear stress to changes in vascular function in the nonexercising upper limbs in response to lower limb cycling exercise training. Initially, five male subjects underwent bilateral brachial artery duplex ultrasound to measure blood flow and shear responses to 30-min cycling exercise at 80% of maximal heart rate. Responses in one forearm were significantly (P < 0.05) attenuated via cuff inflation throughout the exercise bout. An additional 11 subjects participated in an 8-wk cycle training study undertaken at a similar intensity, with unilateral cuff inflation around the forearm during each exercise bout. Bilateral brachial artery flow-mediated dilation responses to a 5-min ischemic stimulus (FMD%), an ischemic handgrip exercise stimulus (iEX), and endothelium-independent NO donor administration [glyceryl trinitrate (GTN)] were measured at 2, 4, and 8 wk. Cycle training increased FMD% in the noncuffed limb at week 2, after which time responses returned toward baseline levels (5.8 ± 4.1, 8.6 ± 3.8, 7.4 ± 3.5, 6.0 ± 2.3 at 0, 2, 4 and 8 wk, respectively; ANOVA: P = 0.04). No changes in FMD% were observed in the cuffed arm. No changes were evident in response to iEX or GTN in either the cuffed or noncuffed arms (P > 0.05) across the 8-wk intervention period. Our data suggest that lower limb cycle training induces a transient increase in upper limb vascular function in healthy young humans, which is, at least partly, mediated via shear stress.     

Adenosine contributes to hypoxia-induced forearm vasodilation in humans.

In humans, hypoxia leads to increased sympathetic neural outflow to skeletal muscle. However, blood flow increases in the forearm. The mechanism of hypoxia-induced vasodilation is unknown. To test whether hypoxia-induced vasodilation is cholinergically mediated or is due to local release of adenosine, normal subjects were studied before and during acute hypoxia (inspired O(2) 10.5%; approximately 20 min). In experiment I, aminophylline (50-200 microg. min(-1). 100 ml forearm tissue(-1)) was infused into the brachial artery to block adenosine receptors (n = 9). In experiment II, cholinergic vasodilation was blocked by atropine (0.4 mg over 4 min) infused into the brachial artery (n = 8). The responses of forearm blood flow (plethysmography) and forearm vascular resistance to hypoxia in the infused and opposite (control) forearms were compared. During hypoxia (arterial O(2) saturation 77 +/- 2%), minute ventilation and heart rate increased while arterial pressure remained unchanged; forearm blood flow rose by 35 +/- 6% in the control forearm but only by 5 +/- 8% in the aminophylline-treated forearm (P < 0.02). Accordingly, forearm vascular resistance decreased by 29 +/- 5% in the control forearm but only by 9 +/- 6% in the aminophylline-treated forearm (P < 0.02). Atropine did not attenuate forearm vasodilation during hypoxia. These data suggest that adenosine contributes to hypoxia-induced vasodilation, whereas cholinergic vasodilation does not play a role.     

Peripheral vascular resistance increases after termination of obstructive apneas.

The mechanisms by which obstructive apneas produce intermittent surges in arterial pressure remain poorly defined. To determine whether termination of obstructive apneas produce peripheral vasoconstriction, we assessed forearm blood flow during and after obstructive events in sleeping patients experiencing spontaneous upper airway obstructions. In all subjects, heart rate was monitored with an electrocardiogram and blood pressure was monitored continuously with digital plethysmography. In 10 patients (protocol 1), we used forearm plethysmography to assess forearm blood flow, from which we calculated forearm vascular resistance by performing venous occlusions during and after obstructive episodes. In an additional four subjects, we used simultaneous Doppler and B-mode images of the brachial artery to measure blood velocity and arterial diameter, from which we calculated brachial flow continuously during spontaneous apneas (protocol 2). In protocol 1, forearm vascular resistance increased 71% after apnea termination (29.3 +/- 15.4 to 49.8 +/- 26.5 resistance units, P < 0.05) with all patients showing an increase in resistance. In protocol 2, brachial resistance increased at apnea termination in all subjects (219.8 +/- 22.2 to 358.3 +/- 46.1 mmHg x l(-1) x min; P = 0.01). We conclude that termination of obstructive apneas is associated with peripheral vasoconstriction.     

Racial differences in central blood pressure and vascular function in young men

Young African-American men have altered macrovascular and microvascular function. In this cross-sectional study, we tested the hypothesis that vascular dysfunction in young African-American men would contribute to greater central blood pressure (BP) compared with young white men. Fifty-five young (23 yr), healthy men (25 African-American and 30 white) underwent measures of vascular structure and function, including carotid artery intima-media thickness (IMT) and carotid artery beta-stiffness via ultrasonography, aortic pulse wave velocity, aortic augmentation index (AIx), and wave reflection travel time (Tr) via radial artery tonometery and a generalized transfer function, and microvascular vasodilatory capacity of forearm resistance arteries with strain-gauge plethysmography. African-American men had similar brachial systolic BP (SBP) but greater aortic SBP (P<0.05) and carotid SBP (P<0.05). African-American men also had greater carotid IMT, greater carotid beta-stiffness, greater aortic stiffness and AIx, reduced aortic Tr and reduced peak hyperemic, and total hyperemic forearm blood flow compared with white men (P<0.05). In conclusion, young African-American men have greater central BP, despite comparable brachial BP, compared with young white men. Diffuse macrovascular and microvascular dysfunction manifesting as carotid hypertrophy, increased stiffness of central elastic arteries, heightened resistance artery constriction/blunted resistance artery dilation, and greater arterial wave reflection are present at a young age in apparently healthy African-American men, and conventional brachial BP measurement does not reflect this vascular burden.     

Vascular recruitment in skeletal muscle during exercise and hyperinsulinemia assessed by contrast ultrasound

The purpose of this study was to noninvasively quantify the effects of insulin on capillary blood volume (capBV) and RBC velocity (V(RBC)) in skeletal muscle in vivo with the use of contrast-enhanced ultrasound. We performed contrast ultrasound of the rat hindlimb adductor muscles at baseline and after 2-h infusions of either insulin (3 or 40 mU x kg(-1) x min(-1)) or saline. Saline-treated animals were also studied during contractile exercise. V(RBC) and capBV were calculated from the relation between pulsing interval and video intensity. Femoral artery blood flow, measured by a flow probe, increased with both contractile exercise and insulin. Contractile exercise increased capBV more than twofold and V(RBC) fivefold. Insulin also increased capBV more than twofold in a dose-dependent fashion but did not significantly alter V(RBC). Saline infusion did not significantly alter capBV, V(RBC), or femoral artery blood flow. We conclude that physiological changes in skeletal muscle capillary perfusion can be assessed in vivo with the use of contrast-enhanced ultrasound. Exercise increases both V(RBC) and capBV, whereas hyperinsulinemia selectively increases only capBV, which may enhance skeletal muscle glucose uptake.     

WISE 2005: stroke volume changes contribute to the pressor response during ischemic handgrip exercise in women.

The mechanism of the pressor response to small muscle mass (e.g., forearm) exercise and during metaboreflex activation may include elevations in cardiac output (Q) or total peripheral resistance (TPR). Increases in Q must be supported by reductions in visceral venous volume to sustain venous return as heart rate (HR) increases. Therefore, this study tested the hypothesis that increases in Q, supported by reductions in splanchnic volume (portal vein constriction), explain the pressor response during handgrip exercise and metaboreflex activation. Seventeen healthy women performed 2 min of static ischemic handgrip exercise and 2 min of postexercise circulatory occlusion (PECO) while HR, stroke volume and superficial femoral artery flow (Doppler), blood pressure (Finometer), portal vein diameter (ultrasound imaging), and muscle sympathetic nerve activity (MSNA; microneurography) were measured followed by the calculation of Q, TPR, and leg vascular resistance (LVR). Compared with baseline, mean arterial blood pressure (MAP) (P < 0.001) and Q (P < 0.001) both increased in each minute of exercise accompanied by a approximately 5% reduction in portal vein diameter (P < 0.05). MAP remained elevated during PECO, whereas Q decreased below exercise levels. MSNA was elevated above baseline during the second minute of exercise and through the PECO period (P < 0.05). Neither TPR nor LVR was changed from baseline during exercise and PECO. The data indicate that the majority of the blood pressure response to isometric handgrip exercise in women was due to mobilization of central blood volume and elevated stroke volume and Q rather than elevations in TVR or LVR resistance.     

Assessment of brachial artery blood flow across the cardiac cycle: retrograde flows during cycle ergometry.

We describe a novel software system that utilizes automated algorithms to perform edge detection and wall tracking of high-resolution B-mode arterial ultrasound images, combined with synchronized Doppler waveform envelope analysis, to calculate conduit arterial blood flow (BF) across the cardiac cycle. Furthermore, we describe changes in brachial arterial BF to the resting forearm during incremental cycle ergometry in eight subjects. During exercise, peak BF during the cardiac cycle increased at each workload (P < 0.001), because of increased velocity in the presence of unaltered cross-sectional area. In contrast, mean BF calculated across each cardiac cycle decreased at lower workloads before increasing at 100 and 160 W (P < 0.001). Differences in the pattern of peak and mean cardiac cycle flows were due to the influence of retrograde diastolic flow, which had a larger impact on mean flows at lower workloads. In conclusion, BF can be measured with high temporal resolution across the cardiac cycle in humans. Resting brachial arterial flow, including retrograde flow, increases during lower limb exercise.     

Nitric oxide-mediated vasodilation becomes independent of beta-adrenergic receptor activation with increased intensity of hypoxic exercise

Hypoxic vasodilation in skeletal muscle at rest is known to include β-adrenergic receptor-stimulated nitric oxide (NO) release. We previously reported that the augmented skeletal muscle vasodilation during mild hypoxic forearm exercise includes β-adrenergic mechanisms. However, it is unclear whether a β-adrenergic receptor-stimulated NO component exists during hypoxic exercise. We hypothesized that NO-mediated vasodilation becomes independent of β-adrenergic receptor activation with increased exercise intensity during hypoxic exercise. Ten subjects (7 men, 3 women; 23 ± 1 yr) breathed hypoxic gas to titrate arterial O(2) saturation to 80% while remaining normocapnic. Subjects performed two consecutive bouts of incremental rhythmic forearm exercise (10% and 20% of maximum) with local administration (via a brachial artery catheter) of propranolol (β-adrenergic receptor inhibition) alone and with the combination of propranolol and nitric oxide synthase inhibition [N(G)-monomethyl-l-arginine (l-NMMA)] under normoxic and hypoxic conditions. Forearm blood flow (FBF, ml/min; Doppler ultrasound) and blood pressure [mean arterial pressure (MAP), mmHg; brachial artery catheter] were assessed, and forearm vascular conductance (FVC, ml·min(-1)·100 mmHg(-1)) was calculated (FBF/MAP). During propranolol alone, the rise in FVC (Δ from normoxic baseline) due to hypoxic exercise was 217 ± 29 and 415 ± 41 ml·min(-1)·100 mmHg(-1) (10% and 20% of maximum, respectively). Combined propranolol-l-NMMA infusion during hypoxic exercise attenuated ΔFVC at 20% (352 ± 44 ml·min(-1)·100 mmHg(-1); P < 0.001) but not at 10% (202 ± 28 ml·min(-1)·100 mmHg(-1); P = 0.08) of maximum compared with propranolol alone. These data, when integrated with earlier findings, demonstrate that NO contributes to the compensatory vasodilation during mild and moderate hypoxic exercise; a β-adrenergic receptor-stimulated NO component exists during low-intensity hypoxic exercise. However, the source of the NO becomes less dependent on β-adrenergic mechanisms as exercise intensity increases.     

Impaired microvascular perfusion: a consequence of vascular dysfunction and a potential cause of insulin resistance in muscle

Insulin has an exercise-like action to increase microvascular perfusion of skeletal muscle and thereby enhance delivery of hormone and nutrient to the myocytes. With insulin resistance, insulin's action to increase microvascular perfusion is markedly impaired. This review examines the present status of these observations and techniques available to measure such changes as well as the possible underpinning mechanisms. Low physiological doses of insulin and light exercise have been shown to increase microvascular perfusion without increasing bulk blood flow. In these circumstances, blood flow is proposed to be redirected from the nonnutritive route to the nutritive route with flow becoming dominant in the nonnutritive route when insulin resistance has developed. Increased vasomotion controlled by vascular smooth muscle may be part of the explanation by which insulin mediates an increase in microvascular perfusion, as seen from the effects of insulin on both muscle and skin microvascular blood flow. In addition, vascular dysfunction appears to be an early development in the onset of insulin resistance, with the consequence that impaired glucose delivery, more so than insulin delivery, accounts for the diminished glucose uptake by insulin-resistant muscle. Regular exercise may prevent and ameliorate insulin resistance by increasing "vascular fitness" and thereby recovering insulin-mediated capillary recruitment.     

Effects of combined inhibition of ATP-sensitive potassium channels, nitric oxide, and prostaglandins on hyperemia during moderate exercise.

ATP-sensitive potassium (KATP) channels have been suggested to contribute to coronary and skeletal muscle vasodilation during exercise, either alone or interacting in a parallel or redundant process with nitric oxide (NO), prostaglandins (PGs), and adenosine. We tested the hypothesis that KATP channels, alone or in combination with NO and PGs, regulate exercise hyperemia in forearm muscle. Eighteen healthy young adults performed 20 min of moderate dynamic forearm exercise, with forearm blood flow (FBF) measured via Doppler ultrasound. After steady-state FBF was achieved for 5 min (saline control), the KATP inhibitor glibenclamide (Glib) was infused into the brachial artery for 5 min (10 microg.dl(-1).min(-1)), followed by saline infusion during the final 10 min of exercise (n = 9). Exercise increased FBF from 71 +/- 11 to 239 +/- 24 ml/min, and FBF was not altered by 5 min of Glib. Systemic plasma Glib levels were above the therapeutic range, and Glib increased insulin levels by approximately 50%, whereas blood glucose was unchanged (88 +/- 2 vs. 90 +/- 2 mg/dl). In nine additional subjects, Glib was followed by combined infusion of NG-nitro-L-arginine methyl ester (L-NAME) plus ketorolac (to inhibit NO and PGs, respectively). As above, Glib had no effect on FBF but addition of L-NAME + ketorolac (i.e., triple blockade) reduced FBF by approximately 15% below steady-state exercise levels in seven of nine subjects. Interestingly, triple blockade in two subjects caused FBF to transiently and dramatically decrease. This was followed by an acute recovery of flow above steady-state exercise values. We conclude 1) opening of KATP channels is not obligatory for forearm exercise hyperemia, and 2) triple blockade of NO, PGs, and KATP channels does not reduce hyperemia more than the inhibition of NO and PGs in most subjects. However, some subjects are sensitive to triple blockade, but they are able to restore FBF acutely during exercise. Future studies are required to determine the nature of these compensatory mechanisms in the affected individuals.     

Immediate exercise hyperemia in humans is contraction intensity dependent: evidence for rapid vasodilation.

We tested the hypothesis that rapid vasodilation proportional to contraction intensity contributes to the immediate (first cardiac cycle after initial contraction) exercise hyperemia. Ten healthy subjects performed single 1-s isometric forearm contractions at 5, 10, 15, 20, 30, 50, and 70% maximal voluntary contraction intensity (MVC) in arm above heart (AH) and below heart (BH) positions. Forearm blood flow (FBF; brachial artery mean blood velocity, Doppler ultrasound), mean arterial pressure (arterial tonometry), and heart rate (electrocardiogram) were measured beat by beat. Venous emptying (measured with a forearm strain gauge) was already maximized at 5% MVC, indicating that increases in contraction intensity did not further empty the forearm veins. Immediate increases in FBF were linearly proportional to contraction intensity from 5 to 70% MVC in AH (slope = 4.4 +/- 0.5%DeltaFBF/%MVC). In BH, the immediate increase in FBF demonstrated a curvilinear relationship with increasing contraction intensity and was greater than AH at 15, 20, 30, and 50% MVC (P < 0.05). Peak changes in FBF were greater in BH vs. AH from 10 to 50% MVC, even when venous refilling was complete (P < 0.05). These data support the existence of a rapid-acting vasodilatory mechanism(s) at the onset of human forearm exercise.     

Hypercapnia-induced cerebral and ocular vasodilation is not altered by glibenclamide in humans

Carbon dioxide is an important regulator of vascular tone. Glibenclamide, an inhibitor of ATP-sensitive potassium channel (K(ATP)) activation, significantly blunts vasodilation in response to hypercapnic acidosis in animals. We investigated whether glibenclamide also alters the cerebral and ocular vasodilator response to hypercapnia in humans. Ten healthy male subjects were studied in a controlled, randomized, double-blind two-way crossover study under normoxic and hypercapnic conditions. Glibenclamide (5 mg po) or insulin (0.3 mU. kg(-1). min(-1) iv) were administered with glucose to achieve comparable plasma insulin levels. In control experiments, five healthy volunteers received glibenclamide (5 mg) or nicorandil (40 mg) or glibenclamide and nicorandil in a randomized, three-way crossover study. Mean blood flow velocity and resistive index in the middle cerebral artery (MCA) and in the ophthalmic artery (OA) were measured with Doppler sonography. Pulsatile choroidal blood flow was assessed with laser interferometric measurement of fundus pulsation. Forearm blood flow was measured with venous occlusion plethysmography. Hypercapnia increased ocular fundus pulsation amplitude by +18.2-22.3% (P < 0. 001) and mean flow velocity in the MCA by +27.4-33.3% (P < 0.001), but not in the OA (2.1-6.5%, P = 0.2). Forearm blood flow increased by 78.2% vs. baseline (P = 0.041) after nicorandil administration. Glibenclamide did not alter hypercapnia-induced changes in cerebral or ocular hemodynamics and did not affect systemic hemodynamics or forearm blood flow but significantly increased glucose utilization and blunted the nicorandil-induced vasodilation in the forearm. This suggests that hypercapnia-induced changes in the vascular beds under study are not mediated by activation of K(ATP) channels in humans.     

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.