RESUMO
Breathlessness during daily activities is the primary symptom in patients with heart failure (HF). Poor correlation between the hemodynamic parameters of left ventricular performance and perceived symptoms suggests that other factors, such as skeletal muscle function, play a role in determining exercise capacity. We investigated the effect of 6 wk of high-intensity, one-legged cycling (HIC; 8 × 4 at 90% one-legged cycling max) on 1) the ability to override sympathetic vasoconstriction (arterial infusion of tyramine) during one-legged knee-extensor exercise (KEE), 2) vascular function (arterial infusion of ACh, sodium nitroprusside, tyramine, and ATP), and 3) exercise capacity in HF patients with reduced ejection fraction ( n = 8) compared with healthy individuals ( n = 6). Arterial tyramine infusion lowered leg blood flow and leg vascular conductance at rest and during KEE before the training intervention in both groups ( P < 0.05) but not during KEE after the training intervention. There was no difference between groups. The peak vasodilatory response to ATP was blunted in HF patients ( P < 0.05), whereas there was no difference in ACh- and sodium nitroprusside-induced vasodilation between HF patients and healthy individuals. ACh-induced vasodilation increased in HF patients after the training intervention ( P < 0.05). HIC improved aerobic capacity in both groups ( P < 0.05), whereas only HF patients made improvements in the 6-min walking distance ( P < 0.05). These results suggest that exercise hyperemia and functional sympatholysis are not altered in HF patients and that functional sympatholysis is improved with HIC in both HF patients and healthy individuals. Moreover, these results suggest that the peak vasodilatory response to ATP is blunted in HF. NEW & NOTEWORTHY The ability to override sympathetic vasoconstrictor activity (by arterial tyramine infusion) during exercise is not different between heart failure patients and healthy individuals and is improved by high-intensity, one-legged cycling training. The peak vasodilatory response to ATP is reduced in heart failure patients.
Assuntos
Trifosfato de Adenosina/administração & dosagem , Ciclismo , Terapia por Exercício/métodos , Tolerância ao Exercício/efeitos dos fármacos , Insuficiência Cardíaca/terapia , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/inervação , Sistema Nervoso Simpático/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Vasodilatadores/administração & dosagem , Idoso , Dinamarca , Feminino , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/fisiopatologia , Humanos , Hiperemia/fisiopatologia , Extremidade Inferior , Masculino , Pessoa de Meia-Idade , Contração Muscular , Fluxo Sanguíneo Regional , Volume Sistólico , Sistema Nervoso Simpático/fisiopatologia , Simpatomiméticos/administração & dosagem , Fatores de Tempo , Resultado do Tratamento , Função Ventricular EsquerdaRESUMO
Background We evaluated the association of cardiac adipose tissue including epicardial adipose tissue and pericardial adipose tissue with incident cardiovascular disease and mortality, coronary artery calcium, carotid intima media thickness and inflammatory markers. Design A prospective study of 200 patients with type 2 diabetes and elevated urinary albumin excretion rate (UAER). Methods Cardiac adipose tissue was measured from baseline echocardiography. The composite endpoint comprised incident cardiovascular disease and all-cause mortality. Coronary artery calcium, carotid intima media thickness and inflammatory markers were measured at baseline. Cardiac adipose tissue was investigated as continuous and binary variable. Analyses were performed unadjusted (model 1), and adjusted for age, sex (model 2), body mass index, low-density lipoprotein cholesterol, smoking, glycated haemoglobin, and systolic blood pressure (model 3). Results Patients were followed-up after 6.1 years for non-fatal cardiovascular disease ( n = 29) or mortality ( n = 23). Cardiac adipose tissue ( p = 0.049) and epicardial adipose tissue ( p = 0.029) were associated with cardiovascular disease and mortality in model 1. When split by the median, patients with high cardiac adipose tissue had a higher risk of cardiovascular disease and mortality than patients with low cardiac adipose tissue in unadjusted (hazard ratio 1.9, confidence interval: 1.1; 3.4, p = 0.027) and adjusted (hazard ratio 2.0, confidence interval: 1.1; 3.7, p = 0.017) models. Cardiac adipose tissue ( p = 0.033) was associated with baseline coronary artery calcium (model 1) and interleukin-8 (models 1-3, all p < 0.039). Conclusions In type 2 diabetes patients without coronary artery disease, high cardiac adipose tissue levels were associated with increased risk of incident cardiovascular disease or all-cause mortality even after accounting for traditional cardiovascular disease risk factors. High cardiac adipose tissue amounts were associated with subclinical atherosclerosis (coronary artery calcium) and with the pro-atherogenic inflammatory marker interleukin-8.
Assuntos
Tecido Adiposo/fisiopatologia , Adiposidade , Albuminúria/epidemiologia , Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Nefropatias Diabéticas/epidemiologia , Pericárdio/fisiopatologia , Tecido Adiposo/diagnóstico por imagem , Idoso , Albuminúria/diagnóstico , Albuminúria/mortalidade , Biomarcadores/sangue , Doenças Cardiovasculares/diagnóstico por imagem , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/fisiopatologia , Espessura Intima-Media Carotídea , Angiografia Coronária , Dinamarca/epidemiologia , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/mortalidade , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/mortalidade , Ecocardiografia , Feminino , Humanos , Incidência , Mediadores da Inflamação/sangue , Interleucina-8/sangue , Estimativa de Kaplan-Meier , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Dinâmica não Linear , Pericárdio/diagnóstico por imagem , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Fatores de TempoRESUMO
OBJECTIVE: Sympathetic vasoconstriction regulates peripheral circulation and controls blood pressure, but sepsis is associated with hypotension. We evaluated whether apparent loss of sympathetic vasoconstrictor responsiveness relates to distended smooth muscles or to endotoxemia and/or hypoxia. DESIGN: Prospective descriptive study. SETTING: Hospital research laboratory. SUBJECTS: Ten healthy young men (age [mean ± SD], 31 ± 8 yr; body weight, 83 ± 10 kg) participated in the study. INTERVENTIONS: Leg blood flow and mean arterial pressure were determined, whereas leg vascular conductance was calculated during 1) adenosine infusion (vasodilator control), 2) hypoxia (FIO2 = 10%), 3) endotoxemia, and 4) endotoxemia + hypoxia. Leg sympathetic vasoconstrictor responsiveness (reduction in leg vascular conductance) was evaluated by femoral artery tyramine infusion. MEASUREMENTS AND MAIN RESULTS: Endotoxemia increased body temperature from 36.9 ± 0.4°C to 38.6 ± 0.5°C (p < 0.01) and plasma tumor necrosis factor-α from 6 pg/mL (3-8 pg/mL) to 391 pg/mL (128-2258 pg/mL) (p < 0.01; median [range]). Mean arterial pressure decreased similarly during endotoxemia (-11% ± 16%) and endotoxemia + hypoxia (-10% ± 15%; both p < 0.05). Leg blood flow and leg vascular conductance were not affected by endotoxemia, whereas both were elevated by adenosine infusion (leg blood flow, +94% ± 61%; leg vascular conductance, +97% ± 57%), hypoxia (leg blood flow: +93% ± 58%; leg vascular conductance, +100% ± 115%), and endotoxemia + hypoxia (leg blood flow, +67% ± 120%; leg vascular conductance, +65% ± 57%; p < 0.05). Endotoxemia lessened the tyramine-induced reduction in leg vascular conductance (-28% ± 13%) compared with the reduction during adenosine infusion (-47% ± 5%; p < 0.05). Also, endotoxemia + hypoxia (-17% ± 21%) attenuated the tyramine-induced reduction in leg vascular conductance compared with both adenosine infusion and hypoxia (-45% ± 13%; p < 0.05). CONCLUSIONS: Both endotoxemia and combined hypoxia and endotoxemia blunted sympathetic vasoconstrictor responsiveness. Furthermore, tyramine normalized the doubled leg vascular conductance during administration of adenosine, suggesting that distension of vascular smooth muscles does not explain blunted sympathetic vasoconstrictor responsiveness during endotoxemia.
Assuntos
Endotoxemia/fisiopatologia , Hipóxia/fisiopatologia , Perna (Membro)/irrigação sanguínea , Sistema Nervoso Simpático/efeitos dos fármacos , Vasoconstritores/farmacologia , Adenosina/farmacologia , Inibidores da Captação Adrenérgica/farmacologia , Adulto , Pressão Arterial/efeitos dos fármacos , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Artéria Femoral/efeitos dos fármacos , Humanos , Masculino , Norepinefrina/metabolismo , Estudos Prospectivos , Tiramina/farmacologia , Vasoconstrição/efeitos dos fármacos , Vasodilatadores/farmacologia , Adulto JovemRESUMO
Acute myocardial infarction continues to be a major cause of morbidity and mortality. Timely reperfusion can substantially improve outcomes and the administration of cardioprotective substances during reperfusion is therefore highly attractive. Adenosine diphosphate (ADP) and uridine-5-triphoshate (UTP) are both released during myocardial ischemia, influencing hemodynamics. Both mediate the release of tissue plasminogen activator (t-PA), which can reduce infarct size (IS). The objective of this study was to investigate whether exogenous ADP and UTP administration during reperfusion could reduce myocardial IS and whether this correlated to t-PA release or improvements in hemodynamic responses. Hemodynamic variables and t-PA were measured in 22 pigs before, during, and after 45 min of left anterior coronary artery occlusion. During reperfusion, the pigs were randomized to 240 min of intracoronary infusion of ADP, UTP, or control (no intervention). Ischemic area compared to the area at risk [IS/AAR] was measured. [IS/AAR] was 52 ± 11% in the control animals. ADP decreased [IS/AAR] by 19% (P < 0.05), while UTP increased [IS/AAR] by 15% (P < 0.05). Cardiac output (CO) increased from 3.4 to 3.5 L/min (P < 0.05) and mean arterial pressure (MAP) decreased from 87 to 73 mmHg in the ADP group (P < 0.05). t-PA concentration increased in the ADP and UTP group from 2.0 ng/mL to 2.5 and 2.4 ng/mL, respectively (P < 0.05) but remained unchanged in the control group. In conclusion, intracoronary ADP infusion during reperfusion reduces IS by â¼20% independently from systemic release of t-PA. ADP-induced reduction in both preload and afterload could account for the beneficial myocardial effect.
RESUMO
OBJECTIVE: The administration of endotoxin to healthy humans reduces cerebral blood flow but its influence on dynamic cerebral autoregulation remains unknown. We considered that a reduction in arterial carbon dioxide tension would attenuate cerebral perfusion and improve dynamic cerebral autoregulation in healthy subjects exposed to endotoxemia. DESIGN: Prospective descriptive study. SETTING: Hospital research laboratory. SUBJECTS: Ten healthy young subjects (age: 32 ± 8 yrs [mean ± SD]; weight: 84 ± 10 kg; weight: 184 ± 5 cm; body mass index: 25 ± 2 kg/m2) participated in the study. INTERVENTIONS: Systemic hemodynamics, middle cerebral artery mean flow velocity, and dynamic cerebral autoregulation evaluated by transfer function analysis in the very low (<0.07 Hz), low (0.07-0.15 Hz), and high (>0.15 Hz) frequency ranges were monitored in these volunteers before and after an endotoxin bolus (2 ng/kg; Escherichia coli). MEASUREMENTS AND MAIN RESULTS: Endotoxin increased body temperature of the subjects from 36.8 ± 0.4°C to 38.6 ± 0.5°C (p < .001) and plasma tumor necrosis factor-α from 5.6 (2.8-6.7) pg/mL to 392 (128-2258) pg/mL (p < .02). Endotoxemia had no influence on mean arterial pressure (95 [74-103] mm Hg vs. 92 [78-104] mm Hg; p = .75), but increased cardiac output (8.3 [6.1-9.5] L·min(-1) vs. 6.0 [4.5-8.2] L·min(-1); p = .02) through an elevation in heart rate (82 ± 9 beats·min(-1) vs. 63 ± 10 beats·min(-1); p < .001), whereas arterial carbon dioxide tension (37 ± 5 mm Hg vs. 41 ± 2 mm Hg; p < .05) and middle cerebral artery mean flow velocity (37 ± 9 cm·sec(-1) vs. 47 ± 10 cm·sec(-1); p < .01) were reduced. In regard to dynamic cerebral autoregulation, endotoxemia was associated with lower middle cerebral artery mean flow velocity variability (1.0 ± 1.0 [cm·sec(-1)] Hz vs. 2.8 ± 1.5 [cm·sec(-1)] Hz; p < .001), reduced gain (0.52 ± 0.11 cm·sec(-1) x mm Hg(-1) vs. 0.74 ± 0.17 cm·sec(-1) x mm Hg(-1); p < .05), normalized gain (0.22 ± 0.05 vs. 0.40 ± 0.17%·%; p < .05), and higher mean arterial pressure-to-middle cerebral artery mean flow velocity phase difference (p < .05) in the low frequency range (0.07-0.15 Hz). CONCLUSIONS: These data support that the reduction in arterial carbon dioxide tension explains the improved dynamic cerebral autoregulation and the reduced cerebral perfusion encountered in healthy subjects during endotoxemia.
Assuntos
Dióxido de Carbono/sangue , Circulação Cerebrovascular/fisiologia , Endotoxemia/fisiopatologia , Homeostase/fisiologia , Artéria Cerebral Média/fisiologia , Adulto , Velocidade do Fluxo Sanguíneo , Humanos , Pressão Parcial , Estudos ProspectivosRESUMO
OBJECTIVE: Sympathetic vasoconstriction is blunted in contracting human skeletal muscles (functional sympatholysis). In young subjects, infusion of adenosine and ATP increases blood flow, and the latter compound also attenuates α-adrenergic vasoconstriction. In patients with type 2 diabetes and age-matched healthy subjects, we tested 1) the sympatholytic capacity during one-legged exercise, 2) the vasodilatory capacity of adenosine and ATP, and 3) the ability to blunt α-adrenergic vasoconstriction during ATP infusion. RESEARCH DESIGN AND METHODS: In 10 control subjects and 10 patients with diabetes and normal endothelial function, determined by leg blood flow (LBF) response to acetylcholine infusion, we measured LBF and venous NA, with and without tyramine-induced sympathetic vasoconstriction, during adenosine-, ATP-, and exercise-induced hyperemia. RESULTS: LBF during acetylcholine did not differ significantly. LBF increased ninefold during exercise and during adenosine- and ATP-induced hyperemia. Infusion of tyramine during exercise did not reduce LBF in either the control or the patient group. During combined ATP and tyramine infusions, LBF decreased by 30% in both groups. Adenosine had no sympatholytic effect. CONCLUSIONS: In patients with type 2 diabetes and normal endothelial function, functional sympatholysis was intact during moderate exercise. The vasodilatory response for adenosine and ATP did not differ between the patients with diabetes and the control subjects; however, the vasodilatory effect of adenosine and ATP and the sympatholytic effect of ATP seem to decline with age.
Assuntos
Acetilcolina/farmacologia , Diabetes Mellitus Tipo 2/fisiopatologia , Adenosina/administração & dosagem , Adenosina/farmacologia , Trifosfato de Adenosina/administração & dosagem , Trifosfato de Adenosina/farmacologia , Fatores Etários , Exercício Físico , Feminino , Humanos , Hiperemia/induzido quimicamente , Hiperemia/etiologia , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/efeitos dos fármacos , Fluxo Sanguíneo Regional/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacosRESUMO
Nucleotides, including ADP, ATP and uridine triphosphate (UTP), are discharged profusely in the circulation during many pathological conditions including sepsis. Sepsis can cause hypotension and systemic activation of the coagulation and fibrinolytic systems in humans, which may cause disseminated intravascular coagulation. We investigated whether nucleotide-induced cardiovascular collapse as provoked by systemic infusion of adenosine, ADP, ATP, UTP and nitric oxide affected the haemostatic system as assessed by whole blood thromboelastography (TEG) analysis. Ten pigs received a randomized infusion of adenosine, ADP, ATP, UTP or nitric oxide until mean arterial pressure was reduced to approximately 40% of baseline simulating sepsis-induced hypotension. The effect of the infusions on the haemostatic system was evaluated by TEG, and endothelial release of tissue plasminogen activator and plasminogen activator inhibitor-1 was measured. In contrast to the other infused substrates, ADP caused a reduction in maximum amplitude (71.4 to 64.2; P < 0.05), and reduced the angle, representing the thrombus formation (75.6 to 66.4; P < 0.05), indicating hypocoagulation. Despite increases in t-PA release (2.1 to 2.7 ng/ml; P < 0.05) and reductions in plasminogen activator inhibitor (33.9 +/- 10.9-17.8 +/- 4.4 ng/ml; P < 0.05) no increased fibrinolysis was found when whole blood was evaluated by TEG. Circulating ADP induces hypocoagulation without signs of increased fibrinolysis as evaluated by TEG. The potential clinical significance of these findings should be investigated further because ADP discharged systemically may possibly contribute to the coagulopathy observed in severe sepsis.
Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Nucleosídeos/farmacologia , Nucleotídeos/farmacologia , Animais , Óxido Nítrico/administração & dosagem , Óxido Nítrico/farmacologia , Nucleosídeos/administração & dosagem , Nucleotídeos/administração & dosagem , SuínosRESUMO
OBJECTIVE: Extracellular nucleotides and nucleosides are involved in regulation of skeletal muscle blood flow. Diabetes induces cardiovascular dysregulation, but the extent to which the vasodilatatory capacity of nucleotides and nucleosides is affected in type 2 diabetes is unknown. The present study investigated 1) the vasodilatatory effect of ATP, uridine-triphosphate (UTP), and adenosine (ADO) and 2) the expression and distribution of P2Y(2) and P2X(1) receptors in skeletal muscles of diabetic subjects. RESEARCH DESIGN AND METHODS: In 10 diabetic patients and 10 age-matched control subjects, leg blood flow (LBF) was measured during intrafemoral artery infusion of ATP, UTP, and ADO, eliciting a blood flow equal to knee-extensor exercise at 12 W (approximately 2.6 l/min). RESULTS: The vasodilatatory effect of the purinergic system was 50% lower in the diabetic group as exemplified by an LBF increase of 274 +/- 37 vs. 143 +/- 26 ml/micromol ATP x kg, 494 +/- 80 vs. 234 +/- 39 ml/micromol UTP x kg, and 14.9 +/- 2.7 vs. 7.5 +/- 0.6 ml/micromol ADO x kg in control and diabetic subjects, respectively, thus making the vasodilator potency as follows: UTP control subjects (100) > ATP control subjects (55) > UTP diabetic subjects (47) > ATP diabetic subjects (29) > ADO control subjects (3) > ADO diabetic subjects (1.5). The distribution and mRNA expression of receptors were similar in the two groups. CONCLUSIONS: The vasodilatatory effect of the purinergic system is severely reduced in type 2 diabetic patients. The potency of nucleotides varies with the following rank order: UTP > ATP > ADO. This is not due to alterations in receptor distribution and mRNA expression, but may be due to differences in receptor sensitivity.
Assuntos
Diabetes Mellitus Tipo 2/fisiopatologia , Receptores Purinérgicos P2/fisiologia , Vasodilatação/fisiologia , Adenosina/farmacologia , Trifosfato de Adenosina/farmacologia , Velocidade do Fluxo Sanguíneo/fisiologia , Índice de Massa Corporal , Colesterol/sangue , Diabetes Mellitus Tipo 2/sangue , Exercício Físico , Feminino , Humanos , Perna (Membro)/irrigação sanguínea , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/fisiopatologia , Receptores Purinérgicos P2X , Receptores Purinérgicos P2Y2 , Valores de Referência , Fluxo Sanguíneo Regional/fisiologia , Uridina Trifosfato/farmacologiaRESUMO
Sympathetic vasoconstriction is blunted in the vascular beds of contracting skeletal muscle in humans, presumably due to the action of vasoactive metabolites (functional sympatholysis). Recently, we demonstrated that infusion of ATP into the arterial circulation of the resting human leg increases blood flow and concomitantly blunts alpha-adrenergic vasoconstriction in a similar manner to that during moderate exercise. Here we tested the hypothesis that ATP, rather than its dephosphorylated metabolites, induces vasodilatation and sympatholysis in resting skeletal muscle via activation of ATP/UTP-selective receptors. To this aim, we first measured leg blood flow (LBF), mean arterial pressure (MAP), cardiac output , leg arterial-venous (a-v) O(2) difference, plasma ATP and soluble nucleotidase activities during intrafemoral artery infusion of adenosine, AMP, ADP, ATP or UTP in nine healthy males. Comparison of the doses of nucleotides and adenosine required for a similar increase in LBF from approximately 0.5 l min(-1) at baseline to approximately 3.5 l min(-1) (without altering MAP but increasing Q significantly) revealed the following rank order of vasoactive potency: ATP (100) = UTP (100) >> adenosine (5.8) > ADP (2.7) > AMP (1.7). The infusions did not cause any shifts in plasma ATP level or soluble serum nucleotidase activities. Combined infusion of the vasodilatory compounds and the sympathetic vasoconstrictor drug tyramine increased plasma noradrenaline in all hyperaemic conditions, but only caused leg and systemic vasoconstriction and augmented O(2) extraction during adenosine, AMP and ADP infusion (LBF from 3.2 +/- 0.3 to 1.8 +/- 0.2 l min(-1); 3.7 +/- 0.4 to 1.7 +/- 0.2 l min(-1) and 3.3 +/- 0.4 to 2.4 +/- 0.3 l min(-1), respectively, P < 0.05). These findings in humans suggest that the vasodilatory and sympatholytic effects of exogenous ATP in the skeletal muscle vasculature are largely mediated via ATP itself rather than its dephosphorylated metabolites, most likely via binding to endothelial ATP/UTP-selective P2Y(2) receptors. These data are consistent with a role of ATP in skeletal muscle hyperaemia in conditions of increased sympathetic nerve drive such as exercise or hypoxia.
Assuntos
Trifosfato de Adenosina/administração & dosagem , Velocidade do Fluxo Sanguíneo/fisiologia , Músculo Esquelético/irrigação sanguínea , Receptores de Superfície Celular/metabolismo , Receptores Purinérgicos P2/metabolismo , Sistema Nervoso Simpático/fisiologia , Vasoconstrição/fisiologia , Vasodilatação/fisiologia , Adenosina/administração & dosagem , Adulto , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Humanos , Hiperemia/fisiopatologia , Perna (Membro)/irrigação sanguínea , Masculino , Músculo Esquelético/inervação , Músculo Esquelético/fisiologia , Esforço Físico/fisiologia , Descanso/fisiologia , Tiramina/administração & dosagem , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacosRESUMO
Despite increases in muscle sympathetic vasoconstrictor activity, skeletal muscle blood flow and O2 delivery increase during exercise in humans in proportion to the local metabolic demand, a phenomenon coupled to local reductions in the oxygenation state of haemoglobin and concomitant increases in circulating ATP. We tested the hypothesis that circulating ATP contributes to local blood flow and O2 delivery regulation by both inducing vasodilatation and blunting the augmented sympathetic vasoconstrictor activity. In eight healthy subjects, we first measured leg blood flow (LBF) and mean arterial pressure (MAP) during three hyperaemic conditions: (1) intrafemoral artery adenosine infusion (vasodilator control), (2) intrafemoral artery ATP infusion (vasodilator), and (3) mild knee-extensor exercise (approximately 20 W), and then compared the responses with the combined infusion of the vasoconstrictor drug tyramine, which evokes endogenous release of noradrenaline from sympathetic nerve endings. In all three hyperaemic conditions, LBF equally increased from approximately 0.5 +/- 0.1 l min(-1) at rest to approximately 3.6 +/- 0.3 l min(-1), with no change in MAP. Tyramine caused significant leg vasoconstriction during adenosine infusion (53 +/- 5 and 56 +/- 5% lower LBF and leg vascular conductance, respectively, P < 0.05), which was completely abolished by both ATP infusion and exercise. In six additional subjects resting in the sitting position, intrafemoral artery infusion of ATP increased LBF and leg vascular conductance 27 +/- 3-fold, despite concomitant increases in venous noradrenaline and muscle sympathetic nerve activity of 2.5 +/- 0.2- and 2.4 +/- 0.1-fold, respectively. Maximal ATP-induced vasodilatation at rest accounted for 78% of the peak LBF during maximal bicycling exercise. Our findings in humans demonstrate that circulating ATP is capable of regulating local skeletal muscle blood flow and O2 delivery by causing substantial vasodilatation and negating the effects of increased sympathetic vasoconstrictor activity.
Assuntos
Trifosfato de Adenosina/administração & dosagem , Músculo Esquelético/irrigação sanguínea , Sistema Nervoso Simpático/fisiologia , Vasoconstrição/fisiologia , Vasodilatação/fisiologia , Adenosina/administração & dosagem , Adulto , Feminino , Humanos , Hiperemia/fisiopatologia , Perna (Membro)/irrigação sanguínea , Masculino , Músculo Esquelético/inervação , Músculo Esquelético/fisiologia , Esforço Físico/fisiologia , Descanso/fisiologia , Tiramina/administração & dosagem , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacosRESUMO
Nitric oxide (NO) is capable of blunting alpha-adrenergic vasoconstriction in contracting skeletal muscles of experimental animals (functional sympatholysis). We therefore tested the hypothesis that exogenous NO administration can blunt alpha-adrenergic vasoconstriction in resting human limbs by measuring forearm blood flow (FBF; Doppler ultrasound) and blood pressure in eight healthy males during brachial artery infusions of three alpha-adrenergic constrictors (tyramine, which evokes endogenous norepinephrine release; phenylephrine, an alpha1-agonist; and clonidine, an alpha2-agonist). To simulate exercise hyperemia, the vasoconstriction caused by the alpha-agonists was compared during adenosine-mediated (>50% NO independent) and sodium nitroprusside-mediated (SNP; NO donor) vasodilation of the forearm. Both adenosine and SNP increased FBF from approximately 35-40 to approximately 200-250 ml/min. All three alpha-adrenergic constrictor drugs caused marked reductions in FBF and calculated forearm vascular conductance (P < 0.05). The relative reductions in forearm vascular conductance caused by the alpha-adrenergic constrictors during SNP infusion were similar (tyramine, -74 +/- 3 vs. -65 +/- 2%; clonidine, -44 +/- 6 vs. -44 +/- 6%; P > 0.05) or slightly greater (phenylephrine, -47 +/- 6 vs. -33 +/- 6%; P < 0.05) compared with the responses during adenosine. In conclusion, these results indicate that exogenous NO sufficient to raise blood flow to levels simulating those seen during exercise does not blunt alpha-adrenergic vasoconstriction in the resting human forearm.
Assuntos
Agonistas alfa-Adrenérgicos/farmacologia , Extremidades/irrigação sanguínea , Óxido Nítrico/farmacologia , Receptores Adrenérgicos alfa/fisiologia , Vasoconstrição/efeitos dos fármacos , Vasodilatadores/farmacologia , Adenosina/farmacologia , Adulto , Clonidina/farmacologia , Antebraço/irrigação sanguínea , Humanos , Fluxometria por Laser-Doppler , Masculino , Doadores de Óxido Nítrico/farmacologia , Nitroprussiato/farmacologia , Fenilefrina/antagonistas & inibidores , Fenilefrina/farmacologia , Receptores Adrenérgicos alfa/efeitos dos fármacos , Receptores Adrenérgicos alfa 1/efeitos dos fármacos , Receptores Adrenérgicos alfa 1/fisiologia , Receptores Adrenérgicos alfa 2/efeitos dos fármacos , Receptores Adrenérgicos alfa 2/fisiologia , Fluxo Sanguíneo Regional/efeitos dos fármacos , Fluxo Sanguíneo Regional/fisiologia , Tiramina/antagonistas & inibidores , Tiramina/farmacologiaRESUMO
Sympathetic vasoconstriction is blunted in the vascular beds of contracting skeletal muscles. We sought to determine whether this blunted vasoconstriction is specific for post-junctional alpha1- or alpha2-adrenergic receptors. We measured forearm blood flow (Doppler ultrasound) and calculated the vascular conductance (FVC) responses to brachial artery infusions of tyramine (which evokes endogenous noradrenaline release), phenylephrine (an alpha1 agonist) and clonidine (an alpha2 agonist) in 10 healthy men during rhythmic handgrip exercise (10-15 % of maximum) and during a control non-exercise vasodilator condition (intra-arterial adenosine). Steady-state FVC during exercise and adenosine was similar in all trials (range: 243-272 and 234-263 ml min-1 (100 mmHg)-1, respectively; P > 0.5). During exercise the percentage reductions in FVC in response to tyramine (-24 +/- 7 vs. -55 +/- 6 %), phenylephrine (-12 +/- 8 vs. -37 +/- 8 %) and clonidine (-17 +/- 6 vs. -49 +/- 4 %) were significantly less compared with adenosine (all P < 0.05). The magnitude of the blunted vasoconstrictor responses was similar for both receptor subtypes. These findings are in contrast to those from studies in animals demonstrating that alpha2-adrenergic receptor-mediated vasoconstrictor responses are much more sensitive to contraction-induced inhibition than alpha1-mediated responses. We conclude that vasoconstrictor responses mediated via both post-junctional alpha1- and alpha2-adrenergic receptors are blunted in contracting human skeletal muscles.