Local release of ATP into the arterial inflow and venous drainage of human skeletal muscle: insight from ATP determination with the intravascular microdialysis technique.
ABSTRACT Intraluminal ATP could play an important role in the local regulation of skeletal muscle blood flow, but the stimuli that cause ATP release and the levels of plasma ATP in vessels supplying and draining human skeletal muscle remain unclear. To gain insight into the mechanisms by which ATP is released into plasma, we measured plasma [ATP] with the intravascular microdialysis technique at rest and during dynamic exercise (normoxia and hypoxia), passive exercise, thigh compressions and arterial ATP, tyramine and ACh infusion in a total of 16 healthy young men. Femoral arterial and venous [ATP] values were 109 ± 34 and 147 ± 45 nmol l(−1) at rest and increased to 363 ± 83 and 560 ± 111 nmol l(−1), respectively, during exercise (P < 0.05), whereas these values did not increase when exercise was performed with the other leg. Hypoxia increased venous plasma [ATP] at rest compared to normoxia (P < 0.05), but not during exercise. Arterial ATP infusion (≤1.8 μmol min(−1) increased arterial plasma [ATP] from 74 ± 17 to 486 ± 82 nmol l(−1) (P < 0.05), whereas it remained unchanged in the femoral vein at ∼150 nmol l(−1). Both arterial and venous plasma [ATP] decreased during acetylcholine infusion (P < 0.05). Rhythmic thigh compressions increased arterial and venous plasma [ATP] compared to baseline conditions, whereas these values did not change during passive exercise or tyramine infusion. These results demonstrate that ATP is released locally into arterial and venous plasma during exercise and during hypoxia at rest. Compression of the vascular system could contribute to the increase during exercise whereas there appears to be little ATP release in response to increased blood flow, vascular stretch or sympathetic ATP release. Furthermore, the half-life of arterially infused ATP is <1 s.
Article: Heterologous cell-cell interactions: thromboregulation, cerebroprotection and cardioprotection by CD39 (NTPDase-1).[show abstract] [hide abstract]
ABSTRACT: Blood platelets maintain vascular integrity and promote primary and secondary hemostasis following interruption of vessel continuity. Biochemical or physical damage to the coronary, carotid or peripheral arteries is followed by excessive platelet activation and recruitment culminating in vascular occlusion and tissue ischemia. Currently inadequate therapeutic approaches to stroke and coronary artery disease are a public health issue. Following our demonstration of neutrophil leukotriene production from arachidonate released from activated aspirin-treated platelets, we studied interactions between platelets and other blood cells, leading to concepts of transcellular metabolism and thromboregulation. Thrombosis has a proinflammatory component whereby biologically active substances are synthesized by interactions between different cell types that could not individually synthesize the product(s). Endothelial cells control platelet reactivity via three biochemical systems-autacoids leading to production of prostacyclin and nitric oxide, and endothelial ecto-ADPase/CD39/NTPDase-1. The autacoids are fluid-phase reactants, not produced by tissues in the basal state. They are only synthesized intracellularly and released upon interactions of cells with an agonist. When released, autacoids exert fleeting actions in the immediate milieu, and are rapidly inactivated. CD39 is an integral component of the endothelial cell surface and is substrate-activated. It maintains vascular fluidity in the complete absence of prostacyclin and nitric oxide, indicating that they are ancillary components of hemostasis. Therapeutic implications for the autacoids have not been compelling because of their transient, local and fleeting action, and limited potency. Conversely, CD39, acting solely on the platelet releasate, is efficacious in three different animal models. It metabolically neutralizes a prothrombotic platelet releasate via deletion of ADP--the major recruiting agent responsible for formation of an occlusive thrombus. In addition, solCD39 reduced ATP- and ischemia-induced norepinephrine release in the heart. This reduction can prevent fatal arrhythmia. Moreover, solCD39 ameliorated the sequelae of stroke in CD39 null mice. CD39 represents the next generation of cardioprotective and cerebroprotective molecules.Journal of Thrombosis and Haemostasis 01/2004; 1(12):2497-509. · 5.73 Impact Factor
Article: Report of a workshop on problem-based learning and its implications for medical education in the UK. Held 7 June 1996 at the Royal Society of Medicine, London.Postgraduate Medical Journal 08/1997; 73(861):449-59. · 1.94 Impact Factor
Article: Circulating ATP-induced vasodilatation overrides sympathetic vasoconstrictor activity in human skeletal muscle.[show abstract] [hide abstract]
ABSTRACT: 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.The Journal of Physiology 08/2004; 558(Pt 1):351-65. · 4.72 Impact Factor