Cardiovascular pharmacologyExtracellular ATP signaling in equine digital blood vessels
Introduction
Adenosine 5′-triphosphate (ATP) contributes to the maintenance of vascular tone. It is released from perivascular nerves as a cotransmitter with noradrenaline and from endothelial cells in response to changes in blood flow (shear stress) and hypoxia (Ralevic, 2009). The P2X receptor family consists of seven ion channel subunits (P2X1–7) that can combine to form either trimeric homomers (P2X1–7) or heteromers (P2X1/2, 2/3, 2/6, 1/4, 1/5, 4/6, 4/7), all of which are ligand-gated ion channels. There are eight G protein-coupled P2Y receptor subtypes (P2Y1, 2, 4, 6, 11–14), which may also form heteromultimeric complexes (Burnstock, 2007).
The P2X1 receptor subtype is the principal P2 receptor expressed on vascular smooth muscle (Bo and Burnstock, 1993, Hansen et al., 1999, Wallace et al., 2006). P2X2 receptor subunits are also expressed on smooth muscle cells of rat mesenteric, renal and pulmonary arteries (Hansen et al., 1999). P2X4 receptor subunits are expressed in rat aorta, vena cava, coronary, pulmonary, renal and femoral arteries (Soto et al., 1996, Nori et al., 1998). It is generally accepted that P2X receptors play a role in the maintenance of vascular tone, and depending on their location and expression, can mediate both vasoconstriction (e.g. P2X1), and/or vasodilation (e.g. P2X2 and/or P2X4) (Burnstock, 2010).
P2Y receptors are involved in mediating vasodilatation (Wallace et al., 2006). P2Y1, 2, 4, 6 receptors have been shown to mediate endothelium-dependent vasodilatation (Knight et al., 2003). Interestingly, ATP-mediated vasodilatation (in the rat mesenteric bed) has been shown to be mediated via endothelial nitric oxide or endothelium-derived hyperpolarizing factor (Stanford et al., 2001). That the application of uridine 5′-triphosphate (UTP) elicits smooth muscle constriction suggests that P2Y2, 4 and/or P2Y6 are also players mediating vasoconstriction in some vessels (Erlinge and Burnstock, 2008, Gitterman and Evans, 2001).
The contribution of ATP, when released from perivascular nerves as a co-transmitter with noradrenaline, varies greatly between vascular bed, vessel type and species (Knight et al., 2003, Wallace et al., 2006, Erlinge and Burnstock, 2008). For example, the rabbit mesenteric artery is predominantly purinergic, whereas the rabbit pulmonary artery is mainly noradrenergic (Knight et al., 2003). A change in the ratio of ATP to noradrenaline release from sympathetic nerves has also been linked to animal models of hypertension and in the postsynaptic vascular response to temperature changes (Pelleg and Burnstock, 1990, Kluess et al., 2005, Ralevic, 2009).
The anatomical arrangement of the equine digital vasculature bed is complex and is involved in thermoregulatory function (Zerpa et al., 2010). Furthermore, it has been proposed that increased post-capillary resistance, due to venoconstriction, could be one of the pathophysiological mechanisms involved in the development of laminitis in horses (Moore et al., 2004). The aim of this study was to describe the extracellular ATP signaling in equine digital vessels.
Section snippets
Animals and tissues
Equine digital arteries (EDA) and veins (EDV) were collected in a local abattoir. The hind limbs of healthy mixed breed adult horses of either gender were removed within 10 min of death. The digital artery was cannulated and 120 ml of ice-cold modified Krebs Henseleit (Krebs solution) was infused through the catheter. The skin was then reflected from above the coronet band to reveal the digital coronet venous plexus and the plantar digital artery. The digital coronet venous plexus and the distal
Frequency–response curves from equine digital arteries and veins.
EFS of autonomic nerves in rings of EDA and EDV caused frequency-dependent constriction, with peak responses obtained at 32 Hz. The EFS-induced constriction was abolished by pre-treatment with TTX (1 μM) in EDA (96.8±0.5% inhibition, n=4, P<0.05, Fig. 1A), and in EDV (97.8±0.9% inhibition, n=4, P<0.05, Fig. 1C). The presence of the endothelium did not modify the EFS-induced constriction in either EDA or EDV (Fig. 1B and D, respectively).
EFS, in the presence of the non-selective α-adrenoceptor
Discussion
The effect of P2 receptor antagonists on EFS-mediated constriction and the contractile response to natural and synthetic P2 receptor agonists in conjunction with the immunoreactivity for P2X receptors in the smooth muscle of EDA and EDV demonstrate the presence of P2X receptors on vascular smooth muscle mediating constriction of EDA and EDV. Furthermore, and not surprisingly given that ATP and noradrenaline are cotransmitters in sympathetic nerves, we also report dual control of both EDA and
Acknowledgments
Acknowledgments go to Dr Yoel Berhane for his assistance and advice with organ bath experiments.
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