Identification of two distinct vasodilator pathways activated by ATP in the mesenteric bed of the rat

Abstract

1 Adenosine 5'-triphosphate (ATP) has important roles in the cardiovascular system, modulating vascular tone by acting as both a vasoconstrictor and a vasodilator. 2 The dilator function of ATP is traditionally thought to be monophasic and mediated primarily by nitric oxide (NO). 3 Here we have identi®ed the endothelium-dependent biphasic nature of ATP-induced vasodilatation of the rat isolated mesenteric bed and investigated the two distinct pathways involved. 5 At doses upwards of 1610 78 moles (1610 78 ± 3610 77 moles), ATP also induced prolonged vasodilatations which were unaltered by L-NAME, L-NAME (1610 73 M) and indomethacin (1610 75 M), or by ODQ, but were abolished in the presence of KCl. 6 In addition, the cannabinoid CB 1 receptor antagonist SR141716A (1610 75 M) was found to inhibit the second prolonged phase of vasodilatation. However, at the concentration used SR141716A is reported to be non-selective. A second CB 1 receptor antagonist, AM251 (1610 76 M), had a small but signi®cant inhibitory eect on the second phase of ATP-induced vasodilatation. SR141716A, AM251 and KCl (6610 72 ± 1.2610 71 M) all inhibited anandamideinduced relaxation of the isolated mesenteric bed. 7 These observations demonstrate that ATP stimulates vasodilatation of the mesenteric bed by two distinct mechanisms involving the release of NO and an EDHF. In the absence of better pharmacological tools we can only speculate as to the involvement of an endogenous CB 1 receptor ligand in these responses.

Purinergic receptors in the splanchnic circulation

“…In a second study, Ralevic [134] concluded that smooth muscle P2X receptors were responsible for a biphasic response: contraction and prolonged relaxation, although a role of P2Y receptors could not be excluded, since the sustained relaxation was not abolished by P2X receptor dessensitization [135]. Concurrently with the studies of Ralevic, prolonged relaxation to ATP has been reported to be abolished by removal of the endothelium [161]. In a even more recent study [62], it was clearly shown that α,β-mATP induced endothelium-dependent vasodilation which was also independent from the contractile effect.…”

“…Recent reports of ATP inducing endothelium-independent relaxations [59,135] and the evidence for the presence of P2X 1 receptors on vascular endothelial cells [62] increased the complexity of the effects of ATP on splanchnic circulation. ATP can induce three types of response in mesenteric arterial bed of the rat [62,72,135,161]: (1) contraction, mainly mediated by smooth muscle P2X 1 receptors, (2) rapid and transient relaxation, mainly mediated by P2Y 2 receptors, and (3) slow and sustained relaxation. The mechanism responsible for this prolonged relaxation is controversial and has only very recently started to be characterized [62,134,135].…”

Prejunctional and peripheral effects of the cannabinoid CB1 receptor inverse agonist rimonabant (SR 141716)

“…Whereas all of the above studies on vascular tone used administration of exogenous cannabinoids, several other studies tested vascular rimonabant effects in the absence of exogenously added cannabinoids. Some of these studies, particularly when using high rimonabant concentrations, reported effects that apparently are unrelated to CB 1 receptors, as they were also observed in CB 1 knockout mice (Bukoski et al 2002) or failed to be mimicked by other CB 1 -receptor antagonists (Stanford et al 2001). Such nonspecific effects may occur, e.g., by direct effects on Ca 2+ channels (White and Hiley 1998).…”

P2X1 receptors and the endothelium

“…At low doses ATP induces a transient dilation mediated by the activation of P2Y receptors and the consequent co-release of NO and prostacyclin. At higher doses dilation induced by ATP consists of two discernible phases, the transient phase followed by a sustained phase, which is mediated by the release of EDHF (Stanford et al 2001, Harrington & Mitchell 2004. The emergence of the second and sustained phase of endothelial dependent dilation induced by ATP coincided with the emergence of the typical P2X 1 mediated vasoconstrictor response.…”

“…ATP and other purines act via the purinergic (P2) receptors located throughout the blood vessels to induce both vasodilation and contraction, depending on the receptor subtype activated. Traditionally it was thought that activation of P2Y receptors located on the endothelium induced vasodilation of the artery via the release of NO and prostacyclin (Ralevic & Burnstock 1991, Boeynaems et al 2000 or endothelium derived hyperpolarising factor (EDHF) (Stanford et al 2001, Malmsjo et al 2002. On the other hand, activation of P2Y and P2X receptors located on the smooth muscle cells induce contraction (Ralevic & Burnstock 1988); the pharmacology of which has been fully characterised (Ralevic & Burnstock 1991, North 2002.…”