Heterogeneity of ATP receptors in aortic endothelial cells. Involvement of P2y and P2u receptors in inositol phosphate response.

Motte, Serge; Pirotton, Sabine; Boeynaems, Jean‐Marie

doi:10.1161/01.res.72.3.504

Cited by 95 publications

(55 citation statements)

References 18 publications

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“…A role for plasma ATP in the regulation of vascular tone (10, 29, 49) has been reported. This process has been shown to involve an interaction with P 2y purinergic receptors on endothelial cells, resulting in the stimulation of NO synthesis as well as the formation of prostacyclin, both of which mediate local vasodilation (14,29,32). Consistent with these earlier studies, we observed that the administration of ATP, in the range found to be released in our experiments in response to nitrite (Figs.…”

Section: Effect Of Atp On Blood Pressure (Bp)supporting

confidence: 92%

Nitrite enhances RBC hypoxic ATP synthesis and the release of ATP into the vasculature: a new mechanism for nitrite-induced vasodilation

Cao¹,

Bell

Mohanty³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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Cao Z, Bell JB, Mohanty JG, Nagababu E, Rifkind JM. Nitrite enhances RBC hypoxic ATP synthesis and the release of ATP into the vasculature: a new mechanism for nitrite-induced vasodilation. Am J Physiol Heart Circ Physiol 297: H1494 -H1503, 2009. First published August 21, 2009 doi:10.1152/ajpheart.01233.2008.-A role for nitric oxide (NO) produced during the reduction of nitrite by deoxygenated red blood cells (RBCs) in regulating vascular dilation has been proposed. It has not, however, been satisfactorily explained how this NO is released from the RBC without first reacting with the large pools of oxyhemoglobin and deoxyhemoglobin in the cell. In this study, we have delineated a mechanism for nitrite-induced RBC vasodilation that does not require that NO be released from the cell. Instead, we show that nitrite enhances the ATP release from RBCs, which is known to produce vasodilation by several different methods including the interaction with purinergic receptors on the endothelium that stimulate the synthesis of NO by endothelial NO synthase. This mechanism was established in vivo by measuring the decrease in blood pressure when injecting nitrite-reacted RBCs into rats. The observed decrease in blood pressure was not observed if endothelial NO synthase was inhibited by N -nitro-L-arginine methyl ester (L-NAME) or when any released ATP was degraded by apyrase. The nitrite-enhanced ATP release was shown to involve an increased binding of nitrite-modified hemoglobin to the RBC membrane that displaces glycolytic enzymes from the membrane, resulting in the formation of a pool of ATP that is released from the RBC. These results thus provide a new mechanism to explain nitrite-induced vasodilation. nitrite reduction; nitric oxide; anerobic glycolysis; hypoxia; red blood cell; adenosine 5Ј-triphosphate NITRIC OXIDE (NO) as a vasodilator plays a major role in regulating blood flow and vascular tone (19,20). A role for red blood cell (RBC) deoxygenation in the delivery of NO has been proposed (22). RBC-delivered NO has been considered as contributing to normal physiological hypoxic vasodilatation (43), as well as a source for the additional NO required under various pathological conditions (12,18,24,40). It, however, needs to be explained how the RBC increases the availability of NO. Two pathways have been proposed for RBC-induced NO-associated vasodilation under hypoxic conditions: 1) the release of some of the adenosine 5Ј-triphosphate (ATP) from RBCs under hypoxic conditions (10, 49) and 2) the interaction of this ATP with purinergic receptors (4) stimulate the synthesis of NO by endothelial NO synthase (eNOS) (2, 10, 49). The direct release of NO from RBCs under hypoxic conditions (8,22,26,33,42) has a vasodilatory effect. The source of the RBC-derived NO has been extensively studied. RBCs have been reported to have NO synthase activity (26), although the role of this enzyme has not been established. The original hypothesis for the accumulation of RBC NO (22) involved NO released from the endothelium being taken up...

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Section: Effect Of Atp On Blood Pressure (Bp)supporting

confidence: 92%

Nitrite enhances RBC hypoxic ATP synthesis and the release of ATP into the vasculature: a new mechanism for nitrite-induced vasodilation

Cao¹,

Bell

Mohanty³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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“…How this occurs is not yet known. P2y-and P2u-purinoceptors have been suggested to couple differently to G-proteins on the basis of pertussis toxin attenuation of P2U-but not P2Y-mediated inositol phosphate accumulation in bovine aortic endothelial cells (Motte et al, 1993). PPADS potentiated the constrictor effects of methoxamine, as observed previously in this preparation (Windscheif et al, 1994).…”

Section: -supporting

confidence: 71%

Discrimination by PPADS between endothelial P_2Y‐ and P_2U‐ purinoceptors in the rat isolated mesenteric arterial bed

Ralevic

Burnstock

1996

British J Pharmacology

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1 The main aim of this study was to characterize the antagonistic effects of pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) at coexisting endothelial P2Y-and P2u-purinoceptors. Studies were conducted in Krebs-perfused mesenteric arterial preparations isolated from the rat, with tone raised by methoxamine (5-50 gM). 5 Indomethacin (10 gM) had no effect on vasodilator responses to 2MeSATP, ADP, ATP or UTP.6 In conclusion, these results show that PPADS is an antagonist at endothelial P2y-but not P2U-purinoceptors in rat mesenteric arteries. These receptors cannot be discriminated by inhibition of prostaglandin synthesis; P2y-purinoceptors are, however, sensitive to ADP. Selective antagonism by use of PPADS showed that ATP acts at P2u-and not P2Y-purinoceptors. Ap3A and NADP mediate vasodilatation via P2Y-purinoceptors, whereas vasodilatation to Ap2A is mediated partly via P.-and possibly via P2U-purinoceptors.

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“…It has been known for a long time that P2Y 1 and P2Y 2 receptors are coexpressed on endothelial cells isolated from the aorta and other vessels and mediate endothelium-dependent relaxation and prostacyclin release in response to nucleotides (Motte et al, 1993;Communi et al, 1995;Buvinic et al, 2002). However, recent studies on the mouse aorta revealed in an unexpected way that although the endotheliumdependent relaxation by ATP was severely decreased in P2Y 2 Ϫ/Ϫ mice, the relaxing effect of UTP was maintained, indicating the involvement of another receptor (Guns et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Knockout Mice Reveal a Role for P2Y₆ Receptor in Macrophages, Endothelial Cells, and Vascular Smooth Muscle Cells

et al. 2008

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P2Y receptors are G-protein-coupled receptors activated by extracellular nucleotides. The P2Y 6 receptor is selectively activated by UDP, and its transcript has been detected in numerous organs, including the spleen, thymus, intestine, blood leukocytes, and aorta. To investigate the biological functions of this receptor, we generated P2Y 6 -null mice by gene targeting. The P2Y 6 knockout (KO) mice are viable and are not distinguishable from the wild-type (WT) mice in terms of growth or fertility. In thioglycollate-elicited macrophages, the production of inositol phosphate in response to UDP stimulation was lost, indicating that P2Y 6 is the unique UDP-responsive receptor expressed by mouse macrophages. Furthermore, the amount of interleukin-6 and macrophage-inflammatory protein-2, but not tumor necrosis factor-␣, released in response to lipopolysaccharide stimulation was significantly enhanced in the presence of UDP, and this effect was lost in the P2Y 6 KO macrophages. The endothelium-dependent relaxation of the aorta by UDP was abolished in KO P2Y 6 mice. The contractile effect of UDP on the aorta, observed when endothelial nitric-oxide synthase is blocked, was also abolished in P2Y 6 -null mice. In conclusion, we generated P2Y 6 -deficient mice and have shown that these mice have a defective response to UDP in macrophages, endothelial cells, and vascular smooth muscle cells. These observations might be relevant to several physiopathological conditions such as atherosclerosis or hypertension.

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Heterogeneity of ATP receptors in aortic endothelial cells. Involvement of P2y and P2u receptors in inositol phosphate response.

Cited by 95 publications

References 18 publications

Nitrite enhances RBC hypoxic ATP synthesis and the release of ATP into the vasculature: a new mechanism for nitrite-induced vasodilation

Nitrite enhances RBC hypoxic ATP synthesis and the release of ATP into the vasculature: a new mechanism for nitrite-induced vasodilation

Discrimination by PPADS between endothelial P_2Y‐ and P_2U‐ purinoceptors in the rat isolated mesenteric arterial bed

Knockout Mice Reveal a Role for P2Y₆ Receptor in Macrophages, Endothelial Cells, and Vascular Smooth Muscle Cells

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Heterogeneity of ATP receptors in aortic endothelial cells. Involvement of P2y and P2u receptors in inositol phosphate response.

Cited by 95 publications

References 18 publications

Nitrite enhances RBC hypoxic ATP synthesis and the release of ATP into the vasculature: a new mechanism for nitrite-induced vasodilation

Nitrite enhances RBC hypoxic ATP synthesis and the release of ATP into the vasculature: a new mechanism for nitrite-induced vasodilation

Discrimination by PPADS between endothelial P2Y‐ and P2U‐ purinoceptors in the rat isolated mesenteric arterial bed

Knockout Mice Reveal a Role for P2Y6 Receptor in Macrophages, Endothelial Cells, and Vascular Smooth Muscle Cells

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Discrimination by PPADS between endothelial P_2Y‐ and P_2U‐ purinoceptors in the rat isolated mesenteric arterial bed

Knockout Mice Reveal a Role for P2Y₆ Receptor in Macrophages, Endothelial Cells, and Vascular Smooth Muscle Cells