Purinergic Signalling (2008) 4:1–20 DOI 10.1007/s11302-007-9078-7 REVIEW P2 receptors in cardiovascular regulation and disease David Erlinge & Geoffrey Burnstock Received: 3 May 2007 /Accepted: 22 August 2007 /Published online: 21 September 2007 # Springer Science + Business Media B.V. 2007 Abstract The role of ATP as an extracellular signalling Introduction molecule is now well established and evidence is accumulating that ATP and other nucleotides (ADP, UTP and UDP) play Ever since the first proposition of cell surface receptors for important roles in cardiovascular physiology and pathophysi- nucleotides [1, 2], it has become increasingly clear that, in ology, acting via P2X (ion channel) and P2Y (G protein- addition to functioning as an intracellular energy source, the coupled) receptors. In this article we consider the dual role of purines and pyrimidines ATP, adenosine diphosphate ATP in regulation of vascular tone, released as a cotransmitter (ADP), uridine triphosphate (UTP) and uridine diphosphate from sympathetic nerves or released in the vascular lumen in (UDP) can serve as important extracellular signalling response to changes in blood flow and hypoxia. Further, molecules [3, 4] acting on 13 P2X homo- and heteromul- purinergic long-term trophic and inflammatory signalling is timer ionotropic and 8 P2Y metabotropic receptor subtypes described in cell proliferation, differentiation, migration and [5, 6] (Table 1). To terminate signalling, ectonucleotidases death in angiogenesis, vascular remodelling, restenosis and are present in the circulation and on cell surfaces, rapidly atherosclerosis. The effects on haemostasis and cardiac degrading extracellular ATP into ADP, AMP and adenosine regulation is reviewed. The involvement of ATP in vascular [7, 8]. Evidence is accumulating suggesting an important role diseases such as thrombosis, hypertension and diabetes will for the purinergic system in cardiovascular regulation [9–15]. also be discussed, as well as various heart conditions. The It stimulates vasoconstriction and vasodilatation, growth of purinergic system may be of similar importance as the vascular smooth muscle cells and endothelial cells, angio- sympathetic and renin-angiotensin-aldosterone systems in genesis, is involved in vascular remodelling, stimulates cardiovascular regulation and pathophysiology. The extracel- platelet aggregation, regulates coagulation, inflammation lular nucleotides and their cardiovascular P2 receptors are now and several aspects of cardiac function. It is involved in entering the phase of clinical development. blood pressure regulation, development of myocardial infarction, heart failure and xenograft rejection. The physi- Keywords ATP . Cardiovascular . Heart . Pathophysiology . ological effects of the purinergic signalling system are Purine . Pyrimidine . P2X . P2Y. Receptor dependent on the release of extracellular nucleotides, the degradation by ectonucleotides, the type of P2 receptors expressed on the cells, their desensitisation rates and their D. Erlinge second messengers. P2 receptors have highly specific organ Department of Cardiology, Lund University Hospital, distributions and they can be rapidly up- or downregulated. 22185 Lund, Sweden The purinergic system may be of similar importance as the e-mail: [email protected] sympathetic and renin-angiotensin-aldosterone systems in G. Burnstock (*) cardiovascular regulation and pathophysiology. The involve- Autonomic Neuroscience Centre, ment of purinergic signalling in a variety of different Royal Free and University College Medical School, cardiovascular clinical conditions has been addressed to a Rowland Hill Street, London NW3 2PF, UK limited extent previously [15–19] and the large number of e-mail: [email protected] new discoveries calls for a review to summarise the most 2 Purinergic Signalling (2008) 4:1–20 Table 1 Receptor classification, intracellular signalling, ligands and selective agonists and antagonists P2 subtype I.c. signalling Ligand Selective agonist Selective antagonist Non-selective antagonist P2Y1 ↑IP3 ADP (ATP) MRS2365 MRS 2179, MRS2500 P2Y2 ↑IP3 UTP = ATP MRS2498, UTPγS, Suramin > RB2 INS3717 P2Y4 ↑IP3 UTP (=ATP in rodents) UTPγS, INS3717 – RB2 > Suramin P2Y6 ↑IP3 UDP MRS2666, MRS2578 MRS2633, UDPβS P2Y11 ↑IP3, ↑cAMP ATP AR-C67085MX, NF157 Suramin > RB2 NF546 P2Y12 ↓cAMP ADP – Clopidogrel, prasugrel, AZD6140, INS50589, AR-C9931 (cangrelor) P2Y13 ↓cAMP ADP – MRS2211 P2Y14 IP3 UDP-glucose, UDP-glucose, – UDP-galactose UDP-galactose P2X1 Positive ion ATP α,β-mATP NF023, NF449 TNP-ATP, Ip5I channel P2X2 Positive ion ATP – NF770 Suramin, channel isoPPADS, RB2 P2X3 Positive ion ATP α,β-mATP A317491, NF110 Suramin channel P2X4 Positive ion ATP Ivermectin – TNP-ATP channel potentiates P2X5 Positive ion ATP –– Suramin, PPADS channel P2X6 Positive ion ATP –– – channel P2X7 Positive ion ATP – KN62, KN04, MRS2427 Coomassie channel brilliant blue G Ectonucleotidase Apyrase, human ARC67156 SolCD39 important roles of the purinergic system in cardiovascular resulting in vasodilatation [22] and dual purinergic neural regulation and disease. and endothelial control of vascular tone established [23, 24]. The research field has grown rapidly since the term P2 receptor was coined [2]. In preparation of this review more Neuronal regulation of vascular tone than 2,700 references on P2 receptors and cardiovascular regulation were found in PubMed. Among the 15 receptor ATP is, together with NA and neuropeptide Y (NPY), a subtypes, one is the target for one of the most widely used cotransmitter in sympathetic neurons [11, 25, 26], and medical drugs—the platelet inhibitor clopidogrel (Plavix). sensory-motor nerves during “axon reflex” activity release As will be reviewed here, several of the other 15 receptors ATP to dilate or constrict vessels [27, 28](Fig.1). The con- are promising drug targets to prevent cardiovascular disease. tribution of ATP to sympathetic contraction varies between vascular beds [25]. For example, it may mediate up to 50% of the neurogenic vasoconstriction via P2X1 receptors as Regulation of vascular tone seen in mesenteric arteries [29], about 70% in rabbit saphe- nous arteries and 100% in rabbit jejunal artery, while NA Vasoconstriction produced by ATP released as a cotrans- acts as a prejunctional modulator [30]. In the renal vascu- mitter with noradrenaline (NA) from perivascular sympathet- lature both P2X1 and P2Y2 receptors are important for ic nerves was recognised early [20, 21]. However, following neurogenic contraction. P2X1 receptors mediate contraction the seminal discovery of endothelium-dependent vasodilata- in afferent but are absent in the efferent renal arterioles [31, tion by Furchgott in the early 1980s, it was shown that ATP 32]. The result is that extracellular nucleotides selectively acted on endothelial cells to release endothelial derived influence preglomerular resistance without having an effect relaxing factor [later shown to be largely nitric oxide (NO)] on postglomerular tone. ATP is also released locally in the Purinergic Signalling (2008) 4:1–20 3 RBC Hypoxia Vascular lumen Low pH Adrenaline P2Y13 Platelet activation - (collagen etc) ATP UTP ADP + UDP ADP P2X P2Y ATP 4 2 NTPDase1 Shear stress APnA P2Y1 Ado P2Y6 EC Hypoxia NTPDase ADP High glucose 1 Loss of endothelium NO EDHF Pgl NTPDase MEDIA 2 Vasodilatation VSMC High glucose Vasoconstriction Trauma P2Y12 P2Y6 P2X1 P2Y2 NTPDase2 UP4A ADP ADVENTITIA ATP UTP UDP Sensory- + - Motor P2X P2Y Sympathetic Nerve CGRP SP ATP Nerve NTPDase ATP- NA NPY Ado P1(A1) Fig. 1 P2 receptor-mediated regulation of the circulation. See text for and mediate vasoconstriction via P2 receptors on the vascular smooth details. Purines and pyrimidines are released on the luminal side from muscle cell (VSMC). On the adventitial side sympathetic and sensory endothelial cells, platelets and red blood cells (RBC) in response to nerves mediate vasoconstriction. Extracellular nucleotides are rapidly hypoxia, acidosis, adrenaline, shear stress and other stimuli. When the degraded by NTPDase1 on endothelium reducing ATP to AMP, endothelial cell layer is intact, the response is vasodilatation by the followed by conversion to adenosine by CD73 (not shown). In the endothelial release of nitric oxide (NO), endothelium-derived hyper- subendothelium NTPDase2 is present, degrading ATP to ADP, polarising factor (EDHF) and prostaglandins (Pgl). When the maintaining the platelet activating and contractile effects. Ado endothelium is damaged, platelets accumulate, release ATP and ADP adenosine, CGRP calcitonin gene-related peptide, SP substance P kidney in response to increased perfusion pressure, and in skeletal muscle, an effect not obtained by injection of P2X1 receptor knockout mice auto-regulatory responses in adenosine [37], suggesting that ATP and UTP may mediate kidney afferent arterioles are abolished, indicating an impor- this important physiological mechanism. tant role in renal glomerular pressure regulation [32, 33]. ThefirstevidenceofthepresenceofP2receptor Sympathetic nerves express inhibitory P2Y and P1 (A1) subtypes suggested P2X receptors on vascular smooth muscle receptors indicating a P2 receptor-mediated negative feed- cells (VSMC) and P2Y receptors on endothelial cells [38]. back loop both directly by ATP and its degradation product Rat blood vessel immunohistochemistry and human mRNA adenosine [34, 35]. Ectonucleotidases are released from quantification have shown the P2X1 receptor to be the sympathetic nerves together with its substrate