Introduction 1 2 3 4 5 6 1 7 8 9 15 15 19 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 1 ↑IP3 ADP (ATP) MRS2365 MRS 2179, MRS2500  2 ↑IP3 UTP = ATP MRS2498, UTPγS, INS3717  Suramin > RB2 4 ↑IP3 UTP (=ATP in rodents) UTPγS, INS3717 – RB2 > Suramin 6 ↑IP3 UDP MRS2666, MRS2633, UDPβS MRS2578  11 ↑IP3, ↑cAMP ATP AR-C67085MX, NF546 NF157 Suramin > RB2 12 ↓cAMP ADP – Clopidogrel, prasugrel, AZD6140, INS50589, AR-C9931 (cangrelor)  13 ↓cAMP ADP – MRS2211  14 IP3 UDP-glucose, UDP-galactose UDP-glucose, UDP-galactose –  1 Positive ion channel ATP α,β-mATP NF023, NF449 5 2 Positive ion channel ATP – NF770 Suramin, isoPPADS, RB2 3 Positive ion channel ATP α,β-mATP A317491, NF110 Suramin 4 Positive ion channel ATP Ivermectin potentiates – TNP-ATP 5 Positive ion channel ATP – – Suramin, PPADS 6 Positive ion channel ATP – – – 7 Positive ion channel ATP – KN62, KN04, MRS2427 Coomassie brilliant blue G Ectonucleotidase   Apyrase, human SolCD39 ARC67156  2 Regulation of vascular tone 20 21 22 23 24 Neuronal regulation of vascular tone 11 25 26 27 28 1 25 1 29 30 1 2 1 31 32 1 32 33 Fig. 1 RBC NO EDHF Pgl VSMC Ado CGRP SP  1 34 35 36 37 38 1 39 40 1 41 2 6 42 42 43 44 6 6 45 1 6 44 12 46 12 46 12 46 1 1 2 6 12 1 2 Table 2 P2 receptor expression in the cardiovascular system P2 subtype Endothelium VSMC Heart Platelets Red blood cells Inflammatory cells Perivascular sensory nerves Perivascular sympathetic nerves 1 High – – High (Turkey)  Medium Medium (neg. feedback) 2 High High High – – High Low Possible 4 – Possible – – –    6 Medium Medium High – –    11 Possible – High – – High   12 – Medium – High – Low   13 – – – – High Low   14 – – – – –    1 – High Medium High – Medium   2 – – – – –  High Medium (pos. feedback) 3 – – – – –  High  4 High – Low – – High   5 – – – – –    6 – – – – –    7 – Possible – – Low High   VSMC Endothelial regulation 47 1 5 48 50 51 1 11 2 6 40 52 4 53 1 4 40 54 4 2+ 55 56 4 57 4 57 8 58 59 7 60 2A 61 62 1 63 63 2 4 1 2A Red blood cells as regulators of vascular tone 37 64 66 67 69 37 64 3 2 70 2 64 71 72 2 2 Table 3 Release of purines and pyrimidines in the cardiovascular system Source Endothelium VSMC Heart Platelets Red blood cells Inflammatory cells Vascular nerves Stimuli Shear stress, hypoxia, high glucose High glucose, hypoxia Hypoxia Collagen, thromboxane, other platelet activators Hypoxia, adrenaline, deformation Infl. activators Sympathetic nerves, sensory nerve collaterals Mechanism Vesicular Unknown Unknown Vesicular Unknown Unknown or vesicular Vesicular Nucleotide ATP, UTP ATP, UTP ATP, UTP ADP > ATP ATP ATP ATP Target Endothelium VSMC VSMC Cardiomyocytes, blood vessels, intrinsic cardiac neurons Platelets; endothelium or VSMC Endothelium VSMC, endothelium VSMC Degradation NTPDase1 NTPDase2, NTPDase1 NTPDase1 NTPDase1 NTPDase1 NTPDase1 NTPDase1 (co-released) Stimuli Mechanism Target Degradation VSMC 13 73 74 75 7 76 77 Plasmodium 78 79 Hypertension 31 32 80 81 82 1 2 83 84 85 4 5 6 86 1 2 5 6 87 4 88 1 2 88 4 4 57 4 89 4 1 2 6 Pulmonary hypertension 90 69 91 92 Migraine and vascular pain 6 1D 93 94 3 95 3 96 97 Lancet 3 26 Atherosclerosis 98 2 99 100 101 Fig. 2 EC VSCM IL MCP-1 ICAM-1 TSP IDO  Atherosclerosis—P2 receptor-mediated effects on inflammatory cells 102 98 14 103 14 7 2 11 7 104 105 7 106 107 L 108 7 109 7 2 110 2 111 1 112 11 113 11 114 115 11 116 11 11 98 11 Proinflammatory effects on the endothelium 117 118 2 119 2 120 121 2 Restenosis and vascular smooth muscle cell proliferative disease 122 25 123 12 123 125 2 123 6 124 126 127 123 124 12 128 129 125 130 6 2 127 12 13 124 131 2 2 132 133 2 6 134 121 135 136 134 137 Diabetic microvascular disease 138 139 140 141 142 143 2 6 143 2 Vascular remodelling and angiogenesis Vascular remodelling 13 2+ 1 144 2 1 145 145 2 146 147 2 148 149 150 1 2 6 151 4 57 Angiogenesis 7 60 13 152 153 154 155 156 Varicose veins 7 157 1 2 1 158 151 Heart 3 7 60 159 160 60 161 Inotropy 60 162 165 3 2 162 164 167 4 168 3 169 1 60 170 171 60 11 s 60 172 174 11 161 175 164 166 176 177 161 2 4 161 2 6 161 3 2 6 11 3 60 160 Fig. 3 a b c NTPDase  Myocardial infarction 60 60 178 161 179 180 181 11 116 11 182 3 163 183 60 161 184 185 178 186 3 Congestive heart failure 187 11 1 169 6 188 1 189 4 190 11 11 2 6 Chronotropy and arrhythmia 191 60 1 192 Platelets and coagulation Platelets 193 194 196 12 1 1 197 198 4 12 12 199 1 200 202 12 2 1 12 200 203 Fig. 4 t-PA PAI-1 Ado  1 1 1 204 205 206 1 58 207 208 209 210 1 12 12 46 Coagulation 51 211 4 212 Clinical importance of P2 receptor-mediated regulation of platelets 12 213 213 214 215 12 12 Clinical importance of purinergic signalling in cardiovascular disease: future directions 4 12 12 1 1 1 1 Table 4 Cardiovascular disease targets Receptor target Agonist/antagonist activity of therapeutic drug Disease Vascular smooth muscle cell 2 Antagonist Hypertension, restenosis, diabetic microvascular disease, subarachnoidal bleeding 6 Antagonist Hypertension, restenosis, diabetic microvascular disease, subarachnoidal bleeding 12 Antagonist Hypertension, vasospasm 1 Antagonist Hypertension, migraine, subarachnoidal bleeding 6 Agonist Migraine SolNTPDase1 Ectonucleotidase Restenosis, xenograft rejection Endothelial cell 2 Antagonist Atherosclerosis, inflammation 4 Antagonist Vascular remodelling (cancer?), preeclampsia Heart 2 Antagonist Congestive heart failure 6 Antagonist Congestive heart failure 11 Antagonist Congestive heart failure, myocardial infarction 2 Agonist Shock, reduced cardiac output, cardiac protection 6 Agonist Shock, reduced cardiac output 11 Agonist Shock, reduced cardiac output SolNTPDase1 Ectonucleotidase Heart transplantation, myocardial infarction Inflammatory cells 2 Antagonist Atherosclerosis 11 Antagonist Atherosclerosis 7 Antagonist Atherosclerosis Platelets 1 Antagonist Myocardial infarction, stroke, peripheral artery disease 12 Antagonist Myocardial infarction, stroke, peripheral artery disease 1 Antagonist Myocardial infarction, stroke, peripheral artery disease SolNTPDase1 Ectonucleotidase Myocardial infarction, stroke, peripheral artery disease Red blood cell 13 Antagonist Improved peripheral circulation 7 Antagonist Shock Perivascular nociceptive sensory nerves 1 Agonist Migraine, vascular pain 3 Antagonist Migraine, vascular pain Perivascular sympathetic nerves 1 Agonist Hypertension 2 Antagonist Hypertension The table presents possible targets for the development of new pharmaceutical compounds for the treatment of cardiovascular diseases 2 6 1 2 6 12 2 6 11 11 3 19 26