Pharmacological Profile of Purinergic P2Y Receptors Involved in Neurogenic Cardiovascular Modulation Induced by ADP...

Cardiovascular modulation mediated by adenine-based purines is a very complicated and dynamic process driven by adenosine, adenosine diphosphate (ADP), and adenosine triphosphate (ATP). It is orchestrated through the interaction of these molecules with specific purinergic P1, P2Y, and P2X receptors, located throughout the central and peripheral nervous systems. This, along with the constant enzymatic interconversion of these compounds by ectonucleotidases, results in overlapping and highly variable cardiovascular responses. Activation of G protein-coupled purinergic P2Y receptors plays a fundamental role in cardiovascular homeostasis, modulating autonomic integration, neurogenic transmission, and vascular function. Within this context, ADP-sensitive P2Y receptors, particularly the P2Y₁, P2Y₁₂, and P2Y₁₃ subtypes, participate in distinct sensory, autonomic, and functional cardiovascular mechanisms, as identified in several in vitro and in vivo experimental models. Accordingly: (i) the stable and non-hydrolysable ADP analogue, adenosine 5'-O-(β-thio)-diphosphate (ADPβS), has been widely used as a pharmacological tool to investigate P2Y receptor-mediated cardiovascular responses; and (ii) the specific role of P2Y receptors has been confirmed using selective P2Y receptor antagonists, including MRS2500 (P2Y₁), PSB0739 (P2Y₁₂) or MRS2211 (P2Y₁₃). The cardiovascular effects of ADP are complex; depending on the experimental conditions, it can either decrease or increase heart rate, myocardial contractility, vascular tone, and/or systemic blood pressure. These effects are mediated by several P2Y receptors that act at different levels of cardiovascular control, encompassing crucial integration sites within the central nervous system, as well as peripheral autonomic and cardiovascular effector mechanisms such as preganglionic nerves, autonomic ganglia, postganglionic nerves, sensory fibres, vascular smooth muscle, vascular endothelium, and cardiac tissues. In this review, we: (i) summarize the pharmacological profile of the P2Y receptors that mediate cardiovascular responses, with special emphasis on peripheral autonomic, sensory, and vascular mechanisms, revealed in in vivo experimental models; and (ii) highlight the potential of P2Y receptors as therapeutic targets for the treatment of cardiovascular pathologies, including hypertension, coronary vasospasm, ischemic injury, and coagulation problems.