The role of purinergic P2Y12 and P2Y13 receptors in ADPβS-induced inhibition of the cardioaccelerator sympathetic drive in pithed rats

Pharmacological Profile of the Purinergic P2Y Receptors That Modulate, in Response to ADPβS, the Vasodepressor Sensory CGRPergic Outflow in Pithed Rats

“…On the other hand, it must be emphasised that the baseline values of heart rate remained without changes ( p > 0.05) after i.v. treatment with any of the above doses of compounds, as previously reported in pithed rats [ 36 ]. Hence, for the sake of clarity, these data are not shown.…”

“…The pithed rat is a well-established experimental model for studying cardiovascular function [ 4 , 51 ] and has been further optimised for investigating the pharmacological profile of the receptors that modulate, at the peripheral level, the activity of the sympathetic and sensory CGRPergic nerve terminals that innervate the cardiovascular system [ 23 , 26 , 27 , 28 , 29 , 30 , 36 , 52 , 53 , 54 , 55 , 56 , 57 ]. Since central functions are not operative in this model, any change in blood pressure (and/or heart rate) produced by i.v.…”

“…Since central functions are not operative in this model, any change in blood pressure (and/or heart rate) produced by i.v. administration of any compound can be attributed exclusively to peripheral (rather than central) mechanisms [ 23 , 26 , 27 , 28 , 29 , 30 , 36 , 52 , 53 , 54 , 55 , 56 , 57 ]. On this basis, within the context of the present study, it is reasonable to assume that the inhibition of the vasodepressor sensory CGRPergic drive produced by ADPβS is peripheral in nature (i.e., at the level of perivascular sensory CGRPergic nerves, and unrelated to baroreceptor compensatory reflex mechanisms or central actions).…”

“…Hence, the present study has analysed the pharmacological profile of the purinergic P2Y receptors modulating the functionality of the CGRPergic neurovascular junction at the specific level of systemic resistance blood vessels, which are determinant for peripheral vascular tone and, consequently, for DBP. For this purpose, ADPβS (which is a preferential agonist at purinergic P2Y 1 , P2Y 12 and P2Y 13 receptors [ 33 , 36 , 39 , 47 , 58 ]) was used as it has recently been shown to produce (when given i.v.) (i) acute vasodepressor responses in anaesthetized rats [ 33 ]; and (ii) cardiac sympatho-inhibition in pithed rats by activation of purinergic P2Y 12 receptors, and less prominently by P2Y 13 receptors [ 36 ].…”

“…Moreover, our group has reported that in pithed rats (which have an inactive central nervous system) the vasodepressor sensory CGRPergic drive (which involves CGRP release from perivascular sensory nerves [ 3 , 4 ]) can be inhibited by prejunctional 5-HT 1B/1D [ 25 , 26 , 27 ], D 2 -like [ 28 ], α 2 -adrenergic [ 29 ] or H 3 receptors [ 30 ]. Interestingly (i) ATP stimulates the CGRPergic drive by activating prejunctional P2X 2/3 receptors which, in turn, results in systemic vasodilatation and a decrease in DBP [ 24 , 31 , 32 , 33 , 34 ]; (ii) adenosine diphosphate (ADP) is more potent than ATP and related compounds to produce vasodilatation and vasodepressor responses [ 35 ]; and (iii) adenosine 5′-O-2-thiodiphosphate (ADPβS; a stable and non-hydrolysable analogue of ADP) lowers DBP in anaesthetized rats [ 33 ], inhibits CGRP release from rat sensory neurons in dural arteries and trigeminal ganglion in situ by P2Y 13 receptors [ 33 ], and inhibits the cardioaccelerator sympathetic drive in pithed rats mainly by P2Y 12 receptors and less prominently by P2Y 13 receptors [ 36 ].…”