Activation of Dopamine D₃ Receptor Subtypes Inhibits the Neurogenic Systemic Vasodilation Induced by Stimulation of the Perivascular CGRPergic Discharge

Abstract

The sensory nervous system controls cardiovascular homeostasis via capsaicin-sensitive neurons that release calcitonin gene-related peptide (CGRP), which subsequently activates CGRP receptors. How this perivascular CGRPergic discharge is modulated, nevertheless, remains unclear. In pithed rats, systemic vasodilation induced by CGRPergic discharge stimulation results in diastolic blood pressure (BP) decrements that are inhibited by the dopamine D 2 -like receptor agonist quinpirole. Since this inhibition is mediated by raclopride-or haloperidol-sensitive D 2 -like receptors (comprising the D 2 , D 3 , and D 4 subtypes), the present study pharmacologically investigated the specific contribution of these subtypes to the modulation of the systemic CGRPergic vasodilation, using highly specific antagonists. To that end, 55 male Wistar rats were pithed for thoracic (T 9 −T 12 ) spinal stimulation of the perivascular CGRPergic discharge. The resulting frequency-dependent decrements in diastolic BP were inhibited by quinpirole, and this sensory-inhibition was (a) unchanged after i.v. injections of the antagonists L-741,626 (D 2 ) or L-745,870 (D 4 ) and (b) completely blocked by SB-277011-A (D 3 ). Accordingly, we suggest the main role of the D 3 receptor subtypes in the inhibition by quinpirole of the neurogenic CGRPergic systemic vasodilation. These findings contribute to a better understanding of the dopaminergic modulation of the rat perivascular CGRPergic discharge producing systemic vasodilation.

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

“…bolus injections of 1 mL/kg bidistilled water, 300 µg/kg MRS2500, 300 µg/kg PSB0739, 1000 µg/kg MRS2211, 3000 µg/kg MRS2211, 1 mL/kg glibenclamide vehicle (33% PEG, 33% ethanol and 34% NaOH 0.2 M) or 20 mg/kg glibenclamide. The potential influence of this effect of ADPβS (or any other treatment) on the vasodepressor responses by electrical stimulation and exogenous α-CGRP was minimized by calculating these responses as a % change in DBP, as previously established [ 4 , 26 , 27 , 28 , 29 , 30 ]. Furthermore, it is to be noted that the decrease in DBP produced by ADPβS (5.6 µg/kg·min) (i) was blocked after i.v.…”

“…Moreover, it is to be noted that the electrically induced CGRP release from perivascular sensory nerves was not directly measured in our experiments but, alternatively, was determined by the evoked vasodepressor responses, as previously reported [ 26 , 27 , 28 , 29 , 30 , 54 , 55 ], which are specifically blocked by CGRP receptor antagonists [ 4 , 57 ].…”

“…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).…”

“…CGRP release from sensory nerves can be prejunctionally stimulated by endogenous compounds such as anandamide [ 21 ], prostaglandins [ 22 ], bradykinin [ 22 ], acetylcholine [ 23 ] or ATP [ 24 ]. 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 ].…”