Olcegepant (i.v.) selectively blocked the neurogenic and non-neurogenic CGRPergic vasodepressor responses. This blockade by olcegepant potentiated the neurogenic and non-neurogenic noradrenergic vasopressor responses in pithed rats, an effect that might result in an increased vascular resistance and, consequently, in a prohypertensive action.
Calcitonin gene-related peptide (CGRP) released from perivascular sensory nerves plays a role in the regulation of vascular tone. Indeed, electrical stimulation of the perivascular sensory out-flow in pithed rats produces vasodepressor responses, which are mainly mediated by CGRP release. This study investigated the potential role of dopamine D 1 -like and D 2 -like receptors in the inhibition of these vasodepressor responses. For this purpose, male Wistar pithed rats (pre-treated i.v. with 25 mg/kg gallamine and 2 mg/kg min. hexamethonium) received i.v. continuous infusions of methoxamine (20 lg/kg min.) followed by physiological saline (0.02 ml/min.), the D 1 -like receptor agonist SKF-38393 (0.1-1 lg/kg min.) or the D 2 -like receptor agonist quinpirole (0.03-10 lg/kg min.). Under these conditions, electrical stimulation (0.56-5.6 Hz; 50 V and 2 ms) of the thoracic spinal cord (T 9 -T 12 ) resulted in frequency-dependent vasodepressor responses which were (i) unchanged during the infusions of saline or SKF-38393 and (ii) inhibited during the infusions of quinpirole (except at 0.03 lg/kg min.). Moreover, the inhibition induced by 0.1 lg/kg min. quinpirole (which failed to inhibit the vasodepressor responses elicited by i.v. bolus injections of exogenous a-CGRP; 0.1-1 lg/kg) was (i) unaltered after i.v. treatment with 1 ml/kg of either saline or 5% ascorbic acid and (ii) abolished after 300 lg/kg (i.v.) of the D 2 -like receptor antagonists haloperidol or raclopride. These doses of antagonists (enough to completely block D 2 -like receptors) essentially failed to modify per se the electrically induced vasodepressor responses. In conclusion, our results suggest that quinpirole-induced inhibition of the vasodepressor sensory CGRPergic out-flow is mainly mediated by pre-junctional D 2 -like receptors.It has been widely documented that dopamine regulates a broad range of physiological functions (including cardiovascular homeostasis), and it contributes to blood pressure control due to its peripheral action on the kidney, adrenal glands and vascular tone [1][2][3][4][5][6][7]. With the conjunction of structural, transductional and operational (pharmacological) criteria, dopamine receptors can be classified into Regarding resistance blood vessels, these are mainly innervated by sympathetic [8] and primary sensory [9] nerves which modulate the vascular tone. The perivascular sensory nerves are mainly C-fibres originating from the spinal cord and, upon stimulation, cause a non-adrenergic, non-cholinergic (NANC) vasodilatation via the release of neuropeptides, primarily calcitonin gene-related peptide (CGRP) [9]. CGRP is predominantly located in sensory neurons (including perivascular nerves), where it is colocalized with other neuropeptides, such as substance P and neurokinin A [10].Interestingly, Taguchi et al.[9] have shown that electrical stimulation of the thoracic (T 9 -T 12 ) spinal cord in pithed rats receiving i.v. infusions of hexamethonium and methoxamine caused vasodepressor responses, which are ma...
BACKGROUND AND PURPOSEQuinpirole (a dopamine D2-like receptor agonist) inhibits the cardioaccelerator sympathetic outflow in pithed rats by sympathoinhibitory D2-like receptors. The present study was designed to identify pharmacologically the specific D2-like receptor subtypes (i.e. D2, D3 and D4) involved in this sympathoinhibition by quinpirole.
EXPERIMENTAL APPROACHOne hundred fourteen male Wistar rats were pithed, artificially ventilated with room air and prepared for either preganglionic spinal (C7-T1) stimulation of the cardioaccelerator sympathetic outflow (n = 102) or i.v. bolus injections of exogenous noradrenaline (n = 12). This approach resulted in frequency-dependent and dose-dependent tachycardic responses, respectively, as previously reported by our group.
KEY RESULTSI.v. continuous infusions of quinpirole (0.1-10 μg kg), but not of saline (0.02 mL min ); and (ii) markedly blocked and abolished by, respectively, 100 and 300 μg kg −1 of the D2 preferring receptor subtype antagonist L-741,626. These doses of antagonists, which did not affect per se the sympathetically induced tachycardic responses, were high enough to completely block their respective receptors.
CONCLUSIONS AND IMPLICATIONSThe cardiac sympathoinhibition induced by 3 μg kg −1 min −1 quinpirole involves the dopamine D2 receptor subtype, with no evidence for the involvement of the D3 or D4 subtypes. This provides new evidence for understanding the modulation of the cardioaccelerator sympathetic outflow.
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