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.
We have recently reported that quinpirole (a D2-like receptor agonist) inhibits the vasopressor sympathetic outflow in pithed rats via sympatho-inhibitory D2-like receptors. Since D2-like receptors consist of D2, D3 and D4 receptor subtypes, this study investigated whether these subtypes are involved in the above quinpirole-induced sympatho-inhibition by using antagonists of these receptor subtypes. One hundred fifty-six male Wistar rats were pithed and prepared for preganglionic spinal (T7-T9) stimulation of the vasopressor sympathetic outflow. This approach resulted in frequency-dependent vasopressor responses which were analysed before and during i.v. continuous infusions of either saline (0.02 ml/min) or quinpirole (1 μg/kg.min) in animals receiving i.v. bolus injections of vehicle [saline or dimethyl sulfoxide (DMSO)] or the antagonists L-741,626 (D2), nafadotride or SB-277011-A (both D3) as well as L-745,870 (D4). Quinpirole inhibited the sympathetically-induced vasopressor responses. This sympatho-inhibition was (a) unaltered after 1 ml/kg saline, DMSO or 100 and 300 μg/kg L-741,626; (b) markedly blocked and abolished by, respectively, 30 and 100 μg/kg nafadotride or 100 and 300 μg/kg SB-277011-A and (c) slightly blocked after 30 and 100 μg/kg L-745,870, but 300 μg/kg L-745,870 produced no blockade whatsoever. Except for 300 μg/kg L-741,626 or 300 μg/kg L-745,870, the doses of the above compounds failed to modify per se the sympathetic vasopressor responses. The inhibition of the vasopressor sympathetic outflow induced by 1 μg/kg.min quinpirole in pithed rats is predominantly mediated by dopamine D3 and, to a lesser extent, by D4 receptor subtypes, with no evidence for the involvement of the D2 subtype.
Epileptic seizures are often accompanied by increased sympathetic cardiovascular activity (even interictally), but it remains unknown whether this increased activity is of central and/or peripheral origin. Hence, this study investigated the cardiovascular alterations produced by amygdala kindling in awake and pithed Wistar rats. Blood pressure (BP) and heart rate (HR) were initially recorded by tail cuff plethysmography in awake control, sham-operated and amygdala-kindled rats before and 24 hr after the kindling process. The after-discharge threshold (ADT) was measured under different conditions to correlate brain excitability with BP and HR in kindled rats. Twenty-four hours after the last kindling seizure, (i) HR, systolic and diastolic BP were increased and (ii) only higher HR values correlated with lower ADT values. Forty-eight hr after the last kindled seizure, all rats were pithed and prepared for analysing the tachycardic, vasopressor and vasodepressor responses by (i) stimulation of the sympathetic or sensory vasodepressor CGRPergic out-flows (stimulus-response curves, S-R curves) and (ii) intravenous injections of noradrenaline or a-CGRP (dose-response curves, D-R curves). Interestingly, (i) the tachycardic S-R and D-R curves were attenuated, whilst the CGRPergic S-R and D-R curves were potentiated in kindled rats, and (ii) the vasopressor noradrenergic S-R and D-R curves were not significantly different in all groups. Therefore, the kindling process may be associated with overstimulation in the central sympathetic and sensory out-flows interictally, producing (i) peripheral attenuation of cardiac sympathetic out-flow and b-adrenoceptor activity and (ii) peripheral potentiation of vasodepressor sensory CGRPergic out-flow and CGRP receptor activity.Epilepsy is a disorder characterized by a pre-disposition to generate spontaneous and recurrent seizures [1]. Postictal (period after a seizure characterized by a reduced susceptibility to present subsequent seizures) and interictal (period between seizures characterized by a susceptibility to present subsequent seizures) phenomena reflect changes in the brain induced by epilepsy such as depression, aggressive behaviour and autonomic dysfunction [2]. In this regard, seizures induce severe autonomic changes such as hyperventilation, apnoea and changes in blood pressure (BP) and heart rate (HR) [3,4] (even interictally). Moreover, several lines of evidence have shown (i) interictal cardiac autonomic dysfunction in patients with temporal lobe epilepsy, such as impaired HR responses and diminished HR variability [5,6], and (ii) higher basal HR in patients with complex partial and secondarily generalized seizures than in control or other epileptic patients [7].Further studies in animal models have also demonstrated a possible autonomic dysfunction associated with epilepsy. For example, Pansani et al. [8] have observed in amygdala-kindled rats (i) a correlation between the number of seizures induced by electrical amygdala kindling and ictal tachycardia, wh...
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