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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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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.

This study compared the cardiac sympatho-inhibitory responses produced by agonists at α -adrenergic (B-HT 933), dopamine D -like (quinpirole) and histamine H /H (immepip) receptors between normoglycaemic and streptozotocin-pretreated (diabetic) pithed rats. Intravenous (i.v.) continuous infusions of B-HT 933, quinpirole or immepip were used in normoglycaemic and diabetic pithed rats to analyse their sympatho-inhibitory effects on the electrically-stimulated cardioaccelerator sympathetic outflow. Both in normoglycaemic and diabetic animals, B-HT 933 (until 100 μg/kg per minute) and quinpirole (until 10 μg/kg per minute) inhibited the tachycardic responses to electrical sympathetic stimulation, but not those to i.v. bolus of exogenous noradrenaline. These sympatho-inhibitory responses were more pronounced in diabetic than in normoglycaemic animals. Accordingly, the areas under the curve for 100 μg/kg per minute B-HT 933 and 10 μg/kg per minute quinpirole in diabetic rats (1065 ± 70 and 920 ± 35, respectively) were significantly smaller (P < .05) than those in normoglycaemic rats (1220 ± 45 and 1360 ± 42, respectively). In contrast, immepip infusions produced cardiac sympatho-inhibition in normoglycaemic (until 10 μg/kg per minute), but not in diabetic (until 100 μg/kg per minute) animals. Our results suggest that in diabetic pithed rats: (i) the more pronounced cardiac sympatho-inhibition to B-HT 933 and quinpirole may be probably due to up-regulation of α -adrenergic and dopamine D -like receptors, respectively; (ii) the histamine H /H receptors do not seem to play a sympatho-inhibitory role; and (iii) there is a differential participation of α -adrenergic and dopamine D -like receptors, which may certainly represent therapeutic targets for the treatment of diabetic complications such as cardiovascular autonomic neuropathy.

Several lines of evidence have shown an association of diabetes with a catecholamines' aberrant homeostasis involving a drastic change in the expression of adrenoceptors. This homeostatic alteration includes, among other things, atypical actions of a 2 -adrenoceptor agonists within central and peripheral a 2 -adrenoceptors (e.g. profound antinociceptive effects in diabetic subjects). Hence, this study investigated the pharmacological profile of the a 2 -adrenoceptor subtypes that inhibit the vasopressor sympathetic out-flow in streptozotocin-pre-treated (diabetic) pithed rats. For this purpose, B-HT 933 (up to 30 lg/kg min) was used as a selective a 2 -adrenoceptor agonist and rauwolscine as a non-selective a 2A/2B/2C -adrenoceptor antagonist; in addition, BRL 44408, imiloxan and JP-1302 were used as subtype-selective a 2A -, a 2B -and a 2C -adrenoceptor antagonists, respectively (all given i.v.). I.v. continuous infusions of B-HT 933 inhibited the vasopressor responses induced by electrical sympathetic stimulation without affecting those by i.v. bolus injections of noradrenaline in both normoglycaemic and diabetic rats. Interestingly, the ED 50 for B-HT 933 in diabetic rats (25 lg/kg min) was almost 1-log unit greater than that in normoglycaemic rats (3 lg/kg.min). Moreover, the sympatho-inhibition induced by 10 lg/kg min B-HT 933 in diabetic rats was (i) abolished by 300 lg/kg rauwolscine or 100 and 300 lg/kg BRL 44408; (ii) partially blocked by 1000 lg/kg imiloxan; and (iii) unchanged by 1000 lg/kg JP-1302. Our findings, taken together, suggest that B-HT 933 has a less potent inhibitory effect on the sympathetic vasopressor responses in diabetic (compared to normoglycaemic) rats and that can probably be ascribed to a down-regulation of a 2C -adrenoceptors.Based on structural, transductional and operational criteria, a 2 -adrenoceptors consist of the a 2A -, a 2B -and a 2C -adrenoceptor subtypes [1]. These receptors play a wide array of functions, including cardiovascular modulation and sympatho-inhibition via autoreceptors [2]. In the particular case of healthy Wistar pithed rats, cardiac sympatho-inhibition is mediated by prejunctional a 2A -and a 2C -adrenoceptors [3], while systemic vascular (vasopressor) sympatho-inhibition has recently been reported to involve a 2A -, a 2B -and a 2C -adrenoceptors [4]. However, in some pathologies (including metabolic diseases), the modulatory role of these receptors seems to be altered. For example, the early stages of streptozotocin-induced diabetes in Wistar rats are characterized by (i) an up-regulation of central a 2 -adrenoceptors [5][6][7]; (ii) an increased noradrenaline overflow and sympathetic tone [8]; and (iii) impaired neurogenic vasomotor mechanisms [9]. Nevertheless, no study has thus far analysed possible alterations in the specific role of the a 2 -adrenoceptor subtypes mediating inhibition of the vasopressor sympathetic out-flow in diabetic rats. On this basis, this study investigated the pharmacological profile of the a 2 -adrenoceptor subtyp...