Predominant role of the dopamine D3 receptor subtype for mediating the quinpirole-induced inhibition of the vasopressor sympathetic outflow in pithed rats

Abstract

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.

The role of dopamine D2, but not D3 or D4, receptor subtypes, in quinpirole‐induced inhibition of the cardioaccelerator sympathetic outflow in pithed rats

“…Nevertheless, Ruiz‐Salinas et al . () showed in pithed rats that the same highest doses of SB‐277011‐A and L‐745,870 abolished and weakly blocked, respectively, quinpirole‐induced inhibition of the vasopressor sympathetic outflow.…”

“…In contrast, Ruiz‐Salinas et al . () have shown, using the same compounds, same doses, same i.v. routes and same species as in our present investigation, that quinpirole‐induced inhibition of the vasopressor sympathetic outflow resembles the pharmacological profile of the D 3 receptor subtype and, to a lesser extent, of the D 4 receptor subtype, with no evidence for the role of the D 2 subtype.…”

“…cardioaccelerator nerve and/or sympathetic ganglia). Accordingly, 300 μg kg −1 of L‐741,626 and L‐745,870 attenuated per se the sympathetically induced vasopressor responses (Ruiz‐Salinas et al ., ).…”

“…On this basis, the present study was designed to identify pharmacologically the specific D 2 ‐like receptor subtypes (i.e. D 2 , D 3 and D 4 ) involved in the above quinpirole‐induced cardiac sympathoinhibition by analysing the effects of antagonists at the D 2 (L‐741,626), D 3 (SB‐277011‐A) and D 4 (L‐745,870) receptor subtypes (see Table ), in doses high enough to block sympathoinhibitory D 2 , D 3 and D 4 receptor subtypes in pithed rats (Ruiz‐Salinas et al ., ).…”

Pharmacological evidence that 5-HT1A/1B/1D, α2-adrenoceptors and D2-like receptors mediate ergotamine-induced inhibition of the vasopressor sympathetic outflow in pithed rats

“…Nevertheless, further experiments using selective antagonists, which fall beyond the scope of the present investigation, will be required to identify the D 2/3/4 subtype involved in the sympatho-inhibition to ergotamine. In this sense, it has been reported that D 3 and D 4 subtypes are predominantly involved in the sympatho-inhibition of the vasopressor sympathetic outflow to quinpirole (Ruiz-Salinas et al, 2013). Consistent with our results, previous studies have demonstrated that ergotamine-induced vascular sympathoinhibition was blocked by yohimbine (α 2 -adrenoceptor antagonist) and sulpiride (D 1/2 -like antagonist) (Badia et al, 1988) and the cardiac sympatho-inhibition to ergotamine is blockade by rauwolscine (α 2 -adrenoceptor antagonist) and haloperidol (D 1/2 -like antagonist) (Cobos-Puc et al, 2009) suggesting that the α 2 -adrenoceptors and also D 2 -like receptors are involved.…”