Pharmacological characterization of ergotamine-induced inhibition of the cardioaccelerator sympathetic outflow in pithed rats

Abstract

Ergotamine inhibits the sympathetically-induced tachycardia in pithed rats. The present study identified the pharmacological profile of this response. Male Wistar rats were pithed and prepared to stimulate the preganglionic (C(7)-T(1)) cardiac sympathetic outflow. Intravenous continuous infusions of ergotamine dose-dependently inhibited the tachycardic responses to sympathetic stimulation, but not those to exogenous noradrenaline. Using several antagonists, the sympatho-inhibition to ergotamine was: (1) partially blocked by rauwolscine (alpha(2)), haloperidol (D(1/2)-like) or rauwolscine plus GR127935 (5-HT(1B/1D)); (2) abolished by rauwolscine plus haloperidol; and (3) unaffected by either saline or GR127935. In animals systematically pretreated with haloperidol, this sympatho-inhibition was: (1) unaffected by BRL44408 (alpha(2A)), partially antagonized by MK912 (alpha(2C)); and (3) abolished by BRL44408 plus MK912. These antagonists failed to modify the sympathetically induced tachycardic responses per se. Thus, the cardiac sympatho-inhibition by ergotamine may be mainly mediated by alpha(2A)/alpha(2C)-adrenoceptors, D(2)-like receptors and, to a lesser extent, by 5-HT(1B/1D) receptors.

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

“…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. Additionally, our study shows that 5-HT 1A/1B/1D receptors appear to mediate predominantly the vascular sympatho-inhibition to ergotamine in comparison to α 2 -adrenoceptors or D 2 -like receptors ( Fig.…”

“…In this sense, we have previously demonstrated that α 2A/2B/2C -adrenoceptor subtypes could operate at high frequencies of stimulation in pithed rats (Villamil-Hernández et al, 2013b). Furthermore, the cardiac sympatho-inhibition to ergotamine mainly involves α 2A -and α 2C -adrenoceptors subtypes (at 1-3 Hz and 0.1-3 Hz, respectively) in pithed rats (Cobos-Puc et al, 2009). Admittedly further experiments using selective antagonists for each α 2 subtype, which fall beyond the scope of the present investigation, will be required to identify the α 2 subtype involved.…”

“…1). It must be emphasised that the doses used of the above antagonists were high enough to block their respective receptors on the sympathetic nerves (Alcántara- Vázquez et al, 2013;Cobos-Puc et al, 2009;Manrique-Maldonado et al, 2011;Villalón et al, 1998;Villamil-Hernández et al, 2013b) by which display affinity (Table 1).…”

“…(i) vasoconstriction in the isolated rat aorta by 5-HT 2A receptors (Kalkman and Schneider, 1996); (ii) cranio-selective vasoconstriction mediated by 5-HT 1B , α 2A/2C -adrenoceptors and, to a lesser extent, by α 1 -adrenoceptors in dogs (Valdivia et al, 2004); (iii) vasopressor responses via α 1A/1B/1D -and α 2A/2C -adrenoceptors in pithed rats (Villamil-Hernández et al, 2013a); or (iv) cardiac sympathoinhibition by activation of α 2A/2C -adrenoceptors, D 2 -like receptors, to a lesser extent, 5-HT 1B/1D receptors in pithed rats (Cobos-Puc et al, 2009). Nevertheless, no attempt has been made to investigate whether ergotamine could be able to inhibit the vasopressor sympathetic outflow and the mechanism(s) and/or receptor(s) involved in this response.…”

Pharmacological Evidence That Dopamine Inhibits the Cardioaccelerator Sympathetic Outflow via D2-Like Receptors in Pithed Rats

“…A possible explanation of the lack of effect of rauwolscine is that all animals undergoing sympathetic stimulation were systematically pretreated with the neuronal noradrenaline reuptake inhibitor desipramine (50 mg/kg, i.v.). Hence, the concentration of noradrenaline in the neuroeffector junction may have reached (sub) maximal levels, as implied by the markedly enhanced tachycardic responses after desipramine over a wide range of stimulation frequencies (see Results) (21); as a result, the subsequent administration of rauwolscine may have had no further effect on this concentration of noradrenaline (18). Admittedly, it has been reported that higher doses of dopamine can stimulate not only dopamine receptors but also b-adrenoceptors and a-adrenoceptors (34).…”