Characterization of mechanisms involved in presynaptic inhibition of sympathetic pressor effects induced by some 5‐HT₁ receptor antagonists

Abstract

1. In a previous study, we showed that the presynaptic inhibitory action of 5-hydroxytryptamine receptor agonists on sympathetic pressor effects obtained in the pithed rats were mainly mediated by activation of 5-HT1A and 5-HT1D receptor subtypes. At the time, we observed that some 5-HT1 receptors antagonists - WAY 100,635 and NAN-190 (both 5-HT1A receptor antagonists), methiothepin (a 5-HT1,2,5,6,7 receptor antagonist) and spiperone (a 5-HT1,2 receptor antagonist) - reduced per se the pressor effects obtained by electrical stimulation. The aim of the present work was to investigate the mechanism participating in this inhibitory effect. 2. The inhibition induced by WAY 100,635 (1000 microg kg-1, i.v.) was blocked after i.v. treatment with idazoxan, an alpha2-adrenoceptor antagonist (300 and 1000 microg kg-1) and was not modified after i.v. treatment with propranolol, a beta-adrenoceptor antagonist (1000 microg kg-1) and sulpiride, a D2 receptor antagonist (1000 microg kg-1). The inhibition induced by spiperone (500 microg kg-1 i.v.) was significantly blocked by sulpiride (1000 microg kg-1) and was not modified by idazoxan or propranolol. 3. Sulpiride (1000 microg kg-1) partially blocked the inhibition induced by methiothepin (50 microg kg-1 i.v.). Only pretreatment with idazoxan (300 microg kg-1) modified the inhibition induced by NAN-190 (100 microg kg-1 i.v.), such inhibition increasing after intravenous administration of idazoxan. 4. All the antagonists used in our experiments failed to inhibit the pressor responses elicited by i.v. noradrenaline administration. 5. The above results suggest that the inhibitory effects of these 5-HT1 receptor antagonists are presynaptic in nature, but not related to the blockade of 5-HT1 receptors subtypes. The simultaneous activation or inhibition of other receptor systems could explain the inhibition produced by each 5-HT1 receptor antagonist studied.

Evidence that the hypotensive effect of WAY 100635, a 5‐HT1A receptor antagonist, is related to vascular α1‐adrenoceptor blockade in the adult rat

“…These observations, along with our findings that injection of this compound induced a decrease in blood pressure in the anaesthetized rat, suggest that WAY 100635‐induced hypotension could be related to vascular α 1 ‐adrenoceptor blockade. In support of this contention, we found that WAY 100635 significantly shifted the phenylephrine pressor effect to the right in the pithed rats, at a dose of 1 mg kg −1 , with no significant effects at lower antagonist doses; similar dose‐related effects have been observed when WAY 100635 antagonized the increase in mean blood pressure induced by electrical stimulation, but not by noradrenaline administration where WAY 100635 did not modify the increase in blood pressure elicited by the catecholamine (Fernandez, Calama, Moran, Martin & San Roman, 2000). We do not know why phenylephrine‐induced pressor effects were blocked by WAY 100635 and those for noradrenaline were not, but a possible explanation could be that phenylephrine acts on α 1 ‐adrenoceptors (and probably on β‐adrenoceptors), while noradrenaline acts on all three adrenoceptors, and part of its pressor effect may be due to α 1 ‐adrenoceptor stimulation.…”

“…The lack of correlation in cardiovascular effects of WAY 100635 in both animal models may involve vascular α 1 ‐adrenoceptor blockade by WAY 100635 in pithed rats, while in anaesthetized rats, besides vascular α 1 ‐adrenoceptor antagonism there could be other mechanism. These could include inhibition of noradrenaline release from sympathetic nerve terminals, via stimulation of presynaptic 5‐HT 1A receptors, as a partial agonist as has been suggested in 5‐HT 1A receptor transfected cells (Welsby, Kellett, Wilkinson & Milligan, 2002), presynaptic α 2 ‐adrenoceptor stimulation (Fernandez, Calama, Moran, Martin & San Roman, 2000), or interaction with other 5‐HT receptors involved in cardiovascular function (5‐HT 7 ? ).…”

Diabetes‐induced changes in the 5‐hydroxytryptamine inhibitory receptors involved in the pressor effect elicited by sympathetic stimulation in the pithed rat

“…A nonselective 5‐HT 1 antagonist, methiothepin (Hoyer et al ., 1994) blocked the electrically induced pressor responses per se , and this inhibitory effect may be accounted for the affinity of this antagonist for α 1 ‐adrenoceptors (Leysen et al ., 1985; Fernández et al ., 2000). In this sense, the inhibition of electrically induced pressor responses by 5‐HT (10 μ g kg −1 min −1 ) was unable to be elicited after i.v.…”

Effect of 5‐hydroxytryptamine on neurogenic vasoconstriction in the isolated, autoperfused hindquarters of the rat

“…The methods used in the present study are related to those implemented in other investigations performed by our group, 17,18 in which we examined total sympathetic stimulation in pithed rats or cardiac stimulation. In such cases, we placed electrodes for electrical stimulation in the stainless steel rod used to pith the rats but, because in the present study we were interested in the hindquarter vascular bed, we had to stimulate this by placing the electrodes in the lumbar sympathetic chains.…”