Most research were not carried out under controlled conditions in which 2-adrenoceptor actions could be investigated

Most research were not carried out under controlled conditions in which 2-adrenoceptor actions could be investigated. the combination ritanserin/prazosin significantly reduced the initial pressor response, although neither of the second option compounds alone experienced any effect. The pressor response to MDMA (5?mg?kg?1) at 1?min was converted to a depressor response by prazosin and to a lesser degree methiothepin and methoxyidazoxan. The depressor response to MDMA (5?mg?kg?1) was Taxifolin significantly reduced by methoxyidazoxan (0.1?mg?kg?1), and by the noradrenaline re-uptake blocker cocaine 10?mg?kg?1 but not 1?mg?kg?1. However, probably the most designated reduction in the depressor response was produced by the combination of methoxyidazoxan and cocaine. It is concluded that the initial pressor response to MDMA (5?mg?kg?1) in anaesthetized rats involves 2- and possibly 1-adrenoceptors and 5-HT2 receptors, the pressor component at 1?min is largely 1-adrenoceptor mediated, and the sustained depressor response involves 2-adrenoceptors. shows the number of animals analyzed. Differences between organizations were compared by Analysis of Variance and Dunnett’s test (for comparisons with vehicle) or Tukey test (comparison of Taxifolin all organizations). Means were considered significantly different when ideals were 0.05. Results Pithed rat preparation Pressor reactions to injected agonists In pithed rats, resting diastolic blood pressure (DBP) was 35.81.7?mmHg (ideals see Table 1). Asterisks denote the significance of difference of effects of MDMA following test medicines from effects of MDMA in vehicle experiments (Analysis of Variance and Dunnett’s test: ideals see Table 1). Asterisks denote the significance of difference of effects of MDMA following test medicines from effects of MDMA in vehicle experiments (Analysis of Variance and Dunnett’s test: ideals see Table 1). Asterisks denote the significance of difference of effects of MDMA following test medicines from effects of MDMA in vehicle experiments (Analysis of Variance and Dunnett’s test: em P /em 0.05). Data taken from Number 4. Heart rate in anaesthetized rats In anaesthetized rats, resting heart rate was 3893?min?1 ( em n /em =124). In independent vehicle experiments, MDMA (1, 5 and 20?mg?kg?1) raised heart rate by 774 ( em n /em =3), 748 ( em n /em =15) and 8512?min?1 ( em n /em =4). Of the antagonist mixtures used, prazosin (0.1?mg?kg?1), cocaine (1?mg?kg?1), and Taxifolin methoxyidazoxan (0.1?mg?kg?1) alone or in combination with cocaine, significantly reduced the tachycardia to MDMA (5?mg?kg?1). However, all except cocaine (1?mg?kg?1) significantly raised resting heart rate. Cocaine (1?mg?kg?1) significantly reduced the tachycardia to MDMA (5?mg?kg?1) to 359?min?1 ( em n /em =6, em P /em 0.05). Conversation We have previously demonstrated that MDMA offers two actions in the rat atrium and vas deferens: the well-known indirect actions to displace noradrenaline from nerve terminals and a direct agonist action on prejunctional 2-adrenoceptors on nerve terminals to inhibit neurotransmitter launch (Lavelle em et al /em ., 1999). hCIT529I10 While the former action of MDMA is definitely well recorded, the second option action as an 2-adrenoceptor Taxifolin agonist is definitely novel. Since 2-adrenoceptor agonists have major actions influencing blood pressure by central and peripheral actions, we have examined the vascular actions of MDMA in the anaesthetized rat. MDMA (5?mg?kg?1) was chosen as the test dose because it produced a biphasic effect on DBP. MDMA (1?mg?kg?1) produced only a pressor response, even though depressor component could be revealed in the presence of prazosin. MDMA (20?mg?kg?1) produced a biphasic response, but the depressor component developed much more slowly. The following antagonist drugs were used: the 1-adrenoceptor antagonist prazosin, the 2-adrenoceptor antagonist methoxyidazoxan (the 2-adrenoceptor antagonist yohimbine was employed in some studies in Taxifolin the pithed rat), the non-selective 5-HT receptor antagonist methiothepin (0.1?mg?kg?1) (Bradley em et al /em ., 1986; Docherty, 1988), the 5-HT1A receptor antagonist WAY 100635 (0.1?mg?kg?1) (Saxena em et al /em ., 1998) the 5-HT1B receptor antagonist GR 55562 (1?mg?kg?1) (MacLean em et al /em ., 1996), the 5-HT1D receptor antagonist BRL 15572 (0.1?mg?kg?1) (Saxena em et al /em ., 1998), the 5-HT2 receptor antagonist ritanserin, the noradrenaline re-uptake blocker cocaine. However, studies in the pithed rat exposed that methiothepin (0.1?mg?kg?1) and methoxyidazoxan (1?mg?kg?1) had significant antagonist actions at 1-adrenoceptors, and were approximately 10 and 100 instances less potent than prazosin, respectively. Studies in the pithed rat shown peripheral vasoconstrictor actions of MDMA (1 and 5?mg?kg?1). Studies with prazosin suggested the predominant response is definitely 1-adrenoceptor mediated, but since prazosin did not abolish the response to MDMA (1?mg?kg?1), the response cannot be exclusively 1-adrenoceptor mediated (compare effects of prazosin against phenylephrine in Number 1a). Actually yohimbine/prazosin/methiothepin or ritanserin/prazosin/methoxyidazoxan in combination did not completely block the pressor response to MDMA (5?mg?kg?1). However, since yohimbine/prazosin/methiothepin or ritanserin/prazosin/methoxyidazoxan experienced significantly higher effects than prazosin only, it is likely that 2-adrenoceptors and/or 5-HT2 receptors will also be involved in pressor reactions to MDMA. Results acquired with ritanserin suggest that any 5-HT2.