Background and purpose:We examined whether cannabinoid CB1 and histamine H3 receptors resemble a2-adrenoceptors in that their presynaptically mediated cardiovascular effects are less marked in urethane-than in pentobarbitone-anaesthetized pithed rats. Experimental approach: Effects of the cannabinoid agonist CP-55,940 and the H3 receptor agonist imetit on electrically induced tachycardic and vasopressor responses, respectively, was compared in pithed rats anaesthetized with urethane or pentobarbitone. The affinity of urethane for the three receptors was measured by radioligand binding studies in rat brain cortex membranes and its potency assessed in superfused mouse tissues preincubated with 3 H-noradrenaline. Key results: The neurogenic tachycardic response was less markedly inhibited by CP-55,940 in urethane-than in pentobarbitone-anaesthetized pithed rats. Imetit inhibited the neurogenic vasopressor response after pentobarbitone but not after urethane. The catecholamine-induced tachycardic and vasopressor response did not differ between rats anaesthetized with either compound. Urethane 10 mM (plasma concentration reached under anaesthesia) did not affect binding to CB1 or H3 receptors and a2 adrenoceptors, nor did it alter the inhibitory effect of agonists at the three receptors on electrically evoked 3 H-noradrenaline release. Conclusions and implications:Urethane, but not pentobarbitone, abolished the H3 receptor-mediated vascular response in pithed rats and attenuated the CB1 receptor-mediated cardiac response much more than pentobarbitone. The weaker effects of CB1, H3 and a2 receptor agonists cannot be explained by antagonism by urethane at the three receptors in vitro. Pentobarbitone, but not urethane, is suitable as an anaesthetic for investigations of inhibitory presynaptic receptor function in pithed and anaesthetized rats. (2009) British Journal of Pharmacology IntroductionPithed animals offer the opportunity to study the influence of pre- (Armstrong and Boura, 1973) and postsynaptic receptors (Shipley and Tilden, 1947) on cardiovascular parameters under conditions that resemble the in vivo situation in many respects. One major advantage of such preparations is the fact that basal blood pressure and heart rate (HR) are very stable since they are no longer under the control of reflex loops involving the central nervous system (CNS). Prior to pithing, the animals have to be anaesthetized. The choice of the anaesthetic is of crucial importance on the effect of test drugs on cardiovascular parameters studied later in the pithed animal. For instance, in pithed rats the cardiovascular responses to a2-adrenoceptor agonists acting at pre-and postsynaptic a2-adrenoceptors wereCorrespondence: E Schlicker,
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