In conscious, freely-moving, male, Sprague-Dawley rats, the regional haemodynamic responses to the synthetic cannabinoids, WIN-55212-2 and HU 210, were compared. The possible involvement of cannabinoid, CB1-receptors, or β2-adrenoceptors in the responses to WIN-55212-2 and HU 210 were investigated using the CB1-receptor antagonist, AM 251, or the β2-adrenoceptor antagonist, ICI 118551, respectively. Both WIN-55212-2 (150 μg kg−1) and HU 210 (100 μg kg−1) had pressor, renal, and mesenteric vasoconstrictor and hindquarters vasodilator actions, although the effects of HU 210 were much more sustained than those of WIN-55212-2. Lower doses of the cannabinoids (WIN-55212-2, 50 μg kg−1, HU 210, 10 μg kg−1) had less consistent actions. All the significant cardiovascular effects of WIN-55212-2 and HU 210 were antagonized by pretreatment with AM 251 (3 mg kg−1). Furthermore, pretreatment with the β2-adrenoceptor antagonist, ICI 118551, inhibited the hindquarters vasodilator effects of WIN-55212-2 and of HU 210. On the basis of the present findings, and our earlier work, it is suggested that, in conscious rats, the pressor and vasoconstrictor effects of HU 210 and WIN-55212-2 involve cannabinoid-receptor-mediated increases in sympathetic activity. The accompanying hindquarters vasodilator actions of these agonists are cannabinoid receptor-mediated and appear to involve β2-adrenoceptors. Keywords: Cannabinoids, HU 210, WIN-55212-2, haemodynamics Introduction Previously (Gardiner et al., 2001), we have drawn attention to the complexity of the cardiovascular effects of cannabinoids as described in the literature, and have suggested that this might reflect variations in experimental conditions. Considering the in vivo studies, it appears that the state of anaesthesia influences the cardiovascular response to synthetic cannabinoids, since we have recently reported that WIN-55212-2, which has been shown to have marked hypotensive effects in anaesthetized rats (Lake et al., 1997), has dose-dependent pressor and renal and mesenteric vasoconstrictor effects in conscious rats, with hindquarters vasodilator actions being seen only with the higher doses of the cannabinoid (Gardiner et al., 2001). In our previous study, we made no formal assessment of the involvement of cannabinoid receptors in the vasoconstrictor or vasodilator responses to WIN-55212-2. Thus, the first aim of the present study was to determine the effects of the cannabinoid, CB1-receptor antagonist, AM 251 (Gatley et al., 1996, 1997) on the cardiovascular responses to WIN-55212-2 in conscious rats. We considered this an important experiment since, unlike SR 141716A, AM 251 is commercially available and yet there are no published in vivo data on the cardiovascular effects of AM 251, either on baseline haemodynamic status, or on responses to cannabinoids. In addition, since we (Gardiner et al., 2001) have hypothesized that the hindquarters vasodilator action of WIN-55212-2 could be mediated by β2-adrenoceptors, our second aim was to assess the effects of the β2-adrenoceptor antagonist, ICI 118551 (Bilski et al., 1983), on responses to WIN-55212-2. In anaesthetized rats, other cannabinoid agonists, such as HU 210, which differ structurally from WIN-55212-2 (for review see Pertwee, 1997), have also been reported to cause CB1-receptor-mediated hypotension, and this has been taken as a sign of vasodilatation (e.g., Lake et al., 1997). However, it is clear from our studies with WIN-55212-2, that it is only by monitoring regional haemodynamics that one can get a proper picture of the processes underlying any effects substances, such as cannabinoids, have on systemic arterial blood pressure. Very recently, some work has been published which indicates a complex regional haemodynamic profile associated with administration of HU 210 in urethane-anaesthetized rats (Wagner et al., 2001). However, because of the technique they used, Wagner et al. (2001) were restricted to making measurements at a single point in time following HU 210 administration. We know of only one report of the cardiovascular effects of HU 210 in conscious rats (Vidrio et al., 1996), and in that study, the cannabinoid was administered i.p., and measurements were restricted to blood pressure and heart rate, monitored indirectly. Therefore, the final aim of the present study was to make continuous measurements of the regional haemodynamic effects of HU 210 in conscious rats, to ascertain whether or not they resembled those of WIN-55212-2, and to determine the effects of cannabinoid receptor antagonism (with AM 251), or β2-adrenoceptor antagonism (with ICI 118551), thereupon. Some of the results have been presented to the British Pharmacological Society (Gardiner et al., 2002a,2002b).