Role of Central Versus Peripheral Mechanisms in the Cardiovascular Effects of Cannabinoids

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Early work with THC suggested that cannabinoids lower blood pressure through a centrally mediated sympatho-inhibitory mechanism (Vollmer et al. 1974). However, the hypotension elicited by anandamide in urethane-anesthetized rats is not associated with any change in the activity of sympathetic premotor neurons in the medullary vasomotor center or in the activity of sympathetic postganglionic nerves (Varga et al. 1996), which ruled out centrally mediated sympatho-inhibition or ganglionic blockade as possible underlying mechanisms, at least for anandamide. Intra-cerebroventricular administration in rabbits of the potent synthetic cannabinoid WIN55,212-2 was found to increase rather than decrease sympathetic tone, which also argues against a central mechanism for the hypotensive effect (Niederhoffer and Szabo 2000). Yet, the pressor response triggered by electrical stimulation of the vasomotor center was reversibly inhibited by anan-damide, whereas the effect of exogenous phenylephrine was unaffected, suggesting a presynaptic-inhibitory effect of norepinephrine release from peripheral sympathetic nerve terminals (Varga et al. 1996). Indeed, stimulation of presynaptic CBi receptors inhibits norepinephrine release both in vitro (Ishac et al. 1996; Deutsch et al. 1997; Schlicker et al. 1997; Christopoulos et al. 2001; Vizi et al. 2001) and in vivo (Malinowska et al. 1997; Niederhoffer and Szabo 2000). However, when sympathetic tone is eliminated by ganglionic blockade and vascular tone is restored by vasopressin infusion, the hypotensive response to the potent synthetic cannabinoid HU-210 remains unchanged, although its bradycardic effect is lost (Wagner et al. 2001b). This suggests that cannabinoid-induced bradycardia may be due to inhibition of sympathetic tone to the heart, but the hypotensive response is due to direct vasodilation, as also indicated by its presence in rats following chemical sympathetic denervation (Vidrio et al. 1996).

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