The in vivo cardiovascular effects of cannabinoids are complex and may involve modulation of the autonomic outflow in both the central and peripheral nervous systems as well as direct effects on the myocardium and vasculature. However, their peripheral actions appear to play the dominant role, at least upon systemic administration at the doses used by most investigators. Moreover, the effects of endocannabinoids are complicated by their rapid metabolism, which may liberate other vasoactive substances and their precursors (reviewed in Mechoulam et al. 1998; Kunos et al. 2002; Randall et al. 2002; Ralevic et al. 2002).
In humans, the acute effect of smoking cannabis usually manifests as an increase in heart rate with no significant change in blood pressure (Kanakis et al. 1976). However, chronic use of cannabis in man, as well as both acute and prolonged administration of THC to experimental animals, elicit a long-lasting decrease in bloodpressureandheartrate (Rosenkratz 1974; Benowitz and Jones 1975). Because of the well-known effects of cannabinoids on central nervous system function, early studies of their cardiovascular actions concentrated on the ability of these compounds to inhibit sympathetic tone as the underlying mechanism. Indeed, cross-perfusion experiments in dogs have provided some evidence for a centrally mediated sympatho-inhibitory effect of THC, although additional peripheral sites of action could not be ruled out (Vollmer et al. 1974). Already at this early stage, the potential use of these compounds as antihypertensive agents was considered (Archer 1974), in the hope that their neurobehavioral and cardiovascular effects would turn out to be separable. That this may be possible to achieve was first suggested by a 1977 publication of the biological effects of abnormal cannabidiol, a synthetic analog of the neurobehaviorally inactive, plant-derived cannabinoid, cannabidiol (Adams et al. 1977). However, more than two decades have elapsed before this promising observation was followed up and extended (see below).
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