The recreational use of the plant Cannabis sativa and the attempt to exploit their potential therapeutic use have been described over the centuries. The popularity of marijuana, one of the most common forms of consumption as a recreational substance and as a drug, reflects its ability to later sensory perceptions and to reduce anxiety. Other non-psychoactive actions of marijuana, like pain relief, were also described in ancient texts. However, the biochemical and pharmacological study of this substance has a fairly recent start. The first attempts to isolate the cannabinoids (phytocannabinoids) of Cannabis sativa, conducted in mid-twentieth century, led to very rudimentary pharmacological investigations. In the sixties, the chemical structures of Δ-9-tetrahydrocannabinol (Δ 9-THC) and cannabidiol were described, their procedures for synthesis were found and THC was identified as the major phytocannabinoid among the 60 existing phytocannabinoids in Cannabis sativa.
Although the THC, cannabidiol and other phytocannabinoids present bioactivity with potential use (anti-inflammatory, anti-convulsive and antiemetic, for example), THC is the only psychotropic cannabinoid present in Cannabis sativa
. Because of its psychoactivity and early availability in synthetic form as a research tool, THC quickly gained the status of cannabinoid prototype and became the target of numerous studies during the 70's and the 80's. Much of this research, in vivo, focused on the effects of THC in animal models using synthetic analogues, some of which radiolabeled as molecular probes for the interactions of the cannabinoids with the tissues. Given the psychotropic effects of THC, many biological investigations used brain and its plasma membranes, in order to describe the action of cannabinoids.[1
Their connection with the plasma membranes of the brain is greedy, saturable and stereospecific, according to the responses in vivo
and in vitro
. These characteristics suggested that cannabinoid pharmacology could be mediated by receptors, which led to the research of THC binding sites in mammalian, to justify their psychotropic effects. These studies were the basis for the discovery and cloning of two G protein-coupled receptors (GPCR) for cannabinoids, called CB1 and CB2, which in humans share about 44% of homologous sequence.[5
] The CB1 receptor has its preferential location in the central nervous system (CNS), reflecting his prevalence as the most abundant GPCR in the brain. CB1 receptors can be found in cortex, cerebellum, hippocampus and basal ganglia, which are brain regions that control motor functions and cognitive, emotional and sensory actions. Thus, activation of central CB1 receptors is responsible for most of the behavioral and psychotropic effects of cannabinoids.[6
] These receptors are also present in high density in the brainstem, hypothalamus and pituitary gland, affecting the perception of pain, hormonal activity, thermoregulation and cardiovascular, gastrointestinal and respiratory physiology.[6
] CB1 receptors are also located peripherally (eg. adipocytes, liver, uterus) where are able to regulate basic physiological processes, such as energy balance and reproduction.[6
] Although they are detectable in trace concentrations in brain, CB2 receptors are expressed mainly in immune cells and hematopoietic cells, osteoblasts and osteoclasts, mediating immune responses, inflammation, neuropathic pain and bone remodeling.[5
Endocannabinoids (EC) are involved in several physiological functions, among which, special attention has been given to the regulation of appetite by central mechanisms and its influence on obesity.[7
] Considering these innovative findings, the research for new pharmacological agents has drastically increased and the discovery of rimonabant, a synthetic antagonist of CB1 receptors, has confirmed the important role of endocannabinoid system on the modulation of food ingestion and energetic balance.[9
] These facts led to the first clinical studies using rimonabant as a new tool against obesity and its associated metabolic disorders. However, psychiatricside-effects, namely central, which include increased risk of depression and even suicide, US Food and Drug Administration declined permission for rimonabant, and in October 2008, rimonabant was also suspended across the EU. After rimonabant withdrawal, other CB1 antagonist drugs have also tested, including the taranabant, which was associated with weight loss in rats and in humans.[10
] However, due also to central side effects, including anxiety and depression, the clinical trials were stopped in October 2008 (EMEA. The European Medicines Agency recommends suspension of the marketing authorisation of Acomplia: http://www.emea.europa.eu 2008
Although several other different influences of endocannabinoids have been discussed during the last years, including in inflammation, diabetes, cancer, affective and neurodegenerative diseases, and epilepsy.[12
] the most recent findings are related to their cardiovascular actions,[13
] which seem to be very ample bust also complex. The endocannabinoid system (ECS), which includes the endocannabinoids and its receptors, have been implicated in hypotensive stages associated with hemorrhagic chock, both endotoxic and cardiogenic, and even to advanced liver cirrhosis; on the other hand, recent evidence suggests that ECS plays an important role in cardiovascular regulation associated with hypertension, as well as a protective role in ischemia grafting. The development of atherosclerotic plaque and the metabolic stages associated to obesity are also matter of study of possible ECS pharmacomodulation.
This article reviews the effects of endocannabinoids on the cardiovascular system, focusing on their role on cardiovascular pathophysiology and on new therapeutic opportunities in this field.