Cannabinoids and Cardiovascular Effects

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Most of the research on cannabinoids has focused on the CNS, yet there are very well-described effects of synthetic and endogenous cannabinoids in the periphery,

Heart

Reflex f HR

Blood Pressure Ach

Fig. 13. Control of blood pressure by baroreceptor reflexes: A9-tetrahydrocannabinol causes reflex tachycardia through CB1-mediated vasodilatation. ACh, acetylcholine; NE, norepinephrine; BP, blood pressure; TPR, total peripheral resistance; HR, heart rate; CNS, central nervous system.

Blood Vessels

Fig. 13. Control of blood pressure by baroreceptor reflexes: A9-tetrahydrocannabinol causes reflex tachycardia through CB1-mediated vasodilatation. ACh, acetylcholine; NE, norepinephrine; BP, blood pressure; TPR, total peripheral resistance; HR, heart rate; CNS, central nervous system.

particularly at the level of vascular tone, resulting in complex blood pressure and cardiac responses. In humans, the acute administration of cannabinoids causes marked tachycardia and a small increase in blood pressure, whereas in chronic users, hypotension and bradycardia are generally noted (85,86). Blood vessel tone and heart contractility act in concert to regulate blood pressure thanks to what is known as baroreceptor reflexes, which involve the autonomic nervous system. Principles of hemodynamics illustrate how blood pressure is directly proportional to the total peripheral resistance (how constricted blood vessels are) and to the cardiac output (how much blood is forced by the pump in the vasculature, the "plumbing"). Cardiac output is itself controlled by heart rate (how fast the pump is working) and stroke volume (how much blood is ejected at each contraction of the heart).

Total peripheral resistance is the main determinant of blood pressure, and the vasculature is mainly under sympathetic innervation control. Any vasoconstriction (increased resistance) results in increased blood pressure and the firing of receptors situated in the carotid sinuses and the aortic arch. These receptors in turn inform cardiovascular centers of the brainstem (in the rostral ventrolateral medulla and the nucleus of tractus solitarius), which adapt the autonomic balance between sympathetic and parasympathetic outflow to the cardiovascular system in order to restore the blood pressure to lower levels (see Fig. 13). The net effect of increased blood pressure is increased parasympathetic activity to decrease the heart rate and contractility and decreased sympathetic outflow to decrease peripheral resistance of the vasculature.

The effects of cannabinoids could therefore be mediated centrally; CB1 receptors are found in these cardiovascular centers (87), and intravenous injection of CB1 agonists decreases sympathetic outflow centrally (probably through presynaptic inhibition), leading to vasodilatation and hypotension (88). The responses, being absent in CB1 knockout mice, suggest that the hypotension and bradycardia resulting from increased parasympathetic and decreased sympathetic outflows are CB1 mediated (37). These effects observed in animals would explain the chronic findings in humans using Cannabis, but not the marked tachycardia associated with acute use of the drug. The marked tachycardia would require a decreased parasympathetic and increased sympathetic activity, as would occur centrally if inhibition of parasympathetic outflow was occurring or peripherally if a marked vasodilatation was induced by cannabinoids. Interestingly, Glass et al. (31) showed a high density of CB1 receptors in the dorsal motor nucleus of the vagus in the brainstem (parasympathetic centers), and inhibition of this center through CB1 would result in decreased parasympathetic outflow. It could also explain other measured effects of THC in humans besides tachycardia, such as a degree of mydriasis and an antiemetic effect.

To confuse the issue of the cardiovascular effects of cannabinoids further, anandamide is a vasodilator in vitro in selective isolated vessel preparations and not others, pointing at a direct effect on smooth muscle tone of the vasculature (89). Subsequent studies have suggested that anandamide acts through inhibition of calcium release in smooth muscle cells (90). Recently, anandamide has been implicated as a natural ligand of the vanilloid receptor VR1 (91). VR1 receptors are found on sensory nerves, and stimulation results in calcium entry and release by the nerve of a number of transmitters, which could be associated with vasodilatation, such as nitric oxide, substance P, neurokinins, ATP, and calcitonin gene-related peptide. For example, nitric oxide diffuses to the smooth muscle and increases cGMP as a mode of vasodilatation, and calcitonin gene-related peptide binds to G protein-linked receptors, which increase cAMP, another way of causing relaxation of vascular smooth muscle.

It is important to note that at this point in time, no precise molecular action of cannabinoids has been found, and every mechanism proposed has been confirmed and refuted by research. Methodology issues, in vitro versus in vivo effects, and species differences may be explanatory. Most recently, Offertaler et al. (92) suggested the existence of a non-CB1, non-CB2, non-VR1 endothelial anandamide receptor. This receptor would be G protein-coupled and result in MAPK activation. Could the tachycardia from Cannabis use in humans be simply a result of a direct vasodilatory effect resulting in sympathetically mediated baroreceptor reflexes?

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