Cardiovascular Effects Of Cannabinoids Research Articles

Cardiovascular Effects of Cannabinoids.

Marijuana is now one of the most widely used substances in the United States that has been rising in prevalence given increasing legalization and recreational and medical usage. Despite its widespread use, there have been increasing concerns regarding the cardiovascular safety of marijuana. Recent studies have found a link between marijuana use and the development of cardiovascular disease. Most notably, marijuana has been found to be associated with various cardiac complications, including atherosclerosis, myocardial infarction, stroke, cardiomyopathy, arrhythmia, and arteritis. Given these growing concerns, this article seeks to examine the effects and significance of marijuana on cardiovascular health.

Cannabinoidergic Regulation of the Functional State of the Heart. The Role of the Autonomic Nervous System

Cannabinoids have been shown to induce long-lasting hypotension and bradycardia, which can be preceded by transient tachycardia and hypertension associated with activation of vanilloid TRPV1 receptors. Prolonged hypotension and bradycardia are consequences of the stimulation of cannabinoid CB1 receptors. Endogenous cannabinoids are not involved in regulating heart rate or arterial blood pressure in intact animals. Cannabinoid-induced bradycardia results from the sympatholytic and vagotonic actions of cannabinoids. Prolonged hypotension results from cannabinoid-induced vasorelaxation. Activation of presynaptic CB1 receptors located on sympathetic terminals innervating the heart and arteries leads to inhibition of noradrenaline release from these terminals. Endogenous cannabinoids have cardioprotective effects in coronary occlusion, inhibiting sympathetic influences on the myocardium. Anandamide, which activates TRPV1 receptors, can induce the Bezold–Jarisch reflex. Stimulation of presynaptic CB1 receptors promotes reductions in CGRP (calcitonin gene-related peptide) release from the afferent terminals of the vagus nerve. Stimulation of vanilloid TRPV1 receptors, conversely, induces CGRP release from the sensory fibers of the vagus nerve. The brainstem nuclei may take part in the cardiovascular effects of cannabinoids seen on i.v. administration of CB agonists.

CB1 receptor activation in the rat paraventricular nucleus induces bi-directional cardiovascular effects via modification of glutamatergic and GABAergic neurotransmission

We have shown previously that the cannabinoid receptor agonist CP55940 microinjected into the paraventricular nucleus of the hypothalamus (PVN) of urethane-anaesthetized rats induces depressor and pressor cardiovascular effects in the absence and presence of the CB1 antagonist AM251, respectively. The aim of our study was to examine whether the hypotension and/or hypertension induced by CP55940 given into the PVN results from its influence on glutamatergic and GABAergic neurotransmission. CP55940 was microinjected into the PVN of urethane-anaesthetized rats twice (S1 and S2, 20 min apart). Antagonists of the following receptors, NMDA (MK801), β2-adrenergic (ICI118551), thromboxane A2–TP (SQ29548), angiotensin II–AT1 (losartan) or GABAA (bicuculline), or the NO synthase inhibitor L-NAME were administered intravenously 5 min before S2 alone or together with AM251. The CP55940-induced hypotension was reversed into a pressor response by AM251, bicuculline and L-NAME, but not by the other antagonists. The CP55940-induced pressor effect examined in the presence of AM251 was completely reversed by losartan, reduced by about 50–60 % by MK801, ICI118551 and SQ29548, prevented by bilateral adrenalectomy but not modified by bicuculline and L-NAME. Parallel, but smaller, changes in heart rate accompanied the changes in blood pressure. The bi-directional CB1 receptor-mediated cardiovascular effects of cannabinoids microinjected into the PVN of anaesthetized rats depend on stimulatory glutamatergic and inhibitory GABAergic inputs to the sympathetic tone; the glutamatergic input is related to AT1, TP and β2-adrenergic receptors and catecholamine release from the adrenal medulla whereas the GABAergic input is reinforced by NO.

Cannabinoid activation of peroxisome proliferator‐activated receptors: an update and review of the physiological relevance

AbstractSince 2002, evidence has been building that cannabinoids, including endocannabinoids and endocannabinoid‐like compounds, phytocannabinoids and synthetic cannabinoid ligands, bind to and activate the different isoforms of the nuclear receptors, peroxisome proliferator‐activated receptors (PPARs; α, β, and γ). This has been shown through the use of reporter gene assays, binding studies, the use of antagonists and knockout animals. Increasing use of tools to assess a potential role for PPAR activation in underpinning the physiological effects of cannabinoids means that a picture is emerging of the relevance of PPAR activation by cannabinoids. There is now evidence that activation of PPARα and γ mediate some of the anti‐inflammatory, analgesic, neuroprotective, and cardiovascular effects of cannabinoids, sometimes in combination with activation of the more traditional target sites of action such as CB1, CB2, and TRPV1. There is also a role for PPARα activation by cannabinoids in some of their central effects including memory acquisition, reward processing, food intake and body weight regulation. Activation of PPARγ plays a role in the apoptotic effects of cannabinoids. However, much further work is required to fully establish the profile of cannabinoid compounds at all isoforms of the PPAR family and the relevance of this in normal physiology and pathological situations. WIREs Membr Transp Signal 2013, 2:17–25. doi: 10.1002/wmts.73For further resources related to this article, please visit the WIREs website.Conflict of interest: The author declare no conflict of interest.

Cannabis-associated arteritis

To investigate the hypothesis that cases of arteritis similar to thromboangiitis obliterans (TAO) and associated with the use of cannabis were caused by cannabis or THC (dronabinol), or that cannabis use is a co-factor of TAO. A systematic review on case reports and the literature on so-called cannabis arteritis, TAO, and cardiovascular effects of cannabinoids was conducted. Fifteen reports with 57 cases of an arteritis associated with the use of cannabis and two additional case series of TAO, in which some patients also used cannabis, were identified. Clinical and pathological features of cannabis-associated arteritis do not differ from TAO and the major risk factor of TAO, tobacco use, was present in most, if not in all of these cases. The proposed pathophysiological mechanisms for the development of an arteritis by cannabis use are not substantiated. The hypothesis of cannabis being a causative factor or co-factor of TAO or an arteritis similar to TAO is not supported by the available evidence. The use of the term cannabis arteritis should be avoided until or unless more convincing scientific support is forthcoming.

Acute hypertension reveals depressor and vasodilator effects of cannabinoids in conscious rats

The cardiovascular effects of cannabinoids can be influenced by anaesthesia and can differ in chronic hypertension, but the extent to which they are influenced by acute hypertension in conscious animals has not been determined. We examined cardiovascular responses to intravenous administration of anandamide and the synthetic cannabinoid, (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (WIN55212-2), in conscious male Wistar rats made acutely hypertensive by infusion of angiotensin II (AII) and arginine vasopressin (AVP). Rats were chronically instrumented for measurement of arterial blood pressure and vascular conductances in the renal, mesenteric and hindquarters beds. Anandamide dose-dependently decreased the mean arterial blood pressure of rats made hypertensive by AII-AVP infusion, but not normotensive rats. Interestingly, acute hypertension also revealed a hypotensive response to WIN55212-2, which caused hypertension in normotensive animals. The enhanced depressor effects of the cannabinoids in acute hypertension were associated with increased vasodilatation in hindquarters, renal and mesenteric vascular beds. Treatment with URB597, which inhibits anandamide degradation by fatty acid amide hydrolase, potentiated the depressor and mesenteric vasodilator responses to anandamide. Furthermore, haemodynamic responses to WIN55212-2, but not to anandamide, were attenuated by the CB(1) receptor antagonist, AM251 [N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophen yl)-4-methyl-1H-pyrazole-3-carboxamide]. These results broadly support the literature showing that the cardiovascular effects of cannabinoids can be exaggerated in hypertension, but highlight the involvement of non-CB(1) receptor-mediated mechanisms in the actions of anandamide.

Cardiovascular effects of cannabinoids in conscious spontaneously hypertensive rats.

In anaesthetized spontaneously hypertensive rats (SHR), there is evidence for up-regulation of cannabinoid (CB1) receptors: antagonism of CB1 receptors causes a rise in blood pressure, and administration of the endocannabinoid, anandamide, or inhibition of anandamide degradation causes hypotension. These findings have led to the suggestion that the endocannabinoid system may be a therapeutic target in hypertension. However, since the cardiovascular responses to cannabinoids are substantially influenced by anaesthesia, the purpose of this study was to assess regional haemodynamic responses to cannabinoid receptor stimulation and inhibition in conscious SHR. Cardiovascular responses to i.v. administration of anandamide, the cannabinoid receptor agonist, WIN 55212-2, and the CB(1) receptor antagonist, AM 251, were measured in male SHR, Wistar Kyoto rats and outbred Wistar rats, chronically instrumented for recording renal, mesenteric and hindquarters haemodynamics in the conscious, freely-moving state. Hypotensive responses to anandamide and WIN 55212-2 only occurred in SHR, but these were relatively modest and not associated with CB1 receptor-mediated vasodilatation. In SHR only, anandamide caused bradycardia, which was inhibited by AM 251. Furthermore, a pressor response to CB1 receptor antagonism occurred only in SHR, but was not associated with vasoconstriction. Moreover, there was some evidence for CB1 receptor-mediated vasoconstrictor actions of anandamide in SHR, which was not seen in the normotensive strains. The results are consistent with activation of CB1 receptors in SHR by endogenous ligands exerting an antihypertensive effect, but the findings do not indicate enhanced CB1 receptor-mediated vasodilator mechanisms in SHR.