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Acute administration of cannabidiol in vivo suppresses ischaemia-induced cardiac arrhythmias and reduces infarct size when given at reperfusion

Cannabidiol (CBD) is a phytocannabinoid, with anti-apoptotic, anti-inflammatory and antioxidant effects and has recently been shown to exert a tissue sparing effect during chronic myocardial ischaemia and reperfusion (I/R). However, it is not known whether CBD is cardioprotective in the acute phase of I/R injury and the present studies tested this hypothesis.

Experimental approach:

Male Sprague-Dawley rats received either vehicle or CBD (10 or 50 µg·kg −1 i.v.) 10 min before 30 min coronary artery occlusion or CBD (50 µg·kg −1 i.v.) 10 min before reperfusion (2 h). The appearance of ventricular arrhythmias during the ischaemic and immediate post-reperfusion periods were recorded and the hearts excised for infarct size determination and assessment of mast cell degranulation. Arterial blood was withdrawn at the end of the reperfusion period to assess platelet aggregation in response to collagen.

Key results:

CBD reduced both the total number of ischaemia-induced arrhythmias and infarct size when administered prior to ischaemia, an effect that was dose-dependent. Infarct size was also reduced when CBD was given prior to reperfusion. CBD (50 µg·kg −1 i.v.) given prior to ischaemia, but not at reperfusion, attenuated collagen-induced platelet aggregation compared with control, but had no effect on ischaemia-induced mast cell degranulation.

Conclusions and implications:

This study demonstrates that CBD is cardioprotective in the acute phase of I/R by both reducing ventricular arrhythmias and attenuating infarct size. The anti-arrhythmic effect, but not the tissue sparing effect, may be mediated through an inhibitory effect on platelet activation.

Introduction

Cannabinoids are a group of pharmacologically active agents, which consist of phytocannabinoids (plant-derived), endocannabinoids (endogenous) and synthetic cannabinoids. In relation to the phytocannabinoids, the parent plant Cannabis sativa consists of over 70 active compounds, the two most abundant being the psychoactive (-)-Δ 9 -tetrahydrocannabinol (Δ 9 -THC) and the non-psychoactive (-)-cannabidiol (CBD). In contrast to Δ 9 -THC, CBD appears to act as an atypical cannabinoid at receptors typically activated by cannabinoids (reviewed by Pertwee, 2008). At low concentrations CBD has been shown to act as an inverse agonist at cannabinoid receptor 1 (CB1), cannabinoid receptor 2 (CB2) and possibly non CB1/CB2 receptors (Thomas et al., 2007), as an agonist at the transient receptor potential vanilloid type 1 (TRPV1; Bisogno et al., 2001) and 5-hydroxytryptamine1A (5-HT1A; Russo et al., 2005) receptors, and as an antagonist at the orphan receptor, G-protein-coupled receptor 55 (GPR55; Ryberg et al., 2007).

Although the precise pharmacological effects of CBD have yet to be fully elucidated, recent studies have demonstrated that it mediates a plethora of actions, including anti-inflammatory, antioxidant and anti-necrotic effects (reviewed by Mechoulam et al., 2007), all of which could confer tissue protective properties. For example CBD exerts an immunosuppressive effect by decreasing tumour necrosis factor-α through enhanced endogenous adenosine signalling (Malfait et al., 2000) and prevents hydrogen peroxide (H2O2)-induced oxidative damage (Hampson et al., 1998). Moreover, CBD has been shown to inhibit mast cell uptake of anandamide (Rakhshan et al., 2000), which could explain observations that preservation of endocannabinoid levels ameliorates immunological-induced activation of mast cells (Vannacci et al., 2004), and suggests an additional anti-inflammatory role for CBD.

All of these anti-inflammatory actions of CBD would be predictive of a protective role in pathological events involving inflammation, such as ischaemia/reperfusion (I/R) injury. Indeed, a protective role for CBD, through a 5-HT1A receptor-dependent mechanism, in the setting of cerebral I/R injury has recently been demonstrated (Mishima et al., 2005). More recently, Durst et al. (2007) demonstrated that chronic administration of CBD significantly reduced myocardial infarct size measured several days following I/R and that this effect correlated with a pronounced anti-inflammatory effect, as evidenced by a reduced infiltration of inflammatory cells into the myocardium and serum levels of interleukin-6. Interestingly, this protection was not replicated in an ex vivo model of myocardial I/R, leading to the conclusion that the tissue sparing effects were not due to a direct action on the myocardium, but rather to prevention of a systemic inflammatory response. What is not known, however, is whether CBD exerts actions that influence events that occur in the early stages of myocardial ischaemia (such as the development of serious ventricular arrhythmias) and reperfusion (such as immediate tissue injury as opposed to delayed tissue injury).

Reports of the ability of CBD to interfere with some of the processes that play a central role in the early pathological events during I/R, such as platelet activation (Formukong et al., 1989) and ion channel opening (Mamas and Terrar, 1998) led us to predict that CBD may have wider cardioprotective potential than simply preventing the inflammatory response. The primary aim of this study was therefore to determine the effects of a single acute dose of CBD, both immediately prior to ischaemia onset and at the time of reperfusion, on cardiac arrhythmias and infarct size in a rat model of I/R. Because platelet activation (Flores et al., 1994) and mast cell degranulation (Walsh et al., 2009a,b;) are two major contributors to arrhythmogenesis, and there have been reports of CBD affecting both these processes, the second aim was to explore whether or not any cardioprotective effects were accompanied by effects on platelet function and I/R-induced mast cell degranulation.

Methods

Coronary occlusion studies

Male Sprague-Dawley rats (300–400 g), were bred and housed in the University of Aberdeen Medical Research Facility. Animals were maintained at a temperature of 21 ± 2°C, with a 12 h light/dark cycle and with free access to food and tap water. Animals were obtained on a daily basis and allowed to acclimatize before commencing the study. All studies were performed under an appropriate Project License authorized under the UK Animals (Scientific Procedures) Act 1986.

Surgery

Animals were anaesthetized with pentobarbitone sodium salt (60 mg·kg −1 i.p; Sigma Aldrich, Poole, Dorset, UK) and the trachea cannulated to allow artificial respiration when required. The left carotid artery and the right jugular vein were cannulated with Portex polythene tubing (0.58 mm ID × 0.96 mm OD; Smiths Medical International Ltd., Hyde, Kent, UK). Arterial blood pressure was recorded via the left carotid artery using a pressure transducer (MLT844 Physiological Pressure Transducer; AD Instruments, Chalgrove, Oxfordshire, UK). A steel thermistor probe (Fisher Scientific Ltd., Loughborough, Leicestershire, UK) was inserted into the rectum to measure core temperature, which was maintained at 37–38°C with the aid of a Vetcare heated pad (Harvard Apparatus Ltd., Edenbridge, Kent, UK). The animal was then prepared for in vivo occlusion of the left anterior descending coronary artery (Clark et al., 1980) through a left thoracotomy, with rats ventilated on room air (54 strokes·min −1 ; tidal volume, 1.5 mL per 100 g to maintain PCO2 at 18–24 mmHg, PO2 at 100–130 mmHg, and pH at 7.4; Harvard small animal respiration pump; Harvard Apparatus Ltd.). Anaesthesia was maintained throughout by administration of pentobarbitone sodium salt (3–4 mg·kg −1 ) via the venous cannula every 30 min or as required. After placement of the ligature rats were allowed to stabilize for 15 min before drug/vehicle administration and subsequent coronary occlusion. The coronary artery was occluded (CAO) by tightening the ligature to induce regional ischaemia for 30 min, after which the ligature was loosened and the myocardium reperfused for 2 h. A standard limb lead I electrocardiogram (ECG) and mean arterial blood pressure (MABP) were monitored continuously throughout the experimental period using a Power Laboratory (AD Instruments) data acquisition system via a Bridge Amplifier (AD Instruments) and Animal Bio Amplifier (AD Instruments), respectively, and data subsequently analysed using Chart Software (AD Instruments). Any animals that had a starting MABP of

Ex vivo platelet aggregation studies

Following completion of the I/R protocol, blood was withdrawn via the arterial cannula into a tube containing heparin (final blood concentration of 20 U·mL −1 ). Platelet aggregation in response to collagen was then determined using whole blood impedance aggregometry (Chrono-log Aggregometer, Chrono-log Corporation, Havertown, PA, USA); 0.5 mL of whole blood was placed in a cuvette with 0.5 mL of saline (0.9% NaCl) at 37°C and stirred with a magnetic stir bar. Platelet aggregation (expressed in Ω) in response to 5 µg·mL −1 collagen was measured over a period of 10 min and data calculated using Aggrolink® software (Chrono-log Corporation).

Histological measurement of infarct size

Following blood withdrawal the rats were killed by an i.v. overdose of sodium pentobarbitone. The heart was then removed, the aorta cannulated and then gently perfused with saline (2 mL) to flush out residual blood. The ligature was then retied and Evans blue dye (2 mL; 0.5% w/v) perfused through the heart to delineate area at risk. Hearts were then removed and stored at −20°C prior to determination of infarct size. Frozen hearts were sliced into 2–3 mm slices from the apex to the base and allowed to defrost at room temperature. Myocardial tissue slices were then incubated in 1% triphenyltetrazonium chloride (Sigma Aldrich) in phosphate buffered saline for 15 min at 37°C to determine infarct size. Sections were then fixed in 10% buffered formal saline overnight and photographed using a SANYO VPC-E6U digital camera (SANYO Electric Co., Ltd., Osaka, Japan). Left ventricular area, area at risk, and infarct size were determined using computerized planimetry [ImageJ software, National Institute of Health (NIH), Rockville Pike, Bethesda, MD, USA]. Area at risk was expressed as a percentage of total left ventricular area, and infarct size was expressed as a percentage of area at risk.

Histological assessment of cardiac mast cell degranulation

Following infarct size measurement, myocardial tissue slices were embedded in paraffin wax (Thermo Scientific, Runcorn, Cheshire, UK) and 3 µm sections cut. Sections were dehydrated through a series of histosolve (Thermo Scientific) and graded alcohols and incubated in 0.1% w/v toluidine blue (Fisher Scientific Ltd.) at 37°C. After being stained, sections were mounted with a xylene substitute mountant (Thermo Scientific) and covered with a cover slip. Analysis of the tissue was carried out with the use of a Leica DMLB light microscope (Leica Microsystems, Milton Keynes, Bucks, UK) at a magnification of ×400. Mast cells were counted manually and the count encompassed the entire area of the tissue. Mast cell degranulation was determined as a loss of mast cell membrane integrity with extrusion of intracellular granules to the extracellular space or mast cells completely lacking in intracellular granules as described previously (Messina et al., 2000).

Experimental protocols

Four experimental groups were used to investigate the effects of CBD administration on the incidence of ischaemia- and reperfusion-induced arrhythmias, infarct size and platelet aggregation. In the control group, animals were given a bolus i.v. injection of vehicle (n = 19), via the right jugular vein, 10 min prior to CAO and a second bolus injection of vehicle 10 min prior to reperfusion. Preliminary studies in a small group of rats to determine doses of CBD to use in the I/R studies demonstrated that 50 µg·kg −1 induced a small but significant depressor effect, while a lower dose of 10 µg·kg −1 had no effect on MABP. We therefore selected these doses to determine whether a dose sufficient to induce a vascular response was required for any cardioprotective effect to be observed. Therefore, in the pre-ischaemia CBD-treated (CBD-PI) groups, animals were given a bolus i.v. dose of either 10 µg·kg −1 (n = 5) or 50 µg·kg −1 (n = 10), 10 min prior to CAO and an additional bolus injection of vehicle 10 min prior to reperfusion. In the pre-reperfusion CBD-treated group (CBD-PR; n = 7), animals were given a bolus i.v. dose of vehicle, 10 min prior to CAO and an additional bolus injection of CBD (50 µg·kg −1 ), 10 min prior to reperfusion. Because ischaemia itself induces both mast cell degranulation and platelet activation, we undertook a replicate series of experiments for the control and CBD (50 µg·kg −1 ) pre-ischaemic treated protocols in sham-operated time controls (in which the ligature was placed around the left coronary artery but not tightened) to examine the direct effects of vehicle (n = 6) and CBD (50 µg·kg −1 ; n = 9) on cardiac mast cell degranulation and collagen-induced platelet aggregation ex vivo.

Studies to investigate the pharmacological mechanism of CBD

In a separate group of rats we aimed to elucidate the type of receptors CBD acts on in the anaesthetized rat. Animals were anaesthetized and cannulated as previously described. MABP was measured via the carotid cannula and heart rate (HR) was calculated from the ECG. After surgery, rats were allowed to stabilize for 15 min before drug/vehicle administration. Post stabilization, animals were administered a bolus dose of vehicle followed subsequently (at regular intervals) by increasing doses of the proposed GPR55 agonist, O-1602 (5–100 ng·kg −1 ; n = 3–8), firstly in the absence then presence of CBD (50 µg·kg −1 ). To investigate the role of CBD at the CB1 receptor, the haemodynamic effects of the CB1 agonist, arachidonyl-2¢-chloroethylamide (ACEA; 3 mg·kg −1 ; n = 4), were investigated in the absence and then presence of CBD (50 µg·kg −1 ). To compare the effects of CBD on the ACEA-mediated vascular response with a known fatty acid amide hydrolase (FAAH) inhibitor, URB597 (1 mg·kg −1 ; n = 4) was administered to rats prior to the administration of a bolus dose of ACEA (3 mg·kg −1 ), as ACEA is thought to be susceptible to hydrolysis by FAAH.

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In vitro platelet aggregation studies

To further investigate the anti-platelet effects of CBD an additional group of rats (n = 9) was killed by an overdose of pentobarbitone and blood collected via cardiac puncture into a tube containing heparin (final blood concentration of 20 U·mL −1 ). Platelet aggregation was then determined by pre-incubating the blood with either vehicle or CBD (0.1–1000 µM) for 10 min prior to assessing platelet aggregation in response to collagen (5 µg·mL −1 ).

Statistical analyses

For the haemodynamic data (expressed as mean ± SEM) Student’s two-tailed t-test was used to compare pre-injection and post-injection MABP/HR values. One-way analysis of variance ( anova ) and Dunnett’s post hoc test was used to compare pre-occlusion and post-occlusion MABP/HR values. Post-occlusion MABP/HR comparisons between the control and CBD-treated groups were made using a two-way anova and Bonferroni post hoc test. Ventricular and reperfusion arrhythmias were determined from the ECG trace and classified according to the Lambeth Conventions (Walker et al., 1988). The effect of CBD on the number of ventricular ectopic beats [VEBs; reported as singles, salvos, ventricular tachycardia (VT) and total VEB count and values expressed as mean ± SEM] was analysed using a one-way anova and Dunnett’s post hoc test. The effect of CBD on the incidence of VT, reversible and irreversible ventricular fibrillation (VF) and on mortality were analysed using Fisher’s exact test. The effect of CBD treatment on both PR and QT intervals at various time points was investigated using a two-way anova and Bonferroni post hoc test. The effects of CBD on infarct size, ex vivo and in vitro platelet aggregation, mast cell degranulation, and the effects of both CBD and URB597 on ACEA-induced vascular responses were analysed using Student’s t-test or a one-way anova and Dunnett’s post hoc test, where appropriate.

Results

Effects of CBD on haemodynamic variables

Table 1

Summary of MABP and HR in rats given saline or CBD either prior to (time −10 min) ischaemia (performed at time 0 min), or prior to reperfusion (at +30 min)

Time (min) Vehicle CBD-PI (10 µg·kg −1 ) CBD-PI (50 µg·kg −1 ) CBD-PR (50 µg·kg −1 )
MABP (mmHg)
−25 132 ± 3 119 ± 12 133 ± 4 127 ± 3
−10 132 ± 3 115 ± 8 a 134 ± 4 a 128 ± 2
−5 131 ± 3 113 ± 9 118 ± 5 † 127 ± 3
128 ± 3 110 ± 10 132 ± 2 129 ± 3
1 87 ± 5 *** 79 ± 7 *** 90 ± 5 *** 97 ± 5 ***
3 94 ± 6 *** 89 ± 7 ** 97 ± 5 *** 108 ± 5 **
20 105 ± 4 ** 80 ± 5 *** 112 ± 4 ** 112 ± 4 * b
25 107 ± 4 ** 86 ± 8 ** 111 ± 3 ** 110 ± 3 *
30 106 ± 4 ** 80 ± 9 *** 108 ± 3 ** 106 ± 2 *
31 103 ± 4 89 ± 11 109 ± 8 86 ± 8 ††
35 109 ± 4 95 ± 12 116 ± 6 97 ± 5
60 110 ± 5 92 ± 13 118 ± 3 101 ± 5
150 98 ± 3 99 ± 7 112 ± 3 108 ± 4
HR (BPM)
−25 438 ± 10 387 ± 35 404 ± 21 426 ± 13
−10 429 ± 8 412 ± 33 a 392 ± 20 a 429 ± 12
−5 431 ± 8 460 ± 35 396 ± 23 428 ± 15
429 ± 8 413 ± 48 401 ± 24 426 ± 15
1 429 ± 7 482 ± 26 406 ± 20 429 ± 13
3 425 ± 9 490 ± 48 404 ± 21 431 ± 13
20 401 ± 12 397 ± 52 383 ± 20 409 ± 15 b
25 394 ± 9 430 ± 38 386 ± 20 418 ± 12
30 394 ± 9 445 ± 35 387 ± 22 411 ± 15
31 384 ± 9 464 ± 26 393 ± 22 418 ± 13
35 386 ± 9 476 ± 26 382 ± 27 406 ± 16
60 380 ± 10 420 ± 17 380 ± 23 414 ± 14
150 380 ± 11 426 ± 27 389 ± 18 416 ± 13

CBD, (-)-cannabidiol; CBD-PI, pre-ischaemia CBD-treated group; CBD-PR, pre-reperfusion CBD-treated group; HR, heart rate; MABP, mean arterial blood pressure.

Effect of CBD on I/R-induced ventricular arrhythmias

Effect of pre-ischaemic administration of CBD on (A) ischaemia-induced arrhythmias and (B) the incidence of VF. The incidence of each type of arrhythmia was recorded and the data expressed as mean ± SEM (n = 4–14). *P < 0.05, **P < 0.01 versus vehicle. The incidence of each type of VF was recorded and the data expressed as the mean (n = 5–19). CBD, (-)-cannabidiol; VEB, ventricular ectopic beat; VF, ventricular fibrillation; VT, ventricular tachycardia.

Effect of CBD administration on (A) PR and (B) QT intervals. Both PR and QT intervals were measured from the ECG in milliseconds (ms) and the data expressed as mean ± SEM (n = 7–8). ***P < 0.001 versus pre-ischaemic values. CBD, (-)-cannabidiol; CBD-PI, pre-ischaemia CBD-treated group; CBD-PR, pre-reperfusion CBD-treated group.

Effect of CBD on infarct size

Figure 3 illustrates the effects of the higher dose of CBD (50 µg·kg −1 ) on both area at risk (percentage of left ventricular area) and infarct size (percentage of area at risk). Area at risk was similar across all groups. Administration of CBD (50 µg·kg −1 ) prior to coronary occlusion significantly reduced infarct size, as did its administration immediately prior to reperfusion, when compared with vehicle-treated control rats (both P < 0.001; Figure 3 ).

Effect of CBD administered both prior to ischaemia and prior to reperfusion, on area at risk and infarct size. Area at risk was measured as a percentage of total left ventricular area and infarct size was measured as a percentage of area at risk. Both sets of data are expressed as the mean ± SEM (n = 7–8). ***P < 0.001 versus vehicle. CBD, (-)-cannabidiol; CBD-PI, pre-ischaemia CBD-treated group; CBD-PR, pre-reperfusion CBD-treated group.

Effect of CBD on platelet aggregation

In time-matched sham-operated rats CBD (50 µg·kg −1 ) significantly reduced collagen-induced platelet aggregation ex vivo compared with vehicle-treated sham-operated rats (P < 0.05; Figure 4A ). Administration of CBD (50 µg·kg −1 ) prior to ischaemia similarly attenuated collagen-induced platelet aggregation measured ex vivo (P < 0.05; Figure 4A ). Interestingly, when CBD (50 µg·kg −1 ) was administered immediately prior to reperfusion it did not significantly affect platelet aggregation when compared with the control. In a series of experiments to investigate the in vitro effects of CBD on agonist-induced platelet aggregation only the highest concentration of CBD investigated (1 mM) significantly attenuated collagen-induced platelet aggregation compared with the vehicle (P < 0.05; Figure 4B ).

Effect of CBD (50 µg·kg −1 ) treatment on (A) ex vivo and (B) in vitro platelet aggregation in response to collagen (5 µg·mL −1 ). Platelet aggregation was expressed in terms of ohms (Ω) and expressed as the mean ± SEM (n = 6–9). *P < 0.05 versus vehicle; †P < 0.05 versus I/R. CBD, (-)-cannabidiol; CBD-PI, pre-ischaemia CBD-treated group; CBD-PR, pre-reperfusion CBD-treated group; I/R, ischaemia/reperfusion.

Effect of CBD on I/R-induced cardiac mast cell degranulation

Figure 5 summarizes the effects of CBD on cardiac mast cell degranulation. In vehicle-treated sham-operated animals, approximately 44% of cardiac mast cells were degranulated and similar numbers were found in sham-operated rats given CBD (50 µg·kg −1 ). Myocardial I/R induced significant (P < 0.001) mast cell degranulation in vehicle-treated control rats, when compared with the vehicle sham-operated group; and administration of CBD (50 µg·kg −1 ) either prior to or post CAO did not alter the extent of mast cell degranulation induced by I/R alone.

Effects of CBD (50 µg·kg −1 ) and I/R on the percentage of mast cells degranulated in the rat myocardium. Mast cell degranulation was measured as the percentage of the total number of mast cells present that had undergone degranulation and is expressed as the mean ± SEM (n = 6–9). The percentage incidence of mast cell degranulation was determined at a magnification of ×400 and encompassed an entire cross-section of ventricular tissue. Both sham-operated and I/R animals were treated with a bolus dose of either vehicle or CBD. The effect of I/R alone on mast cell degranulation was determined via a comparison of vehicle-treated I/R animals with vehicle-treated sham-operated animals. ***P < 0.001 versus vehicle sham-operated. CBD, (-)-cannabidiol; CBD-PI, pre-ischaemia CBD-treated group; CBD-PR, pre-reperfusion CBD-treated group; I/R, ischaemia/reperfusion.

Receptor-mediated effects of CBD

The haemodynamic effects of a range of doses (5–100 ng·kg −1 ) of O-1602 (GPR55 agonist) were examined; however, no reproducible measurable depressor response was obtained over the dose range tested (data not shown). Administration of the CB1 receptor agonist, ACEA (3 mg·kg −1 ), induced a depressor response that was unaffected by pretreatment with CBD (50 µg·kg −1 ; Figure 6 ), a proposed CB1 antagonist. Furthermore, a similar ACEA-induced depressor response, to that observed in the presence of CBD, was demonstrated when ACEA was administered in the presence of the selective FAAH inhibitor, URB597 (1 mg·kg −1 ; Figure 6 ).

Receptor-mediated effects of (-)-cannabidiol (CBD). The role of CBD as either a CB1 antagonist or potential fatty acid amide hydrolase (FAAH) inhibitor was investigated by comparing the effects of CBD (50 µg·kg −1 ) and the selective FAAH inhibitor, URB597 (1 mg·kg −1 ), on arachidonyl-2¢-chloroethylamide (ACEA) (3 mg·kg −1 )-mediated vascular responses. Agonist-induced changes in mean arterial blood pressure (MABP) were recorded and expressed as a percentage change in MABP (%Δ; n = 4 for each treatment).

Discussion

Previous studies have demonstrated that prolonged administration of CBD exerts neuroprotective and cardioprotective effects that involve anti-inflammatory, antioxidant and anti-necrotic actions of the compounds (reviewed by Mechoulam et al., 2007). The present study is the first to demonstrate that in the setting of myocardial I/R CBD can provide acute cardioprotection, in that it both suppresses ischaemia-induced ventricular arrhythmias and attenuates infarct size when given immediately prior to ischaemia onset. Moreover, and potentially more clinically relevant, CBD also reduces infarct size when given at the time of reperfusion. These findings imply that the anti-arrhythmic and cytoprotective effects of CBD are achieved through different mechanisms.

Anti-arrhythmic effects of CBD

There are several explanations for the mechanisms underlying the anti-arrhythmic effect of CBD, one of which could be a direct electrophysiological effect. CBD has been reported to inhibit the slow component of the delayed rectifying potassium channel (IKs) in ventricular myocytes (Mamas and Terrar, 1998). IKs blockers prolong cardiac action potential duration and QT interval and suppress electrically induced arrhythmias in the presence of myocardial ischaemia (Tamargo et al., 2004). However ECG analysis revealed that CBD did not prolong QT interval before ischaemia, nor did it further enhance the ischaemia-induced QT prolongation, suggesting that this is an unlikely explanation for CBD’s anti-arrhythmic effects.

The finding that CBD inhibits collagen-induced platelet aggregation ex vivo suggests an alternative mechanism for its anti-arrhythmic effect, as numerous studies have shown that anti-platelet agents are anti-arrhythmic by virtue of their ability to prevent release of arrhythmogenic substances such as thromboxane A2 and 5-hydroxytryptamine (Wainwright et al., 1988; Barnes and Coker, 1995). What is interesting, however, is that CBD only inhibited platelet aggregation ex vivo when given to sham-operated animals or prior to ischaemia, but not when given prior to reperfusion. While this finding supports the notion that an effect on platelets may be responsible for its anti-arrhythmic effect during ischaemia but not following reperfusion, it cannot explain the ability of CBD to preserve tissue from cell death. Moreover, what this observation may also suggest is that, the mechanism by which CBD inhibits collagen-induced platelet aggregation when administered under physiological conditions (i.e. in sham-operated and pre-ischaemia) is somehow absent or abrogated under ischaemic conditions (i.e. administered prior to reperfusion). In addition, as data from the in vitro studies demonstrated that CBD (in micromolar concentrations) did not affect platelet aggregation, this may further support the idea that CBD only modulates platelet aggregation through interference with an endogenous system and not directly.

While there is no immediate explanation for this, recent studies have demonstrated that platelets express both CB1 and CB2 receptors (Deusch et al., 2004) and that the endocannabinoids anandamide (Maccarrone et al., 1999) and 2-arachidonoylglycerol (2-AG; Baldassarri et al., 2008) both induce platelet activation/aggregation, although whether or not through CB1 and/or CB2 receptor activation remains controversial. Studies have demonstrated that levels of 2-AG are increased in the ischaemically preconditioned heart (Wagner et al., 2006), thus ischaemia-induced elevated levels of 2-AG may contribute to platelet activation by abrogating the anti-platelet effects of CBD via competition for the same receptors. However, further studies to investigate the various effects of endocannabinoids within the ischaemic myocardium are clearly required.

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A third explanation for the anti-arrhythmic effect of CBD is through an action on mast cells, as previous studies have demonstrated that CBD induces mucosal mast cell degranulation (Giudice et al., 2007). Treatment with mast cell degranulating agents prior to ischaemia has been shown to elicit a profound anti-arrhythmic effect via the depletion of mast cell-derived cytotoxic compounds (Parikh and Singh, 1997; Walsh et al., 2009a). However, in the present study it was demonstrated that CBD does not induce cardiac mast cell degranulation, as shown by the lack of effect in hearts from rats subjected to sham treatment. Moreover, CBD did not prevent ischaemia-induced mast cell degranulation, a strategy that has also been demonstrated to be cardioprotective (Humphreys et al., 1998; Walsh et al., 2009b). Taken together this evidence does not support the involvement of a cardiac mast cell-dependent pathway in the anti-arrhythmic effects of CBD.

Although we did not investigate this in the current study, CBD may also mediate its anti-arrhythmic effects through modulation of one or more endogenous cardioprotective agents that have demonstrated anti-arrhythmic effects, including anandamide (Ugdyzhekova et al., 2001; Krylatov et al., 2002; Hajrasouliha et al., 2008). In a previous study, CBD (10–20 µM) was shown to inhibit both the anandamide membrane transporter (thus preventing cellular uptake) and FAAH (thus preventing hydrolysis of anandamide) (Bisogno et al., 2001), both of which would elevate endogenous anandamide levels. In the present study, we attempted to determine whether or not CBD behaved in a similar way to the selective FAAH inhibitor, URB597, by assessing their ability to enhance the vascular response to ACEA, which has been shown to be susceptible to FAAH hydrolysis. However, neither URB597 nor CBD augmented the response to ACEA, therefore the question as to whether or not CBD is acting via inhibition of endocannabinoid breakdown remains to be answered. Moreover, whether or not the estimated low plasma concentration of CBD (∼2 µM) achieved in the myocardial I/R study was sufficient to increase endogenous anandamide levels also remains to be determined.

Infarct sparing effect of CBD

In relation to the infarct sparing effect, CBD has previously been shown to protect against both cerebral (Mishima et al., 2005; Hayakawa et al., 2007) and myocardial I/R injury (Durst et al., 2007) and evidence points to this being achieved through a direct anti-inflammatory effect (Weiss et al., 2008) mediated by CB2 receptors (Hajrasouliha et al., 2008). Our data agree with the findings of Durst et al. (2007) in that CBD significantly reduces tissue injury; however, our study significantly extends their observations in two ways. First, the study by Durst’s group involved both prolonged (7 day) CBD administration and a much later time point for assessment of tissue injury (i.e. at a time when the key pathological events are inflammation and scar formation), whereas we have assessed tissue injury at a time when immediate lethal injury has occurred (within 2 h of reperfusion) but delayed injury has not yet begun. Thus our data show that CBD can undoubtedly reduce the initial injury that is associated with rapid events such as oxidative stress and activation of death signalling pathways (Logue et al., 2005). Second, we have also shown that CBD can do this when given just before restoration of blood flow, implying a potentially valuable clinical application in patients undergoing clinical reperfusion.

Quite how CBD exerts cardioprotection against immediate lethal injury has yet to be fully explored. One suggestion is that CBD may act as a peroxisome proliferator-activated receptor gamma agonist (O’Sullivan et al., 2009), activation of that has previously been shown to reduce infarct size in a murine model of myocardial I/R via a profound anti-inflammatory effect (Honda et al., 2008). In addition, CBD may confer tissue protection by acting as a CB1 receptor antagonist resulting in preferential activation of CB2 receptors by endocannabinoids, as the bulk of evidence points to endocannabinoids reducing infarct size via activation of CB2 rather than CB1 receptors (Hajrasouliha et al., 2008; Lim et al., 2009). This is in contrast to the effects of synthetic CB1 or CB2 receptor agonists, neither of which reduce infarct size (Underdown et al., 2005), suggesting that endocannabinoid-induced protection may be mediated by receptors other than the typical CB1/CB2 receptors. In support of the latter, our own study demonstrated that CBD does not prevent ACEA-induced hypotension, suggesting that under the present conditions, CBD (at a dose of 50 µg·kg −1 ) does not act as a CB1 receptor antagonist. It could act as an antagonist at the orphan receptor GPR55, which has been proposed as a third cannabinoid receptor (Ryberg et al., 2007), through inhibition of a detrimental effect of anandamide action at this receptor. However, data from the present study suggest that GPR55 receptors are not present on the rat vasculature (due to a lack of observed haemodynamic effects of the GPR55 agonist, O-1602), although this does not rule out the presence of these receptors in the myocardium. To date there are no studies that have explored the role of GPR55 in the setting of acute myocardial I/R, although this clearly would be of value.

Rather than acting through a receptor, CBD may induce a tissue sparing effect through a direct action on ion channels. A very recent study (Ryan et al., 2009) has shown that the neuroprotective effect of CBD may be a result of restoration of intracellular Ca 2+ homeostasis at the level of the mitochondria; using hippocampal slices this group found that under normal physiological conditions CBD had minimal effects on mitochondrial calcium mobilization, while under conditions of high extracellular K + it significantly reduced cytosolic Ca 2+ concentration. This effect was abolished by inhibition of the mitochondrial Na + /Ca 2+ exchanger (NCX), but not via an inhibitor of the mitochondrial permeability transition pore (mPTP), suggesting that, under pathophysiological conditions, CBD improves intracellular Ca 2+ homeostasis through modulation of NCX activity. A similar effect on the cardiomyocyte mitochondria would therefore be expected to help prevent calcium overload, one of the key mechanisms of immediate lethal injury following reperfusion. In addition, anandamide has recently been shown to reduce inositol-1,4,5,-trisphosphate receptor (IP3R)-mediated nuclear Ca 2+ release in cardiomyocyte nuclear envelopes expressing both CB1 and CB2 receptors (Currie et al., 2008). This effect was significantly attenuated by both CB1 and CB2 receptor antagonists, providing the first evidence for a nuclear receptor site of action for cannabinoids in cardiomyocytes. Further study of a cardioprotective role for CBD, mediated at either the mitochondrial or nuclear level, is therefore clearly warranted.

In summary, to our knowledge this is the first study to demonstrate an anti-arrhythmic effect of CBD following myocardial I/R. This study is also the first to demonstrate that acute administration of a single dose of CBD is sufficient to reduce myocardial tissue injury irrespective of whether it is administered prior to or post coronary occlusion. While further detailed studies are required to elucidate the mechanism by which CBD preserves tissue in I/R, these data expand on the currently very limited literature detailing the role of CBD in the cardiovascular system and firmly establishes its potential as a cardioprotective agent.

CBD Oil and AFib: Can Cannabis Help With Atrial Fibrillation?

Atrial fibrillation — or AFib in short — is a condition characterized by irregular heartbeats also known as arrhythmia. When untreated, it can result in heart failure, stroke, blood clotting, and other cardiovascular problems.

It’s estimated that around 2.7 million Americans are living with AFib. Doctors typically prescribe blood thinners such as warfarin to help prevent strokes in patients with this condition.

There’s a growing body of evidence surrounding the benefits of CBD for the cardiovascular system.

Short for cannabidiol, CBD is one of many substances found in cannabis. It’s the second major cannabinoid next to THC, which is the main intoxicating ingredient in marijuana (high-THC cannabis).

Unlike THC, CBD doesn’t get you high, but instead, it helps you enjoy the plethora of health benefits associated with this compound.

In this article, we’ll leave no stone unturned exploring the use of CBD for AFib.

Does CBD Oil Help AFib?

A 2010 study posted by the British Journal of Pharmacology discovered that CBD reduced the total number of irregular, ventricular heartbeats (heart arrhythmia) in a rat model after they had a heart attack. This type of arrhythmia that doesn’t come from the atria but rather from the ventricles is different from AFib, but the said findings could be worth further analysis.

In a 2017 study, the research team learned that a single dose of CBD reduced blood pressure in male subjects. They also noted that CBD lowered blood pressure response to stress in the subject, particularly in the event of cold stress.

Elevated blood pressure is believed to increase the risk of atrial fibrillation in middle-aged men and women.

Another study investigated the theory that CBD can attenuate responses and consequences of stress in animals with anxiety.

In the meantime, experts in another study concluded that CBD inhibited several processes linked to diabetes, pointing to CBD as a potentially therapeutic substance in treating diabetes and other heart-related diseases.

That being said, there are no studies that would investigate CBD’s efficacy as a treatment for atrial fibrillation. Many studies on CBD were conducted on animal models, with only a few small studies on human subjects —butt none directly tackle the problem of AFib.

How does CBD Oil work for AFib?

CBD interacts with the major regulatory network in our bodies known as the endocannabinoid system (ECS). ECS works to promote and maintain homeostasis in the body through its receptors; for that purpose, it releases ligands known as endocannabinoids.

CBD has been found to indirectly engage with cannabinoid receptors type 1 and 2 (CB1 and CB2), but there’s also a growing body of evidence that it works on multiple pathways beyond the ECS.

One study on lab rats found that CBD’s interaction with the ECS causes it to exert cardioprotective effects in the animals. In another study, the authors reported that CBD binds to and activates the PPARgamma receptor, which has been associated with various cardiovascular illnesses.

They also noted that the activation of the said receptor-induced vascular actions in rats.

Good blood pressure control is beneficial for AFib patients. There are already safe, established medications for this condition, but CBD can add yet another choice for patients that want to treat their AFib with holistic remedies.

Potential Benefits of CBD Oil for AFib

  • Some studies highlight CBD’s ability to control blood pressure, which could translate into better AFib control. The studies we’ve mentioned above noted that CBD offers benefits for the cardiovascular system and can help treat another type of arrhythmia but — not AFib specifically.
  • There is evidence that CBD can reduce hypertension, a condition that causes atrial fibrillation.
  • CBD doesn’t have intoxicating properties, so it won’t get you high, unlike THC.
  • CBD is federally legal and you can buy it without a prescription in every state.
  • Public health agencies such as NIH and the FDA acknowledge CBD’s potential therapeutic uses.
  • The WHO issued a case report where they reviewed several clinical trials investigating the efficacy and safety of CBD. The report concluded that CBD is safe and well-tolerated, even when taken in large amounts.

What Are the Limitations of Using CBD Oil for AFib?

  • Most of the studies on CBD were conducted on animal models. There are currently no clinical human trials on the use of CBD for AFib. The effects have not been directly studied with regards to this condition.
  • The only FDA-approved use of CBD is for epilepsy — and it’s not even CBD oil but synthetically isolated CBD.
  • Taking CBD oil alongside other medications, especially blood thinners, can lead to negative interactions. In the case of CBD and blood-thinners, the cross-interaction could trigger bleeding, so always talk to your doctor before taking CBD.
  • The CBD market is unregulated and thus there are many mislabeled products sold online. People choosing to buy CBD for AFib should be particularly cautious of who they’re buying from.
See also  Legit sources for cbd oil

Full-Spectrum CBD vs Isolate: Which Is Better for AFib?

There’s an ongoing debate on the effectiveness of full-spectrum CBD oil vs CBD isolate for different health conditions.

Full-spectrum CBD oil contains the original phytochemical profile of the source plant, including adjunctive cannabinoids, terpenes, and trace amounts of THC (0.3% or less). These compounds work synergistically to enhance the therapeutic effects of your extract, unlike with CBD isolate — which contains nothing but pure CBD.

This means that full-spectrum CBD oil may be more effective for AFib than isolate; for that reason, the full-spectrum option is the desired type of CBD oil among the majority of consumers.

CBD isolate doesn’t have any odor and flavor. It also shouldn’t trigger a false-positive result on a drug test for THC, so if these are the reasons you avoid CBD oil, it may be a good idea to opt for pure CBD.

CBD Dosage for AFib

Since CBD isn’t regulated by the FDA, there are no official dosage recommendations from health agencies. This, in turn, makes it difficult for new consumers to know how much CBD oil they should take to relieve their symptoms and improve overall health.

If you want to figure out the optimal dosage for your individual situation, it will require some trial and error. The good news is that you can take a look at the past studies on CBD and cardiovascular health to compare different dosages and try them out on yourself.

It’s best to start low and slowly increase your dose until you find the amount that provides the expected results.

How to Take CBD for AFib?

Taking CBD oil or vaping CBD extracts are the fastest ways to administer CBD to those with AFib.

Sublingual use (under the tongue) provides relatively high bioavailability and a fast onset of effects. Bioavailability refers to the leftover amount of CBD that your body can use after being metabolized in the digestive tract.

Meanwhile, vaping CBD delivers it to your bloodstream through the lung tissue, so by way of inhaling it you can feel the effects almost instantaneously.

That being said, not everyone is comfortable with vaping, especially if they have AFib. Taking CBD by way of gummies or capsules is an easy way for non-vapers to take CBD oil.

Some brands also sell CBD oil as topicals. These formulations can be used for massage therapies to help people unwind and relax.

Dosage-wise, it’s best to purchase CBD oil because they come with droppers that allow for easy and correct application of the right amount of CBD.

Understanding Atrial Fibrillation

Atrial fibrillation is the most prevalent type of erratic heartbeat that people can experience. Some of the risk factors of AFib include high blood pressure, obesity, age, and existing heart disease.

Despite being associated with irregular electrical impulses, the exact cause of AFib remains unknown to scientists.

The symptoms of Afib include:

  • Chest pains
  • Dizziness
  • Fatigue
  • A feeling of fluttering in the chest
  • Faintness
  • Sweating
  • Shortness of breath
  • Rapid and abnormal heartbeat
  • Weakness

Different Types of Atrial Fibrillation

Medical researchers have outlined at least five types of AFib that can be distinguished based on their underlying causes and duration:

  • Paroxysmal fibrillation – this condition occurs when a person’s heart returns to normal with or without intervention within a week after its beginning. People with this type of AFib may go through such episodes a few times each year — or even daily.
  • Persistent AFib – this type of AFib refers to an abnormal rhythm of the heart that lasts more than one week. It doesn’t return to normal without treatment.
  • Long-standing AFib – it happens when the heart is continuously in an erratic rhythm, lasting more than one year.
  • Permanent AFib – in this case, the disorder lasts indefinitely, with the patient and doctor deciding to discontinue treatment.
  • Nonvalvular AFib – this form of AFib isn’t triggered by a problem with the heart valve.

How Does the Heart Rehabilitate from AFib?

Cardiac rehabilitation is a paramount process for people recovering from heart surgery or heart muscle failure. This program requires medical supervision of your physical activity, education about healthy lifestyle choices, and mental health counseling. Anyone with AFib or any other cardiovascular problem can take part in cardiac rehab.

The program offers many benefits to a person’s health, such as:

  • Strengthening the body after a heart attack
  • Relieving chest pain and other symptoms of heart problems
  • Reducing stress
  • Learning healthier habits
  • Enhancing moods
  • Improving motivation
  • Preventing future cardiovascular issues.

You can sign up for cardiac rehabilitation in a health center or your local hospital. Some programs are implemented in the patient’s home.

Summarizing the Use of CBD for AFib

CBD can exert therapeutic effects on arrhythmic hearts and thus help with atrial fibrillation. Although no direct study implicated this, preliminary studies on animal models of heart diseases have shown that CBD can reduce blood pressure and the total number of irregular, ventricular heartbeats in people after heart attacks.

Abnormal heart rhythm and hypertension are the most probable underlying causes of AFib and require medical care.

CBD is said to interact with receptors of the ECS, which is the believed reason for its cardioprotective properties. Scientists have also observed CBD’s interactions with other receptors outside the ECS.

More clinical trials on humans regarding the use of CBD for AFib are needed, but current evidence holds promise for its potential use as a holistic treatment.

Do you believe in CBD’s cardioprotective effects? How do you take CBD oil to improve your heart health?

References:

  1. Walsh, S. K., Hepburn, C. Y., Kane, K. A., & Wainwright, C. L. (2010). Acute administration of cannabidiol in vivo suppresses ischaemia-induced cardiac arrhythmias and reduces infarct size when given at reperfusion. British journal of pharmacology, 160(5), 1234–1242. (1)
  2. Jadoon, K. A., Tan, G. D., & O’Sullivan, S. E. (2017). A single dose of cannabidiol reduces blood pressure in healthy volunteers in a randomized crossover study. JCI insight, 2(12), e93760. (2)
  3. Granjeiro, E. M., Gomes, F. V., Guimarães, F. S., Corrêa, F. M., & Resstel, L. B. (2011). Effects of intracisternal administration of cannabidiol on the cardiovascular and behavioral responses to acute restraint stress. Pharmacology, biochemistry, and behavior, 99(4), 743–748. (3)
  4. Horváth, B., Mukhopadhyay, P., Haskó, G., & Pacher, P. (2012). The endocannabinoid system and plant-derived cannabinoids in diabetes and diabetic complications. The American journal of pathology, 180(2), 432–442. (4)
  5. Fouad, A. A., Albuali, W. H., Al-Mulhim, A. S., & Jresat, I. (2013). Cardioprotective effect of cannabidiol in rats exposed to doxorubicin toxicity. Environmental toxicology and pharmacology, 36(2), 347–357. (5)
Nina Julia

Nina created CFAH.org following the birth of her second child. She was a science and math teacher for 6 years prior to becoming a parent — teaching in schools in White Plains, New York and later in Paterson, New Jersey.

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CBD: What is it, and can it help the heart?

CBD is the latest health craze to sweep the high street, with claims it can help everything from chronic pain and inflammation to anxiety. But what is CBD, and can it really help the heart? Emily Ray finds out.

What is CBD, and is it legal in the UK?

CBD, or cannabidiol, is a chemical that’s extracted from the leaves and flowers of the cannabis plant. Cannabis itself is an illegal class B drug, as is the compound THC (tetrahydrocannabinol) which it contains. But pure CBD isn’t illegal, as it doesn’t cause the intoxicating effects of cannabis.

What CBD products are available?

The choice of CBD products has exploded recently: you can buy oils, capsules, muscle gels, sprays and oral drops, as well as beer, tea, sweets, hummus and even CBD-infused clothing.

Many of these can be easily picked up from reputable high street stores, such as Holland & Barrett or Boots.

Prices can be high: a 500mg bottle of CBD oil oral drops could set you back as much as £45. Not that this has put people off: over the past two years, sales of CBD have almost doubled in the UK, putting regular users at an estimated quarter of a million.

What is CBD used for?

A 2018 report by the World Health Organization suggested that CBD may help treat symptoms relating to conditions such as cancer, Parkinson’s disease, multiple sclerosis (MS), anxiety, depression, insomnia and Alzheimer’s disease.

However, it also notes that this research is still in the early stages, and that more studies are needed before conclusions can be drawn on whether CBD is effective.

CBD’s popularity has been given a boost by the fact that two CBD-containing medicines have been approved for prescription use by the NHS in England: Epidyolex, which has been found to reduce the number of seizures in children with severe epilepsy, and Sativex, which contains a mixture of CBD and THC, and is licensed for treatment of muscle stiffness and spasms in people with MS.

Does CBD work?

Harry Sumnall, Professor in Substance Use at Liverpool John Moores University, says: “In terms of the products found in shops, there’s virtually no evidence to support the claims made for a lot of them. There’s a lot of marketing that says CBD is a ‘miracle of the modern age’; however, the marketing has actually overtaken the evidence of what it’s effective for.”

“In terms of the products found in shops, there’s virtually no evidence to support the claims made for a lot of them.”

Harry Sumnall, Professor in Substance Use at Liverpool John Moores University

Professor Sumnall argues that while it could be effective for some people, in some of these cases the results could be caused by the placebo effect (where the patient’s belief in a treatment makes them feel better). The placebo effect can be powerful, but Professor Sumnall warns that if people try CBD oil instead of speaking to their doctor, it could cause a problem.

The biggest difference between CBD used in clinical trials and in stores is the dose. Research has shown that some products contain very little CBD (or even none at all). Others contain THC or other illegal drugs, or even alcohol instead of CBD. By contrast, in clinical trials the CBD is purified, manufactured to a very high standard and given at a much higher dose. It is also taken regularly and under medical supervision.

Since 2016, any CBD product that is presented as having medicinal value must be licensed and regulated as a medicine, regardless of whether it is actually effective. Manufacturers must follow very specific and robust rules around production, packaging and the information provided.

But so far, Professor Sumnall points out, CBD products in shops are marketed as food supplements, not medicines, so none of them have gone through this process.

Can CBD help the heart?

Inflammation is part of the process that leads to many diseases, including coronary heart disease, high blood pressure and stroke, and there is some evidence that CBD has anti-inflammatory properties. Other studies have suggested that CBD can have a protective effect on the heart: this has been proven in rats after a heart attack and in mice with some of the heart damage associated with diabetes. But because these studies are often based on findings in a lab or in animals, not in humans, we cannot yet be confident that CBD will benefit the human heart.

There is ongoing research into the use of purer forms of CBD for a variety of conditions, including heart and circulatory diseases and, in particular, diseases of the heart muscle, including myocarditis and some types of cardiomyopathy.

Some of this work is still in animals, and much more research is needed before we can definitively say that CBD can help in this area.

“It’s clear that CBD has potential,” says Professor Sumnall, “but we’re at a very early stage of that research.”

  • Always talk to your doctor if you’re thinking about taking a CBD product to supplement your existing treatment.

Meet the expert

Harry Sumnall is a Professor in Substance Use at the Public Health Institute, Liverpool John Moores University. He was a member of the UK Government’s Advisory Council on the Misuse of Drugs between 2011 and 2019.