Archive for the ‘Heart Problems’ Category

Preventive treatment with cannabinoid agonists has been reported to reduce the infarct size in a mouse model of myocardial ischemia/reperfusion. Here we investigated the possible cardioprotective effect of selective CB₂ cannabinoid receptor activation during ischemia. We performed left coronary artery ligature in C57Bl/6 mice for 30 min, followed by 24 h of reperfusion. Five minutes before reperfusion, mice received intraperitoneal injection of the CB₂ selective agonist JWH-133 (20 mg/kg) or vehicle. Infarct size was assessed histologically and by cardiac troponin I (cTnI) ELISA. Immunohistochemical analysis of leukocyte infiltration, oxidative stress in situ quantification, real-time RT-PCR analysis of inflammatory mediators as well as western blots for kinase phosphorylation was also performed. In addition, we studied chemotaxis and integrin expression of human neutrophils in vitro. JWH-133 significantly reduced the infarct size (I/area at risk: 19.27% ± 1.91) as compared to vehicle-treated mice (31.77% ± 2.7). This was associated with a reduction of oxidative stress and neutrophil infiltration in the infarcted myocardium, whereas activation of ERK 1/2 and STAT-3 was increased. Preinjection of PI3K inhibitor LY294002, MEK 1/2 inhibitor U0126 and JAK-2 inhibitor AG-490 partially abrogated the JWH-133 mediated infarct size reduction. No changes in cardiac CXCL1, CXCL2, CCL3, TNF-α, and ICAM-1 expression levels were found. Furthermore, JWH-133 inhibited the TNF-α induced chemotaxis and integrin CD18/CD11b (Mac-1) upregulation on human neutrophils. Our data suggest that JWH-133 administration during ischemia reduces the infarct size in a mouse model of myocardial ischemia/reperfusion through a direct cardioprotective activity on cardiomyocytes and neutrophils.

Endocannabinoids, such as anandamide and 2-arachidonoylglycerol, are synthesized from membrane phospholipids in the heart and other cardiovascular tissues. They activate cannabinoid CB₁ and CB₂ receptors, TRPV1, peroxisome proliferator-activated receptors and perhaps a novel vascular G-protein-coupled receptor. Inactivation is by cellular uptake and fatty acid amide hydrolase (FAAH). Endocannabinoids relax coronary and other arteries and decrease cardiac work, but seem not to be involved in tonic regulation of cardiovascular function. They act as a stress response system which is activated, for example, in myocardial infarction and circulatory shock. Endocannabinoids are largely protective; they decrease tissue damage and arrhythmia in myocardial infarction, may reduce progression of atherosclerosis (CB₂ receptor stimulation inhibits lesion progression), and FAAH knockout mice (which have enhanced endocannabinoid levels) show decreased cardiac dysfunction with age compared to wild-types. However, endocannabinoids may mediate doxorubicin-induced cardiac dysfunction. Their signaling pathways are not fully elucidated but they can lead to changed expression of a variety of genes, including those involved in inflammatory responses. There is potential for therapeutic targeting of endocannabinoids and their receptors, but their apparent involvement in both protective and deleterious actions on the heart mean that careful risk assessment is needed before any treatment can be introduced.

April 6, 2005 — The active ingredient in marijuana that produces changes in brain messages appears to fight atherosclerosis — a hardening of the arteries.

But puffing pot probably won’t help. The findings, reported in the journal Nature, “should not be taken to mean that smoking marijuana is beneficial for the heart,” says Michael Roth, MD, a professor of medicine at UCLA medical school.

It takes a very specific amount of THC — marijuana’s key chemical — to help the arteries. That dose is too low to produce mood-altering effects in the brain, according to the new study.

“It would be difficult to achieve such specific concentrations in the blood by smoking marijuana,” Roth explains in a Nature editorial.

Smoking Pot: Bad for the Heart?

Smoking marijuana can speed up the pulse and raise blood pressure (followed by a sudden fall upon standing or walking), Roth notes.

“These effects lower the exercise threshold for chest pain [angina], and are an independent risk factor for heart attack and stroke,” he writes. Inhaling marijuana smoke can also impair oxygen delivery via the blood, says Roth.

The best way to take advantage of THC’s artery-protecting effects may be by developing new prescription drugs “rather than using marijuana or oral THC as medicines,” he writes.

Testing THC on Mice

The new study was conducted on mice, not people. First, mice went on an 11-week fatty diet designed to clog their arteries. For the last six weeks of the diet, some mice also got an orally administered low dose of THC along with the high-fat food.

Afterward, the mice who had received THC had fewer signs of atherosclerosis. None of those mice died during treatment or showed unhealthy behavior, says the study.

The results may be due to THC’s anti-inflammatory properties, write the researchers, who included François Mach, MD, of the cardiology division at University Hospital in Geneva, Switzerland. Inflammation has been shown to be associated with the development of atherosclerosis.

Tracing THC’s Effects

The researchers took a closer look at THC. They knew the chemical has two receptors, called CB1 (mainly found in the brain) and CB2 (mostly found outside the brain).

When they used another drug to block CB2 receptors in the mice, THC couldn’t protect the animals’ arteries. As for the CB1 receptors, the THC dose used in the study was too low to affect them, so no “high” was created.

The study and editorial appear in Nature’s April 7 edition.