Cannabinoid receptor 1 inhibition improves cardiac function and remodelling after myocardial infarction and in experimental metabolic syndrome

Abstract

The cannabinoid receptors, CB1 and CB2, are expressed in the heart, but their role under pathological conditions remains controversial. This study examined the effect of CB1 receptor blockade on cardiovascular functions after experimental MI and in experimental metabolic syndrome. MI was induced in Wistar rats by permanent ligation of the left coronary artery. Treatment with the CB1 receptor antagonist rimonabant (10 mg/kg i.p. daily) started 7 days before or 6 h after MI and continued for 6 weeks. Haemodynamic parameters were measured via echocardiography and intracardiac Samba catheter. CB1 blockade improved systolic and diastolic heart function, decreased cardiac collagen and hydroxyproline content and down-regulated TGF-β1. Additionally, rimonabant decreased arterial stiffness, normalised QRS complex duration and reduced brain natriuretic peptide levels in serum. In primary cardiac fibroblasts, rimonabant decreased MMP-9 activity and TGF-β1 expression. Furthermore, rimonabant improved depressed systolic function of spontaneously hypertensive obese rats and reduced weight gain. Blocking of CB1 receptor with rimonabant improves cardiac functions in the early and late stages after MI, decreases arterial stiffness and reduces cardiac remodelling. Rimonabant also has cardioprotective actions in rats characterised by the metabolic syndrome. Inhibition of proteolysis and TGF-β1 expression and reduced collagen content by rimonabant may attenuate destruction of the extracellular matrix and decrease fibrosis after MI.

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

“…In obese humans, high plasma levels of endocannabinoids correlate with impaired coronary endothelial function (646). The proinflammatory effects of CB1 in the cardiovascular system are also revealed using FAAH inhibitors or FAAH null mice in models of atherosclerosis and cardiomyopathy (802). Hence, CB1 inhibition may improve cardiac function and be cardioprotective not only indirectly, by counteracting the metabolic syndrome (see below), but also, in the above conditions as well as in a model of angiotensin II-dependent hypertension, via direct effects on the heart (777).…”

The common pathophysiology underlying the metabolic syndrome, schizophrenia and depression. A review

“…However, newer cannabinoid compounds are emerging and a strong influence on appetite, metabolism and energy homeostasis is consistently reported [105][106][107] . Most importantly, preclinical studies are constantly widening the range of new candidate molecules [108][109][110] .…”

Rehabilitating rimonabant

“…Cardiac and vascular tissue seems to be well outfitted with endocannabinoid receptors, including CB1, CB2, the transient receptor-potential channel TRPV1, and participating molecules. The data presented by Slavic et al [10] imply that blocking CB1 receptors led to the beneficial effects in their model. On the other hand, CB2 receptor activation was found to ameliorate ischemia reperfusion injury in the myocardium.…”

“…In this issue, Slavic et al [10] report on the effect of CB1 inhibition on cardiac function and remodeling after experimental myocardial infarction and after experimental metabolic syndrome. They inspected two different rat models.…”

“…On the other hand, CB2 receptor activation was found to ameliorate ischemia reperfusion injury in the myocardium. Unclear is possible participation of GPR18 and GPR55 in the responses Slavic et al observed [10]. Whether or not blockade of the CB1 receptor would have led to increased occupancy of other receptors is unknown.…”