Cannabinoids in arterial, pulmonary and portal hypertension – mechanisms of action and potential therapeutic significance

Abstract

The endocannabinoid system is overactivated in arterial, pulmonary and portal hypertension. In this paper, we present limited clinical data concerning the role of cannabinoids in human hypertension including polymorphism of endocannabinoid system components. We underline differences between the acute cannabinoid administration and their potential hypotensive effect after chronic application in experimental hypertension. We discuss pleiotropic effects of cannabinoids on the cardiovascular system mediated via numerous neuronal and non‐neuronal mechanisms both in normotension and in hypertension. The final results are dependent on the model of hypertension, age, sex, the cannabinoid ligands used or the action via endocannabinoid metabolites. More experimental and clinical studies are needed to clarify the role of endocannabinoids in hypertension, not only in the search for new therapeutic strategies but also in the context of cardiovascular effects of cannabinoids and the steadily increasing legalization of cannabis use for recreational and medical purposes. Linked Articles This article is part of a themed section on 8 th European Workshop on Cannabinoid Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.10/issuetoc

Chronic Cannabidiol Administration Fails to Diminish Blood Pressure in Rats with Primary and Secondary Hypertension Despite Its Effects on Cardiac and Plasma Endocannabinoid System, Oxidative Stress and Lipid Metabolism

“…The endocannabinoid system is overactivated in hypertension [63]. Chronic CBD administration failed to modify the densities of cannabinoid and cannabinoid-like receptors (the only exception was the decrease in cardiac GPR55 levels in SHR) but decreased cardiac levels of 2-AG, OEA, DEA and DGLEA in DOCA and plasma levels of AEA and LEA in DOCA and of SEA, HEA and DGLEA in SHR.…”

“…The possibility has to be considered that a model of hypertension connected with changes in the renin-angiotensin-aldosterone system (RAAS) (the activity of which is modified by the endocannabinoid system) might have revealed a blood pressure-lowering effect of CBD. Interestingly, opposite effects of a CB 1 receptor antagonist have been found in the cardiovascular system of SHR and of rats with a RAAS-dependent hypertension (for review, see [63]). (4) There are gender-specific differences in hypertension [17,68] and it would be interesting to extend our experiments to female rats.…”

A Guide to Targeting the Endocannabinoid System in Drug Design

“…The ECS control of blood pressure (BP) involves various neuronal and non-neuronal mechanisms. Based on various human and animal studies, CB1 is suggested to play a major role in these actions and while central activation of CB1 increases BP, peripheral activation tends to lower BP [246,247]. However, the activation of either or both CBRs was demonstrated to increase contractility in vascular smooth muscles in vitro [248].…”

“…Cannabinoids, acting peripherally, are generally known to decrease BP. However, the final outcome depends on the type of a cannabinoid ligand, model of hypertension as well as age and sex [247]. For instance, AEA (5 mg/kg/week) decreased BP and reversed all altered cardiovascular markers and parameters in hypertensive rats [249].…”

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“…There are reviews on more translational aspects of cannabinoids. Burkhard Hinz and Robert Ramer describe anti-tumour actions of cannabinoids (Hinz & Ramer, 2019), while Barbara Malinowska and colleagues look at the mechanisms of action and potential therapeutic significance of cannabinoids in different aspects of hypertension (Malinowska, Toczek, Pedzinska-Betiuk, & Schlicker, 2019). Kasia Starowicz (Malek & Starowicz, 2019) and Dave Finn (Okine, Gaspar, & Finn, 2019), with their respective colleagues, describe aspects of cannabinoids in joint repair problems and targetting non-canonical pathways in pain.…”