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, 312 (6), R883-R893

Activation of CB 1 Receptors by 2-arachidonoylglycerol Attenuates Vasoconstriction Induced by U46619 and Angiotensin II in Human and Rat Pulmonary Arteries

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Activation of CB 1 Receptors by 2-arachidonoylglycerol Attenuates Vasoconstriction Induced by U46619 and Angiotensin II in Human and Rat Pulmonary Arteries

Olga Karpińska et al. Am J Physiol Regul Integr Comp Physiol.

Abstract

Recent evidence suggests that endocannabinoids acting via cannabinoid CB1 receptors may modulate vascular responses of various vasoconstrictors in the rodent systemic vasculature. The aim of the study was to investigate whether endocannabinoids modulate the contractile responses evoked by a thromboxane A2 analog (U46619), angiotensin II (ANG II), serotonin (5-HT), and phenylephrine, which stimulate distinct Gq/11 protein-coupled receptors (thromboxane, ANG II type 1, 5-HT2, and α1-adrenergic receptors) in isolated endothelium-intact human and rat pulmonary arteries (hPAs and rPAs, respectively). The CB1 receptor antagonist AM251 (1 μM) and diacylglycerol lipase (2-arachidonoylglycerol synthesis enzyme) inhibitor RHC80267 (40 μM) enhanced contractions induced by U46619 in hPAs and rPAs and by ANG II in rPAs in an endothelium-dependent manner. AM251 did not influence vasoconstrictions induced by 5-HT or phenylephrine in rPAs. The monoacylglycerol lipase (2-arachidonoylglycerol degradation enzyme) inhibitor JZL184 (1 μM), but not the fatty acid amide hydrolase (anandamide degradation enzyme) inhibitor URB597 (1 μM), attenuated contractions evoked by U46619 in hPAs and rPAs and ANG II in rPAs. 2-Arachidonoylglycerol concentration-dependently induced relaxation of hPAs, which was inhibited by endothelium denudation or AM251 and enhanced by JZL184. Expression of CB1 receptors was confirmed in hPAs and rPAs using Western blotting and immunohistochemistry. The present study shows the protective interaction between the endocannabinoid system and vasoconstriction in response to U46619 and ANG II in the human and rat pulmonary circulation. U46619 and ANG II may stimulate rapid endothelial release of endocannabinoids (mainly 2-arachidonoylglycerol), leading to CB1 receptor-dependent and/or CB1 receptor-independent vasorelaxation, which in the negative feedback mechanism reduces later agonist-induced vasoconstriction.

Keywords: 2-arachidonoylglycerol; anandamide; cannabinoid receptor type 1; monoacylglycerol lipase; pulmonary artery.

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