Recent evidence suggests that endocannabinoids acting via cannabinoid CB 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 A analog (U46619), angiotensin II (ANG II), serotonin (5-HT), and phenylephrine, which stimulate distinct G protein-coupled receptors (thromboxane, ANG II type 1, 5-HT, and α-adrenergic receptors) in isolated endothelium-intact human and rat pulmonary arteries (hPAs and rPAs, respectively). The CB 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 CB 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 CB receptor-dependent and/or CB receptor-independent vasorelaxation, which in the negative feedback mechanism reduces later agonist-induced vasoconstriction.

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Endocannabinoid's negative feedback is responsible for diminishing agonist-induced vasoconstriction, which may be clinically important in the treatment of arterial and pulmonary hypertension. Further research is required to establish the importance of the eCB system and its downstream signalling pathways.

The endothelium plays a crucial role in modulating vascular tone by synthesizing and releasing endothelium-derived relaxing factors, including nitric oxide (NO) and prostacyclin I2 (PGI2). Additionally, endothelium-dependent hyperpolarization (EDH) that is NO – and PGI2–independent participates in the relaxation of small-diameter blood vessels (<300 μm). EDH response is initiated by agonists (e.g. acetylcholine, bradykinin) – or shear stress – induced increase of calcium ions level in the endothelium and involves opening of the endothelial small (KCa2.3) and intermediate conductance (KCa3.1) calcium-activated potassium channels. The efflux of potassium ions could elicit the hyperpolarization of the surrounding myocytes by the activation of the inward-rectifier potassium ion channel (KIR) and/or Na+/K+-ATPase. The reduced release and/or bioavailability of NO, which is characteristic for endothelial dysfunction and may result in arterial hypertension, stimulate the generation of EDH signals, as a compensatory mechanism to maintain the endothelial control of vasodilator tone. The contribution of EDH in endothelium-dependent relaxation varies between vascular beds, animal and experimental model. In arterial hypertension the reduced expression/activity of KCa3.1 and KCa2.3 results in impaired vasorelaxation. Currently, the use of modulatory compounds (activators and inhibitors) of KCa3.1 and KCa2.3 as the potential therapeutic targets in cardiovascular diseases is under intensive investigation. It has already been known that application of activators of KCa3.1 and KCa2.3 potassium channels such (as SKA-31) can improve the EDH-type responses, the endothelial function and decrease mean arterial blood pressure. This may suggest the usefulness of these compounds in the treatment of arterial hypertension.