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Endocannabinoids acting at vascular CB1 receptors mediate the vasodilated state in advanced liver cirrhosis

Abstract

Advanced cirrhosis is associated with generalized vasodilation of unknown origin, which contributes to mortality. Cirrhotic patients are endotoxemic, and activation of vascular cannabinoid CB1 receptors has been implicated in endotoxin-induced hypotension. Here we show that rats with biliary cirrhosis have low blood pressure, which is elevated by the CB1 receptor antagonist SR141716A. The low blood pressure of rats with CCl4-induced cirrhosis was similarly reversed by SR141716A, which also reduced the elevated mesenteric blood flow and portal pressure. Monocytes from cirrhotic but not control patients or rats elicited SR141716A-sensitive hypotension in normal recipient rats and showed significantly elevated levels of anandamide. Compared with non-cirrhotic controls, in cirrhotic human livers there was a three-fold increase in CB1 receptors on isolated vascular endothelial cells. These results implicate anandamide and vascular CB1 receptors in the vasodilated state in advanced cirrhosis and indicate a novel approach for its management.

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Figure 1: The effect of CB1-receptor blockade on cardiovascular parameters in rats with CCl4-induced cirrhosis.
Figure 2: The hypotensive effect of anandamide is absent in cirrhotic rats.
Figure 3: CB1 receptor-mediated hypotensive response to monocytes from cirrhotic rats or patients.
Figure 4: Endogenous anandamide in monocytes from cirrhotic and control rats.
Figure 5: CB1 receptors in vascular endothelium are upregulated in cirrhosis.

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Acknowledgements

We thank L. Chedester for assistance with cirrhotic rats. This work was supported in part by National Institutes of Health grant HL-59257 and Commonwealth of Virginia Health Research Board grant 99-04 to G.K., and grant MO-1-RR-00065-38 to the General Clinical Research Center of Virginia Commonwealth University.

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Correspondence to George Kunos.

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Bátkai, S., Járai, Z., Wagner, J. et al. Endocannabinoids acting at vascular CB1 receptors mediate the vasodilated state in advanced liver cirrhosis. Nat Med 7, 827–832 (2001). https://doi.org/10.1038/89953

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