Our previous study has indicated the existence of a novel cannabinoid (CB) receptor in vascular endotheliu. We recently reported that the CB analog """"""""abnormal cannabidiol"""""""" (abn-cbd) does not bind to the two known CB receptors, CB1 and CB2, yet acts as a full agonist in relaxing rat isolated mesenteric artery segments. Vasodilation by abn-cbd is endothelium-dependent, PTX-sensitive, and is inhibited by the BKCa channel inhibitor charybdotoxin, but not by the NO synthase inhibitor L-NAME or the vanilloid VR1 antagonist capsazepine. The cannabidiol analog O-1918 does not bind to CB1 or CB2 receptors and does not cause vasorelaxation at concentrations up to 30 micromolar, but causes concentration-dependent (1-30 micromolar) inhibition of the vasorelaxant effects of abn-cbd and anandamide. In anesthetized mice, O-1918 dose-dependently inhibits the hypotensive effect of abn-cbd, but not of the CB1 agonist HU-210. In HUVEC, abn-cbd induces phosphorylation of protein kinase B/akt and p42/44 MAP kinase, which is inhibited by O-1918, by PTX and by PI3 kinase inhibitors. These findings indicate that abn-cbd is a selective agonist and O-1918 a novel, silent antagonist of an endothelial """"""""anandamide receptor"""""""" which is distinct from CB1 and CB2 receptors and is coupled thropugh Gi/Go to the PI3 kinase/akt signaling pathway. In another recently published study we examined the electrophysiological effects of abn-cbd in human umbilical vein endothelial cells (HUVEC). Voltage steps produced non-inactivating outward currents abolished by iberiotoxin or intracellular BAPTA. ABN-cbd potentiated this current, and this effect was inhibited by PTX or O-1918, but was unaffected by CB1 or CB2 antagonists. cGMP also potentiated this current, and abn-cbd increased the cellular levels of cGMP. Potentiation of the outward current by abn-cbd was blocked by inhibitors of PKG or soluble guanylate cyclase. We conclude that activation of an abn-cbd sensitive GPCR in HUVEC potentiates BKCa current by signalling through PKG to increase channel availability or sensitivity to calcium. Our previous studies implicated macrophage-derived endocannabinoids in endotoxin (LPS)-induced hypotension. We now provide evidence that LPS induces anandamide synthesis in macrophages via a CD14/MAP kinase/PI-3 kinase/NF-kappaB pathway, independently of platelet activating factor (PAF). In contrast, the synthesis of 2-arachidonoyl glycerol is unaffected by LPS but increased by PAF. Macrophages from mice deficient in fattyacid amido hydrolase (FAAH) respond to LPS with a greater increase in anandamide and elicit greater hypotension in normal recipient rats than similarly treated cells from wild-type mice. We conclude that anandamide and 2-AG synthesis are differentially regulaterd and anandamide rather than @-AG is involved in LPS-induced hypotension. In a collaborative study with Dr. N. Stella, the presence of abn-cbd receptors in microglia and their involvement in the control of cell migration has been documented. The results raise the possible therapeutic use of antagonist of these receptors in neuroinflammatory diseases.
| Kunos, George; Osei-Hyiaman, Douglas; Bátkai, Sándor et al. (2009) Should peripheral CB(1) cannabinoid receptors be selectively targeted for therapeutic gain? Trends Pharmacol Sci 30:1-7 |
| Kunos, George (2008) A tribute to Dr. Ting-Kai Li. Alcohol Clin Exp Res 32:2030 |
| Buettner, Christoph; Muse, Evan D; Cheng, Andrew et al. (2008) Leptin controls adipose tissue lipogenesis via central, STAT3-independent mechanisms. Nat Med 14:667-75 |
| Mukhopadhyay, Partha; Batkai, Sandor; Rajesh, Mohanraj et al. (2007) Pharmacological inhibition of CB1 cannabinoid receptor protects against doxorubicin-induced cardiotoxicity. J Am Coll Cardiol 50:528-36 |
| Batkai, Sandor; Osei-Hyiaman, Douglas; Pan, Hao et al. (2007) Cannabinoid-2 receptor mediates protection against hepatic ischemia/reperfusion injury. FASEB J 21:1788-800 |
| Batkai, Sandor; Mukhopadhyay, Partha; Harvey-White, Judith et al. (2007) Endocannabinoids acting at CB1 receptors mediate the cardiac contractile dysfunction in vivo in cirrhotic rats. Am J Physiol Heart Circ Physiol 293:H1689-95 |
| Milman, Garry; Maor, Yehoshua; Abu-Lafi, Saleh et al. (2006) N-arachidonoyl L-serine, an endocannabinoid-like brain constituent with vasodilatory properties. Proc Natl Acad Sci U S A 103:2428-33 |
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| Wagner, Jens A; Abesser, Marco; Karcher, Jan et al. (2005) Coronary vasodilator effects of endogenous cannabinoids in vasopressin-preconstricted unpaced rat isolated hearts. J Cardiovasc Pharmacol 46:348-55 |
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