Cannabinoid CB1 receptor of cat cerebral arterial muscle functions to inhibit L-type Ca2+ channel current

Cannabinoid CB1 receptor of cat cerebral arterial muscle functions to inhib it L-type Ca2+ channel current. Am. J. Physiol. 276 (Heart Circ. Physiol. 4 5): H2085-H2093, 1999.-The CB1 subtype of the cannabinoid receptor is prese nt on neurons in the brain and mediates the perceptual effects of hs-tetrah ydrocannabinol and other cannabinoids. We found that cat cerebral arterial smooth muscle cells (VSMC) contain the protein for the CB1 receptor and exp ress a cDNA that has >98% amino acid homology to the CB1 cDNA expressed in rat and human neurons. Activation of the CB1 cannabinoid receptor has been shown to decrease the opening of N-type voltage-gated Ca2+ channels in neur ons through a pertussis toxin-sensitive GTP-binding protein. In the present study we tested the hypothesis that activation of the cannabinoid CB1 rece ptor in cerebral VSMC inhibits voltage-gated Ca2+ channels and results in c erebral vasodilation. The predominant Ca2+ current identified in cat cerebr al VSMC is a voltage-gated, dihydropyridine-sensitive, L-type Ca2+ current. The cannabimimetic drug WIN-55,212-2 (10-100 nM) induced concentration-dep endent inhibition of peak L-type Ca2+ current, which reached a maximum of 8 2 +/- 4% at 100 nM (n = 14). This effect was mimicked by the putative endog enous CB1-receptor agonist anandamide, which produced a concentration-relat ed reduction of peak L-type Ca2+ current with a maximum inhibition (at 300 nM) of 39 +/- 4% (n = 12). The inhibitory effects of both ligands on peak L -type Ca2+ currents were abolished by pertussis toxin pretreatment and appl ication of the CB1-receptor antagonist SR-141716A (100 nM, n = 5), Both WIN -55,212-2 and anandamide produced concentration-dependent relaxation of pre constricted cerebral arterial segments that was abolished by SR-141716A. Th ese results indicate that the CB1 receptor is expressed in cat cerebral VSM C and that the cerebral vasculature is one of the targets for endogenous ca nnabinoids. These findings suggest that the CB1 receptor and its endogenous ligand may play a fundamental role in the regulation of cerebral arterial tone and reactivity by modulating the influx of Ca2+ through L-type Ca2+ ch annels.