Abstract The CB1 subtype of the cannabinoid receptor is present on neurons in the brain and mediates the perceptual effects of Δ 9 -tetrahydrocannabinol and other cannabinoids. We found that cat cerebral arterial smooth muscle cells (VSMC) contain the protein for the CB1 receptor and express 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 Ca 2+ channels in neurons through a pertussis toxin-sensitive GTP-binding protein. In the present study we tested the hypothesis that activation of the cannabinoid CB1 receptor in cerebral VSMC inhibits voltage-gated Ca 2+ channels and results in cerebral vasodilation. The predominant Ca 2+ current identified in cat cerebral VSMC is a voltage-gated, dihydropyridine-sensitive, L-type Ca 2+ current. The cannabimimetic drug WIN-55,212-2 (10–100 nM) induced concentration-dependent inhibition of peak L-type Ca 2+ current, which reached a maximum of 82 ± 4% at 100 nM ( n = 14). This effect was mimicked by the putative endogenous CB1-receptor agonist anandamide, which produced a concentration-related reduction of peak L-type Ca 2+ current with a maximum inhibition (at 300 nM) of 39 ± 4% ( n = 12). The inhibitory effects of both ligands on peak L-type Ca 2+ currents were abolished by pertussis toxin pretreatment and application of the CB1-receptor antagonist SR-141716A (100 nM, n = 5). Both WIN-55,212-2 and anandamide produced concentration-dependent relaxation of preconstricted cerebral arterial segments that was abolished by SR-141716A. These results indicate that the CB1 receptor is expressed in cat cerebral VSMC and that the cerebral vasculature is one of the targets for endogenous cannabinoids. 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 Ca 2+ through L-type Ca 2+ channels. anandamide WIN-55,2121–2 SR-141716A whole cell patch clamp vasodilation Footnotes Address for reprint requests and other correspondence: C. J. Hillard, Dept. of Pharmacology and Toxicology, 8701 Watertown Plank Rd., Milwaukee, WI 53226 (E-mail: firstname.lastname@example.org ). This study was supported by National Institutes of Health Grants DA-09155 (to C. J. Hillard and W. B. Campbell), R37-HL-33883-13 (to D. R. Harder), and DA08098 (to C. J. Hillard), and by Veterans Affairs Grant 3440-06-P (to D. R. Harder). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “ advertisement ” in accordance with 18 U.S.C. §1734 solely to indicate this fact. Copyright © 1999 the American Physiological Society
AJP - Heart and Circulatory Physiology – The American Physiological Society
Published: Jun 1, 1999
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