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(Hypertension. 2002;39:251.)
© 2002 American Heart Association, Inc.

Scientific Contributions

CB₁ Receptor Antagonist SR141716A Inhibits Ca²⁺-Induced Relaxation in CB₁ Receptor-Deficient Mice

Richard D. Bukoski; Sándor Bátkai; Zoltán Járai; Yanlin Wang; Laszlo Offertaler; William F. Jackson; George Kunos

From the Cardiovascular Disease Research Program, Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University (R.D.B., Y.W.), Durham; National Institute on Alcohol Abuse & Alcoholism, National Institutes of Health (S.B., Z.J., L.O., G.K.), Bethesda, Md; and Department of Biological Sciences, Western Michigan University (W.F.J.), Kalamazoo.

Correspondence to Richard Bukoski, PhD, Director, Cardiovascular Disease Research Program, Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, 700 George St, Durham, NC 27707. E-mail rbukoski{at}wpo.nccu.edu

Mesenteric branch arteries isolated from cannabinoid type 1 receptor knockout (CB₁^-/-) mice, their wild-type littermates (CB₁^+/+ mice), and C57BL/J wild-type mice were studied to test the hypothesis that murine arteries undergo high sensitivity Ca²⁺-induced relaxation that is CB₁ receptor dependent. Confocal microscope analysis of mesenteric branch arteries from wild-type mice showed the presence of Ca²⁺ receptor-positive periadventitial nerves. Arterial segments of C57 control mice mounted on wire myographs contracted in response to 5 µmol/L norepinephrine and responded to the cumulative addition of extracellular Ca²⁺ with a concentration-dependent relaxation that reached a maximum of 72.0±6.3% of the prerelaxation tone and had an EC₅₀ for Ca²⁺ of 2.90±0.54 mmol/L. The relaxation was antagonized by precontraction in buffer containing 100 mmol/L K⁺ and by pretreatment with 10 mmol/L tetraethylammonium. Arteries from CB₁^-/- and CB₁^+/+ mice also relaxed in response to extracellular Ca²⁺ with no differences being detected between the knockout and their littermate controls. SR141716A, a selective CB₁ antagonist, caused concentration-dependent inhibition of Ca²⁺-induced relaxation in both the knockout and wild-type strains (60% inhibition at 1 µmol/L). O-1918, a cannabidiol analog, had a similar blocking effect in arteries of both wild-type and CB₁^-/- mice at 10 µmol/L. In contrast, 1 µmol/L SR144538, a cannabinoid type 2 receptor antagonist, or 50 µmol/L 18-glycyrrhetinic acid, a gap junction blocker, were without effect. SR141716A (1 to 30 µmol/L) was also assessed for nonspecific actions on whole-cell K⁺ currents in isolated vascular smooth muscle cells. SR141716A inhibited macroscopic K⁺ currents at concentrations higher than those required to inhibit Ca²⁺-induced relaxation, and appeared to have little effect on currents through large conductance Ca²⁺-activated K⁺ channels. These data indicate that arteries of the mouse relax in response to cumulative addition of extracellular Ca²⁺ in a hyperpolarization-dependent manner and rule out a role for CB₁ or CB₂ receptors in this effect. The possible role of a nonclassical cannabinoid receptor is discussed.

Key Words: mesenteric arteries • calcium • relaxation • potassium channels

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