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Cannabinoid-Induced Hypotension and Bradycardia in Rats Is 1 Mediated by CB1-Like Cannabinoid Receptors

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Cannabinoid-Induced Hypotension and Bradycardia in Rats Is 1 Mediated by CB1-Like Cannabinoid Receptors 0022-3565/97/2813-1030$03.00/0 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 281, No. 3 Copyright © 1997 by The American Society for Pharmacology and Experimental Therapeutics Printed in U.S.A. JPET 281:1030–1037, 1997 Cannabinoid-Induced Hypotension and Bradycardia in Rats Is 1 Mediated by CB1-Like Cannabinoid Receptors KRISTY D. LAKE, DAVID R. COMPTON, KAROLY VARGA, BILLY R. MARTIN and GEORGE KUNOS Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia Accepted for publication February 19, 1997 ABSTRACT 9 Previous studies indicate that the CB1 cannabinoid receptor an- potency was (-)-11-OH-D -THC dimethylheptyl $ (-)-3-[2- tagonist, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophe- hydroxy-4-(1,1-dimethyl-heptyl)phenyl]-4-[3-hydroxy-propyl]cy- nyl)-4-methyl-1H-pyrazole-3-carboxamide HCl (SR141716A), in- clohexan-1-ol . (-)-3-[2-hydroxy-4-(1,1-dimethyl-heptyl)phenyl]- hibits the anandamide- and D9-tetrahydrocannabinol- (THC) 4-[3-hydroxy-propyl]cyclohexan-1-ol . THC . anandamide $ induced hypotension and bradycardia in anesthetized rats with a (-)-3-[2-hydroxy-4-(1,1-dimethyl-heptyl)phenyl]-4-[3-hydroxy- potency similar to that observed for SR141716A antagonism of propyl]cyclohexan-1-ol, which correlated well with CB1 receptor THC-induced neurobehavioral effects. To further test the role of affinity or analgesic potency (r 5 0.96-0.99). There was no hypo- CB1 receptors in the cardiovascular effects of cannabinoids, we tension or bradycardia after palmitoylethanolamine or (1)-11-OH- examined two additional criteria for receptor-specific interactions: D9-THC dimethylheptyl. An initial pressor response was also ob- the rank order of potency of agonists and stereoselectivity. A served with THC and anandamide, which was not antagonized by series of cannabinoid analogs including the enantiomeric pair SR141716A. We conclude that the similar rank orders of potency, (-)-11-OH-D9-THC dimethylheptyl (1)-11-OH-D9-THC dimethyl- stereoselectivity and sensitivity to blockade by SR141716A indi- heptyl were evaluated for their effects on arterial blood pressure cate the involvement of CB1-like receptors in the hypotensive and and heart rate in urethane anesthetized rats. Six analogs elicited bradycardic actions of cannabinoids, whereas the mechanism of pronounced and long lasting hypotension and bradycardia that the pressor effect of THC and anandamide remains unclear. were blocked by 3 mg/kg of SR141716A. The rank order of In anesthetized animals, the major psychoactive constitu- the brain (Matsuda et al., 1990; Gerard et al., 1991), and in ent of Cannabis sativa, THC, elicits a transient pressor re- some peripheral organs (Shire et al., 1995; Ishac et al., 1996), sponse followed by hypotension and bradycardia (Dewey et and the CB2 receptor identified in macrophages (Munro et al., 1970; Graham and Li, 1973; Estrada et al., 1987). In rats al., 1993; Galiegue et al., 1995). Additionally, a splice variant with genetic or surgically induced hypertension, THC signif- of the CB1 receptor, the CB1A receptor has also been de- icantly lowers mean arterial blood pressure to normotensive scribed (Shire et al., 1995). levels (Stark and Dews, 1980; Birmingham, 1973; Nahas et In 1992, an endogenous cannabinoid receptor ligand, anan- al., 1973), and it has also been shown to prevent immobili- damide (arachidonyl-2-ethanolamide), was extracted and pu- zation stress-induced hypertension (Williams and Ng, 1973). rified from porcine brain (Devane et al., 1992). As with THC, Cannabinoid receptors have been identified in the rat by anandamide binds to cannabinoid receptors (Vogel et al., radioligand binding and autoradiography (Devane et al., 1993; Felder et al., 1993), inhibits adenylate cyclase via an 1988; Herkenham et al., 1990). Subsequently, two cannabi- inhibitory G-protein (Vogel et al., 1993), and inhibits voltage- noid receptors have been cloned: the CB receptor located in 1 gated N-type calcium channels (Felder et al., 1993). In neu- robehavioral assays, anandamide has been shown to mimic Received for publication October 3, 1996. THC in terms of inducing catalepsy, hypomotility, hypother- 1 This work was supported by NIH Grants HL-49938 to G.K., DA-09789 to mia and analgesia (Fride et al., 1993; Smith, et al., 1994). We B.R.M. and AHA Virginia Affiliate Grant VA-96-GS7 to K.V. Support for K.D.L. was by NIH training Grant DA07027. previously demonstrated that in anesthetized rats, anand- ABBREVIATIONS: THC, D9-tetrahydrocannabinol; CP-55,940, (-)-3-[2-hydroxy-4-(1,1-dimethyl-heptyl)phenyl]-4-[3-hydroxy-propyl]cyclohexan- 1-ol; HU-210, (-)-11-OH-D9-THC dimethylheptyl; HU-211, (1)-11-OH-D9-THC dimethylheptyl; WIN-55212-2, O-502, {(R)-(1)-[2,3-dihydro-5- methyl-3-[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-(1-naphthalenyl) methanone} JWH-015, (-)-3-[2-hydroxy-4-(1,1-dimethyl- heptyl)phenyl]-4-[3-hydroxy-propyl]cyclohexan-1-ol;; O-502, 49-(R)-OH-diadduct-D9-THC; O-522, 49-(S)-OH-diadduct-D9-THC; SR141716A, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl; ABN-CBD, abnormal-cannabidiol; MAP, mean arterial blood pressure; HR, heart rate; bpm, beats per minute; ED50, agonist dose producing half-maximal effect, AD50, antagonist dose causing 50% inhibition of agonist response 1030 1997 Cardiovascular Effects of Cannabinoids 1031 amide causes a pressor response followed by hypotension and Mechoulam (Hebrew University, Jerusalem, Israel). CP-55940 and mild bradycardia (Varga et al., 1995), and similar effects SR141716A were provided by Dr. John Lowe at Pfizer Central Re- have been observed in both conscious and anesthetized, spon- search. JWH-015 was synthesized by Dr. John Huffman (Clemson 9 taneously hypertensive rats (Lake et al., 1997). The hypoten- University). D -THC was obtained from the National Institute on sive and bradycardic responses to anandamide and THC are Drug Abuse. WIN-55212-2 was purchased from Research Biochemi- cals International (Natick, MA). Palmitoylethanolamine was pur- inhibited by the selective CB receptor antagonist, 1 chased from BIOMOL Research Laboratories, Inc. (Plymouth Meet- SR141716A (Rinaldi-Carmona et al., 1994), which suggests ing, PA). All drugs were dissolved in 1:1:18 or 1:1:8 (emulphor- the involvement of CB1 receptors (Varga et al., 1995). Acti- ethanol-saline). Emulphor (EL-620, a polyoxyethylated vegetable oil, vation of these receptors was found to inhibit sympathetic GAF Corporation, Linden, NJ) is currently available as Alkmulphor. tone via a presynaptic mechanism at peripheral sympathetic The dosing volume was 0.5 to 1 ml/kg i.v., followed by a catheter line nerve terminals (Varga et al., 1996; Ishac et al., 1996). CB1 flush of 0.2 ml saline. Injection of the same volume of vehicle had no receptors in the brain that mediate the neurobehavioral ef- effect on blood pressure or heart rate. All drugs were injected i.v. as fects of cannabinoids have been characterized not only by bolus doses over a 10- to 15-sec period. their susceptibility to inhibition by SR141716A (Rinaldi Car- Data analysis. MAP was calculated as 1/3(systolic-diastolic BP) mona et al., 1994; Compton et al., 1996), but also by their 1 diastolic BP. Basal MAP and HR for all groups was 102 6 4.8 mmHg and 325 5.4 bpm, respectively (n 96). Time-dependent, selective interaction with cannabinoid enantiomers (Little et 6 5 agonist-induced changes in MAP and HR in the absence or presence al., 1989). Furthermore, the rank order of potency of various of SR141716A were compared using analysis of variance followed by cannabinoid analogs for eliciting neurobehavioral effects cor- Tukey’s post hoc test. The ED50 for each agonist was calculated using relates well with their binding affinities for the brain canna- ALLFIT, a nonlinear sigmoidal curve-fitting program (DeLean et al., binoid receptor (Compton et al., 1992a, 1993). To further test 1977). For anandamide and THC, which produce both a pressor and whether the CB1 receptors mediating neurobehavioral and a subsequent depressor response, ED50s for both components were cardiovascular effects are pharmacologically similar, we an- calculated, using the peak response minus predrug baseline value in alyzed the cardiovascular effects of a series of cannabinoid both cases. The ED50 for the depressor response to THC was calcu- analogs, including enantiomeric pairs, in urethane-anesthe- lated based on the descending portion of the biphasic curve. Corre- tized rats. The results indicate that the pronounced hypo- lation analysis and generation of the Pearson product-moment coef- ficient was performed using the StatView statistical package tension and bradycardia induced by structurally different (Brainpower, Inc., Agoura Hills, CA). Data are presented as mean 6 cannabinoids are mediated by receptors that are pharmaco- S.E. of the mean. logically similar to brain CB1 receptors mediating neurobe- havioral effects. In contrast, the mechanism of the brief pres- Results sor response elicited by some cannabinoids remains unclear. THC (0.02-10 mg/kg, fig. 2A) elicited an initial brief pressor Methods response followed by prolonged and marked hypotension and bradycardia. Dose-response relationships for these latter ef- Animals. Adult male Sprague-Dawley rats weighing 280 to 400 g fects were biphasic with maximal hypotension (-62 6 9 were obtained from Harlan (Indianapolis, IN) and were housed in mmHg) observed at 2 mg/kg and maximal bradycardia suspension cages with food and water ad libitum. The animals were (-140 6 24 bpm) observed at 8 mg/kg of THC, beyond which maintained at 24 to 26°C under a 14:10 hr light/dark cycle and were doses the hypotensive and bradycardic effects were less pro- allowed to acclimate for at least 1 wk before surgery. Surgical preparation. Anesthesia was induced with diethyl nounced (fig.
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