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Cannabinoid CB1 and CB2 Receptors Antagonists AM251 and AM630

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Cannabinoid CB1 and CB2 Receptors Antagonists AM251 and AM630 Pharmacological Reports 71 (2019) 82–89 Contents lists available at ScienceDirect Pharmacological Reports journal homepage: www.elsevier.com/locate/pharep Original article Cannabinoid CB1 and CB2 receptors antagonists AM251 and AM630 differentially modulate the chronotropic and inotropic effects of isoprenaline in isolated rat atria Jolanta Weresa, Anna Pe˛dzinska-Betiuk, Rafał Kossakowski, Barbara Malinowska* Department of Experimental Physiology and Pathophysiology, Medical University of Bialystok, Białystok, Poland A R T I C L E I N F O A B S T R A C T Article history: Background: Drugs targeting CB1 and CB2 receptors have been suggested to possess therapeutic benefit in Received 28 May 2018 cardiovascular disorders associated with elevated sympathetic tone. Limited data suggest cannabinoid Received in revised form 31 July 2018 ligands interact with postsynaptic β-adrenoceptors. The aim of this study was to examine the effects of Accepted 14 September 2018 CB1 and CB2 antagonists, AM251 and AM630, respectively, at functional cardiac β-adrenoceptors. Available online 17 September 2018 Methods: Experiments were carried out in isolated spontaneously beating right atria and paced left atria where inotropic and chronotropic increases were induced by isoprenaline and selective agonists of β1 and Keywords: β -adrenergic receptors. β-Adrenoceptor 2 Results: We found four different effects of AM251 and AM630 on the cardiostimulatory action of Cannabinoid receptor m AM251 isoprenaline: (1) both CB receptor antagonists 1 M enhanced the isoprenaline-induced increase in atrial AM630 rate, and AM630 1 mM enhanced the inotropic effect of isoprenaline; (2) AM251 1 mM decreased the Atria efficacy of the inotropic effect of isoprenaline; (3) AM251 0.1 and 3 mM and AM630 3 mM reduced the isoprenaline-induced increases in atrial rate; (4) AM630 0.1 and 3 mM enhanced the inotropic effect of isoprenaline, which was not changed by the same concentrations of AM251. Conclusions: Our results show that the CB1 and CB2 receptor antagonists AM251 and AM630 have bidirectional effects on the cardiostimulatory action of isoprenaline, most likely related to an interaction with β1-adrenoceptors. Provided that the results translate to human heart, caution should be taken when using CB1 and CB2 receptor antagonists, as an enhanced sympathetic tone accompanies many cardiovascular disorders. © 2018 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved. Introduction Cannabinoids are mainly known to decrease cardiac contractil- ity via CB1 receptors. The above effect is probably responsible in Cannabinoids (CB) exhibit complex cardiovascular effects. In hypertensive rats for the decrease in blood pressure induced by contrast to the large body of information on cannabinoid vascular anandamide and two of its degradation inhibitors, URB597 [4] and effects, surprisingly few studies have focused on cardiac effects. AM3506 [5]. The CB1-receptor-dependent negative inotropic The most well-known acute and chronic physiological changes effects of anandamide, methanandamide, and the synthetic produced by cannabis preparations in humans are tachycardia [1,2] cannabinoid CB receptor agonists HU-210 or CP55940 have been and symptomatic sinus bradycardia and ventricular asystole [3], determined in isolated human atrial muscle [6] and in rat heart [7] respectively. In rats, bradycardia is elicited by acute injection of the and atria [8,9]. A CB2 receptor-mediated positive inotropic effect of major psychoactive component of the cannabis plant, anandamide was identified in rat atria in the presence of the CB1 9 9 D -tetrahydrocannabinol (D -THC), the endocannabinoid ananda- receptor antagonist AM251 [8]. Under physiological conditions mide, its stable analogue methanandamide, or other synthetic none of the CB receptor antagonists modified cardiovascular cannabinoids [1,2]. parameters [1,2]. Unexpectedly, two pairs of antagonists, AM251 (CB1) and AM630 (CB2) in rat ventricular myocytes [10], and SR141716 (CB1) and SR144528 (CB2) in isolated heart [7], consistently led to negative inotropic effects. Moreover, presynaptic CB1 receptors on sympathetic nerve * Corresponding author. E-mail address: [email protected] (B. Malinowska). endings innervating the heart inhibit neurogenic tachycardia and/ https://doi.org/10.1016/j.pharep.2018.09.008 1734-1140/© 2018 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved. J. Weresa et al. / Pharmacological Reports 71 (2019) 82–89 83 or noradrenaline release in human atrial appendages [11 ] and Experimental protocols pithed rats [12]. In rat atria, anandamide [13] or anandamide and CP55940 [14], respectively, decreased or failed to modify the CB1 Atria were pretreated for 30 min with AM251, AM630, CP55940 receptor-mediated neurogenic tachycardia. or cannabidiol, for 60 min with the β1-adrenoceptor antagonist An interaction of cannabinoid ligands with postsynaptic CGP20712A or for 90 min with the β2-adrenoceptor antagonist β-adrenoceptors has also been described. The CB receptor ICI118551. Concentration-response curves (CRCs) were con- agonists WIN55212-2 and HU-210 inhibited cAMP production structed by cumulative addition of each agonist (for each and/or positive ino- and chronotropic effects elicited by the non- preparation only one CRC was determined): isoprenaline, IBMX, selective β-adrenoceptor agonist isoprenaline in rat cultured xamoterol, fenoterol, or CGP12177. CGP12177 was examined in the neonatal cardiomyocytes [15] and Langendorff perfused heart presence of propranolol 200 nM, a concentration that does not [16]. AM251 restored the blunted response to isoprenaline of rat modify the cardiostimulant effects of CGP12177 [27]. All antag- ventricular papillary muscle isolated from bile duct-ligated rats onists, CP55940 or cannabidiol were present during the construc- [17] and attenuated endotoxin/lipopolysaccharide-induced tion of the CRSs. tachycardia in rats [18]. Acute and chronic inhibition of anandamide degradation reduced the occurrence of isoprena- Drugs used line-induced ventricular tachyarrhythmia in rats [19] and differentially modified the ino- and chronotropic effects of (-)-Isoprenaline (Æ)-bitartrate salt, (Æ)-CGP12177 [(Æ)-4-[3- isoprenaline in atria and hearts isolated from hypertensive and [(1,1-dimethylethyl)amino]-2-hydroxypropyl]-1,3-dihydro-2H- normotensive rats [9]. benzimidazole-2-one hydrochloride], (Æ)-CGP20712A [(Æ)-2-hy- Drugs targeting CB1 [e.g. 20] and CB2 [e.g. 21] receptors have droxy-5-[2-[[2-hydroxy-3-[4-[1-methyl-4-(trifluoromethyl)-1H- been suggested as potential remedies against cardiovascular imidazol-2-yl]phenoxy]-propyl]amino]ethoxy]-benzamide meth- disorders associated with elevated sympathetic tone, such as anesulfonate], 3-isobutyl-1-methylxanthine (IBMX), CP55940 hypertension or heart failure [22]. The CB1 receptor antagonists [(-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3- modify hemodynamics and cardiac contractility functions [20]. hydroxy-propyl)-cyclohexanol], (S)-(À)-propranolol hydrochlo- The cardioprotective influence of CB2 receptor stimulation is ride (Sigma-Aldrich, Steinheim, Germany); ICI118551 [erythro- connected primarily with its immunosuppressive properties [21]. (Æ)-1-(7-methylindan-4-yloxy)-3-isopropylaminobutan-2-ol The possibility that cannabinoid receptor antagonists interact hydrochlo-ride], xamoterol hemifumarate, AM630 [6-iodo-2- with β-adrenoceptors, thereby leading to cardiac side effects, must methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxy- be considered. The aim of the present study was to examine the phenyl)methanone], AM251 [N-(piperidin-1-yl)-5-(4-iodo- effect of the CB1 antagonist AM251 and the CB2 antagonist AM630 phenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox- on the chronotropic and inotropic effects of isoprenaline in amide], (-)-cannabidiol (Tocris Bioscience, Bristol, UK); fenoterol isolated rat atria. In order to determine the precise mechanism of hydrobromide (MP Biomedicals, Solon, OH, USA) and pentobarbital the interaction, we also replaced (1) AM251 and AM630 by the sodium (Biowet, Puławy, Poland) were used. Stock solutions of non-selective CB receptor agonist CP55940 [23] and cannabidiol (a isoprenaline, IBMX, CGP12177, CGP20712A, ICI118551, fenoterol, cannabis plant-derived constituent with a low affinity at both CB xamoterol, and propranolol were prepared using distilled water. receptors [23] that has been already approved for the treatment of AM630, AM251, CP55940, and cannnabidiol were dissolved in spasticity in multiple sclerosis or intractable epilepsies [24] and dimethyl sulphoxide (DMSO, Sigma-Aldrich, Steinheim, Germany). (2) isoprenaline by the phosphodiesterase inhibitor IBMX, by The final concentration of DMSO in the organ bath was 0.1% v/v, agonists of β1- (xamoterol) and β2-adrenoceptors (fenoterol) and which enhanced basal HR by about 5% and diminished basal force by an agonist of the low-affinity state of the β1-adrenoceptor by about 10%. Further dilutions were made with Krebs solution. (CGP12177 [25]). Data analysis Materials and methods Results are given as the mean Æ SEM (n = number of animals). Animals Positive chronotropic effects are shown as changes from baseline values. Positive inotropic effects are shown as a percentage of the Experiments were conducted in accordance with the European maximum responses to isoprenaline, fenoterol or IBMX. To Directive 2010/63/EU and with the approval of the local
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