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Effects of Abnormal Cannabidiol on Oxytocin-Induced Myometrial Contractility

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Effects of Abnormal Cannabidiol on Oxytocin-Induced Myometrial Contractility REPRODUCTIONRESEARCH Effects of abnormal cannabidiol on oxytocin-induced myometrial contractility Diarmaid D Houlihan, Michael C Dennedy and John J Morrison Department of Obstetrics and Gynecology, Clinical Sciences Institute, University College Hospital, National University of Ireland Galway, Newcastle Road, Galway, Ireland Correspondence should be addressed to J J Morrison; Email: [email protected] Abstract The objective of this study was to investigate the effects of abnormal cannabidiol (abn-cbd) on oxytocin-induced myometrial contractility occurring during pregnancy. Isometric tension recordings were performed in isolated myometrial strips from biopsies obtained at K K elective cesarean section. The effects of cumulative doses of abn-cbd (10 9–10 5 M) on oxytocin-induced myometrial contractions alone, and on those following pre-incubation with SR 144528, AM 251, methylene blue, and iberiotoxin were measured, and dose– K response curves were constructed. The pD2 ( log EC50) values and the maximal inhibitory (MMI) values that were achieved were compared for each tissue type. Abn-cbd exerted a potent relaxant effect on oxytocin-induced myometrial contractions in vitro. Pre-incubation with the guanylate cyclase inhibitor, methylene blue, and the BKCa channel antagonist, iberiotoxin, significantly ! ! attenuated this effect (for pD2, P 0.01; for MMI, P 0.01). Abn-cbd exerts a potent inhibitory effect on human uterine contractility. This effect is partially mediated through modulation of guanylate cyclase and activation of BKCa channel activity. These findings have implications for physiologic regulation of myometrial quiescence. Reproduction (2010) 139 783–788 Introduction regioisomer of cannabidiol, which mediates a relaxant effect in isolated rat mesenteric artery via a mechanism The endocannabinoids comprise a family of eicosanoid that is distinct from CB1 and CB2 receptor activation and related unsaturated fatty acid derivatives, of which (Jarai et al. 1999), and is independent of nitric oxide anandamide was the first to be described (Devane et al. signaling and vanilloid receptor activation (Offertaler 1992). Two cannabinoid receptors that belong to the et al. 2003). The vascular smooth muscle relaxant effect superfamily of G /G protein-coupled receptors have i o of abn-cbd occurs via a mechanism that involves been cloned (Howlett 2002). The cannabinoid type 1 (CB1) receptor is expressed primarily in the brain and guanylate cyclase signaling and potassium channel peripheral tissues (Matsuda et al. 1990, Howlett 2002), activation, but a distinct receptor mediating this effect while the cannabinoid type 2 (CB2) receptor appears to has not been identified yet (Begg et al. 2003). be confined to the cellular components of the immune Endocannabinoids may play an important role in the system (Berdyshev 2000). In addition to the well- modulation of parturition and pregnancy (Park et al. 2004). Our group has demonstrated previously that described neurobehavioral effects of cannabinoids, the 9 endocannabinoids influence important biological and endogenous and exogenous cannabinoids, D -tetrahy- physiological processes (Hillard 2000, Pertwee 2001, drocannabinol and anandamide, mediate a direct, Wilson & Nicoll 2002). relaxant effect on myometrial contractility in vitro The cannabinoids are known to exert profound through an action at the CB1 receptor, which is sensitive relaxant effects on smooth muscle systems. The to blockade by the CB1 receptor antagonist SR 141716, mechanisms underlying these effects are varied and but not to that by the CB2 receptor antagonist SR 144728 include alteration of sympathetic nervous tone (Ishac (Dennedy et al. 2004). There are no further studies et al. 1996), modulation of vanilloid receptors located investigating other putative mechanisms of cannabinoid- on perivascular nerves (Zygmunt et al. 1999), and induced myometrial relaxation. The aims of this study finally direct interaction with cannabinoid receptors were to investigate the direct effects of the synthetic located on smooth muscle cells and on pre-junctional cannabinoid, abn-cbd, on human uterine contractility neurons in various mammalian tissues (Gebremedhin during pregnancy, and to investigate non-CB1/non-CB2 et al. 1999, Martin et al. 2000, Hinds et al. 2006). mechanisms through which this compound produces Abnormal cannabidiol (abn-cbd) is a synthetic myometrial relaxation. q 2010 Society for Reproduction and Fertility DOI: 10.1530/REP-09-0496 ISSN 1470–1626 (paper) 1741–7899 (online) Online version via www.reproduction-online.org Downloaded from Bioscientifica.com at 10/02/2021 07:07:14PM via free access 784 D D Houlihan and others with the CB1 antagonist, AM 251, or the CB2 antagonist, SR 144528, did not produce an effect on the dose– response curve following the sequential addition of abn- cbd as illustrated in Figs 2 and 3. Post hoc analysis showed that the addition of these compounds did not yield a significant difference in the pD2 or MMI values across these groups (nZ6, Table 1). Conversely, pre-incubation of the tissue baths with both the guanylate cyclase inhibitor, methylene blue, and the selective BKCa, channel antagonist, IbTX, produced a parallel rightward shift of the dose–response compared with vehicle controls. Post hoc analysis of these data showed a significant difference between the pD2 and the MMI values for abn-cbd in the presence and absence of these compounds (nZ6, P!0.01, Table 1). Figures 4 and 5 illustrate the respective dose–response curves. There were no differences in the contractile activity between control strips and those pre-incubated Figure 1 Effects of abn-cbd on myometrial contractions. (A) Repre- with each of the test drugs. sentative recordings of oxytocin-induced contractions of pregnant human myometrium. (B) The effects of cumulative additions of abn-cbd (1 nM–10 mM) at 20-min intervals to this tissue type. The myometrial response to incremental doses of abn-cbd following pre-incubation Discussion with (C) AM 251, (D) SR 144528, (E) methylene blue (MB), and (F) iberiotoxin (IbTX). Our study demonstrates that the compound abn-cbd exerts a potent inhibitory effect on human uterine Results contractility in vitro. The magnitude of this inhibition is comparable to that of other established physiological Abn-cbd exerted a potent concentration-dependent and pharmacological uterorelaxant agents including inhibitory effect on oxytocin-induced myometrial con- human chorionic gonadotropin, cyclooxygenase tractions in vitro. The calculated pD2 for abn-cbd was b G inhibitors, -adrenergic agonists, and oxytocin antagon- 5.81 0.34, while the maximal inhibitory (MMI) ists (Buscher et al. 2001, Dennedy et al. 2001, Slattery G response value was 60.27 4.70%. Representative et al. 2001, Doheny et al.2003). Abn-cbd has a recordings demonstrating the effects of abn-cbd on potency of myometrial relaxation that is similar to the oxytocin-induced myometrial contractions and the naturally occurring cannabinoids, anandamide (pD2 effects of vehicle control on similar strips are shown in value 5.58G0.42 and MMI value 75.8G2.20) and Fig. 1A and B. 9 G D -tetrahydrocannabinol (pD2 value 5.19 0.91 and The effects of pre-treatment with the following agents: MMI value 75.1G1.15; Dennedy et al. 2004). The AM 251 (Fig. 1C), SR 144528 (Fig. 1D), methylene blue findings from this study show that signaling via the CB1 (Fig. 1E), and IbTX (Fig. 1F) on uterine contractions, or CB2 receptor is not a major component of the following the addition of cumulative doses of abn-cbd, abd-cbd-mediated myometrial relaxation. Pre-incubation are demonstrated in Fig. 1. Comparison of pD2 and MMI with methylene blue caused a significant reduction in values for the relaxant effects of abn-cbd on all the inhibitory effect of abn-cbd on myometrial contrac- myometrial contraction types revealed a significant tility. At tissue bath concentrations used in this study, ! difference across the groups (for pD2, P 0.01; for MMI, methylene blue is a selective antagonist of soluble ! P 0.01). The MMI value and pD2 value for each guanylate cyclase and does not influence spontaneous respective group are given in Table 1. Pre-incubation uterine contractile activity (Houlihan et al. 2002, Table 1 pD2 and maximal inhibitory (MMI) values following the sequential addition of cumulative doses of abnormal cannabidiol (abn-cbd) to all tissue types. G G Agonist Antagonist Site of action n pD2 S.E.M. MMI S.E.M.% Abn-cbd None None 6 5.81G0.34 60.27G4.71 Abn-cbd AM 251 CB1 receptor antagonist 6 5.61G0.46 56.32G7.40 Abn-cbd SR 144528 CB2 receptor antagonist 6 5.63G0.33 55.67G6.72 Abn-cbd Methylene blue Guanylate cyclase inhibitor 6 4.48G0.17* 30.40G3.78† G G † Abn-cbd Iberiotoxin BKCa channel antagonist 6 4.52 0.21* 31.17 4.51 ! † ! *P 0.01 versus pD2 values for abn-cbd and all other groups. P 0.01 versus maximal inhibition values for abn-cbd and all groups. Analysis of variance followed by Fisher’s LSD (protected t-test) test. Reproduction (2010) 139 783–788 www.reproduction-online.org Downloaded from Bioscientifica.com at 10/02/2021 07:07:14PM via free access Effects of abn-cbd on myometrial contractions 785 remains the possibility, not proven in this study, that an alternative or novel cannabinoid receptor may be involved. The role of the cannabinoids in human pregnancy and parturition remains incompletely understood, and it is the subject of further study. Serial measurement of the endocannabinoid, anandamide, during human preg- nancy suggests that serum concentrations of this compound increase during pregnancy with peak concentrations detected just before the onset of labor (Habayeb et al. 2004). CB1 receptor inactivation in mice induces preterm labor by altering normal progesterone and estrogen levels, in addition to interfering with the corticotropin-releasing hormone–corticosterone axis during late pregnancy (Wang et al. 2008). We have demonstrated previously the expression of CB1 and CB2 Figure 2 Dose–response curves for abn-cbd in the presence and receptors on human pregnant myometrium, and have absence of the selective CB1 receptor antagonist AM 251.
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