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Cannabidiol Affects the Bezold-Jarisch Reflex via TRPV1 and 5-HT 3 Receptors and Has Peripheral Sympathomimetic Effects in Spontaneously Hypertensive and Normotensive Rats

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Cannabidiol Affects the Bezold-Jarisch Reflex via TRPV1 and 5-HT 3 Receptors and Has Peripheral Sympathomimetic Effects in Spontaneously Hypertensive and Normotensive Rats

Rafał Kossakowski et al. Front Pharmacol.

Abstract

Cannabidiol (CBD) is a nonpsychotropic constituent of Cannabis sativa L. It is suggested to be useful in hypertension. Under in vitro conditions, it activates vanilloid TRPV1 and inhibits serotonin 5-HT3 receptors, i.e., receptors involved in the Bezold-Jarisch reflex stimulation. The aim of our study was to compare the cardiovascular effects of CBD in spontaneously hypertensive (SHR) and normotensive Wistar Kyoto (WKY) rats. Experiments were performed on conscious, urethane-anesthetized, and pithed rats. In pithed SHR and WKY, CBD increased heart rate (HR) and systolic blood pressure (SBP) and decreased diastolic BP (DBP) in a manner insensitive to adrenalectomy. Propranolol strongly impaired the CBD-induced increases in HR and SBP without affecting the decreases in DBP. Desipramine also reduced the CBD-induced effects on HR and SBP and further increased its effects on DBP. In anesthetized rats, bolus i.v. injection of single doses of CBD induced short-lasting decreases in HR, SBP, and DBP, stronger in SHR than in WKY and prevented by bilateral vagotomy. The CBD-induced fall in HR but not in BP was diminished by the TRPV1 receptor antagonist capsazepine and almost completely abolished if CBD was re-injected after previous administration. CBD reduced the Bezold-Jarisch reflex elicited by the 5-HT3 receptor agonist phenylbiguanide but not that evoked by the TRPV1 agonist capsaicin. In conscious rats, CBD did not affect cardiovascular parameters. In isolated left atria, CBD decreased contractile force. Conclusions: Cannabidiol (1) induces the Bezold-Jarisch reflex likely via TRPV1 receptors (which undergo tachyphylaxis) more markedly in SHR than in WKY; (2) inhibits the Bezold-Jarisch reflex induced by activation of 5-HT3 but not TRPV1 receptors; (3) has peripheral sympathomimetic, (4) vasodilatory, and (5) negative inotropic effects. The above properties of CBD should be taken under consideration when CBD is used for therapeutic purposes.

Keywords: 5-HT3 receptors; Bezold-Jarisch reflex; TRPV1 receptors; arterial hypertension; cannabidiol; sympathomimetic.

Figures

Figure 1
Figure 1
Influence of propranolol 0.3 mg/kg (B,D,F,H,J,L) and its vehicle (A,C,E,G,I,K) on changes in heart rate (HR; A–D) and systolic (SBP; E–H) and diastolic (DBP; I–L) blood pressure elicited by cannabidiol (CBD) in urethane-anesthetized and pithed normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. Data are given as the means ± SEM of 5–6 rats. For comparison of mean values, the t test for paired data was used. #p < 0.05; ###p < 0.001 in comparison to the respective values before administration of propranolol (S1).
Figure 2
Figure 2
Influence of desipramine (0.03, 0.09 and 0.3 mg/kg) or its vehicle (0) on the cannabidiol [CBD 3 (A,C,E) and 10 (B,D,F) mg/kg]-induced changes in heart rate (HR; A,B) and systolic (SBP; C,D) and diastolic (DBP; E,F) blood pressure in urethane-anesthetized and pithed normotensive Wistar-Kyoto rats (WKY). Data are given as the means ± SEM of 5–6 rats. For comparison of mean values, the t test for paired data was used. #p < 0.05; ##p < 0.01; ###p < 0.001 in comparison to the respective values before administration of desipramine (S1).
Figure 3
Figure 3
Influence of propranolol 0.3 mg/kg (B) and its vehicle (A) on changes in heart rate (HR) elicited by cannabidiol (CBD) in urethane-anesthetized, pithed and adrenalectomized normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. Data are given as the means ± SEM of 5–6 rats. For comparison of mean values, the t test for paired data was used. #p < 0.05; ###p < 0.001 in comparison to the respective values before administration of propranolol (S1).
Figure 4
Figure 4
Influence of intravenous injection of cannabidiol (CBD) on heart rate (HR; A,D) and systolic (SBP; B,E) and diastolic (DBP; C,F) blood pressure in urethane-anesthetized normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. With one exception all doses of CBD were examined in separate animals. Changes were determined under the following conditions, i.e., in all rats (CONTROL); in rats with comparable basal values (for explanation, see text or legend to Table 1); when CBD 10 mg/kg was given after CBD 30 mg/kg; after vagotomy; and in the presence of capsazepine 0.4 mg/kg or its vehicle. Data are given as the means ± SEM of 5–22 rats. We used the t test for unpaired data (* and $) and the one-way analysis of variance (ANOVA) followed by the Dunnett post hoc test (#). *p < 0.05; **p < 0.01; ***p < 0.001 in comparison to the respective values in WKY; #p < 0.05; ##p < 0.01; ###p < 0.001 in comparison to the respective CONTROL group; $$p < 0.01; $$$p < 0.001 in comparison to the respective group treated with vehicle for capsazepine.
Figure 5
Figure 5
Influence of intravenous injection of cannabidiol (CBD) 10 mg/kg or its vehicle on decreases in heart rate (HR; A,D) and systolic (SBP; B) and diastolic (DBP; C,E) blood pressure induced by bolus injection of phenylbiguanide (A–C) and capsaicin (D,E) in urethane-anesthetized normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. Data are given as the means ± SEM of 6–11 rats. We used the t test for unpaired data. *p < 0.01; **p < 0.01; ***p < 0.001 in comparison to the respective values in WKY; ΔΔp < 0.01; ΔΔΔp < 0.001 in comparison to the respective group treated with vehicle for CBD.
Figure 6
Figure 6
Telemetered heart rate (HR, A), systolic (SBP, B) and diastolic (DBP, C) blood pressure in normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats before and after intraperitoneal injection with cannabidiol (CBD) 10 mg/kg over a time period of about 30 sec or its vehicle at time 0. Data are given as the means ± SEM of 4 rats per group. They were analysed by repeated two-way analysis of variance (ANOVA) with the Bonferroni post hoc test. All values of SBP and DBP in SHR (in the presence of CBD or its vehicle) were higher than their respective values in WKY (p < 0.01). #p < 0.05; ##p < 0.01; ###p < 0.001 vs the respective value at time 0.
Figure 7
Figure 7
Influence of cannabidiol (CBD) or its vehicle on contractile force of left atria isolated from normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. Data are given as the means ± SEM of 5–6 rats. They were analysed by the one-way analysis of variance (ANOVA) followed by the Dunnett post hoc test. Δp < 0.05; ΔΔp < 0.01; ΔΔΔp < 0.001 in comparison to the respective values without CBD. *p < 0.05 in comparison to the respective value in SHR.
Figure 8
Figure 8
Possible mechanisms involved in the cardiovascular effects of cannabidiol (CBD) in normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats.

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References

    1. Ali R. M., Al Kury L. T., Yang K. H., Qureshi A., Rajesh M., Galadari S., et al. . (2015). Effects of cannabidiol on contractions and calcium signaling in rat ventricular myocytes. Cell Calcium 57, 290–299. 10.1016/j.ceca.2015.02.001, PMID: - DOI - PubMed
    1. Alves F. H., Crestani C. C., Gomes F. V., Guimarães F. S., Correa F. M., Resstel L. B. (2010). Cannabidiol injected into the bed nucleus of the stria terminalis modulates baroreflex activity through 5-HT1A receptors. Pharmacol. Res. 62, 228–236. 10.1016/j.phrs.2010.05.003, PMID: - DOI - PubMed
    1. Bevan S., Hothi S., Hughes G., James I. F., Rang H. P., Shah K., et al. . (1992). Capsazepine: a competitive antagonist of the sensory neurone excitant capsaicin. Br. J. Pharmacol. 107, 544–552. 10.1111/j.1476-5381.1992.tb12781.x, PMID: - DOI - PMC - PubMed
    1. Bisogno T., Hanus L., De Petrocellis L., Tchilibon S., Ponde D. E., Brandi I., et al. . (2001). Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br. J. Pharmacol. 134, 845–852. 10.1038/sj.bjp.0704327, PMID: - DOI - PMC - PubMed
    1. Booz G. W. (2011). Cannabidiol as an emergent therapeutic strategy for lessening the impact of inflammation on oxidative stress. Free Radic. Biol. Med. 51, 1054–1061. 10.1016/j.freeradbiomed.2011.01.007, PMID: - DOI - PMC - PubMed

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