Cannabidiol Affects the Bezold-Jarisch Reflex via TRPV1 and 5-HT3 Receptors and Has Peripheral Sympathomimetic Effects in Spontaneously Hypertensive and Normotensive Rats

Rafał Kossakowski; Eberhard Schlicker; Marek Toczek; Jolanta Weresa; Barbara Malinowska

doi:10.3389/fphar.2019.00500

Cannabidiol Affects the Bezold-Jarisch Reflex via TRPV1 and 5-HT₃ Receptors and Has Peripheral Sympathomimetic Effects in Spontaneously Hypertensive and Normotensive Rats

Front Pharmacol. 2019 May 22:10:500. doi: 10.3389/fphar.2019.00500. eCollection 2019.

Authors

Rafał Kossakowski¹, Eberhard Schlicker², Marek Toczek¹, Jolanta Weresa¹, Barbara Malinowska¹

Affiliations

¹ Department of Experimental Physiology and Pathophysiology, Medical University of Białystok, Bialystok, Poland.
² Department of Pharmacology and Toxicology, University of Bonn, Bonn, Germany.

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.