Triphasic cardiovascular response to cannabinoids – Focus on underlying mechanisms

Abstract

The endocannabinoid anandamide exerts complex effects on the cardiovascular system [Malinowska et al., Br J Pharmacol, 2011]. Thus, rapid intravenous injection of anandamide and its stable analogue methanandamide in anaesthetized rats and mice induces typical triphasic changes. Phase I, the so-called BezoldJarisch reflex, is characterized by a rapid bradycardia and hypotension associated with a decrease in cardiac contractility and an increase in total peripheral resistance. Phase II is a brief pressor response associated with an increase in cardiac contractility and blood flow in the mesenteric and renal arteries. Phase III comprises a prolonged (lasting up to 10 min) and marked decrease in blood pressure, mesenteric and renal blood flow, a marked decrease in cardiac contractility and a slight decrease in heart rate and total peripheral resistance. Phase I is mediated via vanilloid TRPV1 receptors since it was induced also by the TRPV1 receptor agonist capsaicin (but not by the CB1 receptor agonist CP55940), blocked by the TRPV1 receptor antagonists capsazepine and ruthenium red (but not by the CB1 receptor antagonist rimonabant) and absent in TRPV1 / mice. Phase II consists of a peripheral component that is most probably located in blood vessels, is sensitive to nifedipine, ruthenium red and pentobarbitone and, hence, probably represents a Ca-dependent mode of action and a central component. The paraventricular nucleus of the hypothalamus (PVN) may contribute to the latter since a pressor effect was obtained after injection of anandamide, methanandamide or CP55940 (intraventricularly or directly into the PVN). This effect only occurred when the peripheral CB1 receptors were blocked by administration of CB1 receptor antagonists, including AM6545 that does not reach the brain. It was sensitive to adrenalectomy and counteracted by antagonists of CB1, NMDA, thromboxane A2 and b2adrenergic receptors [AM251 (directly into the PVN), MK-801, SQ29548 and ICI118551, respectively] suggesting that the latter four receptors are involved in the events ultimately leading to the anandamide-induced adrenal secretion of catecholamines. Importantly, the hypotensive effect of intravenously administered CP55940 was reversed into a hypertensive one in the presence of AM6545 and both responses were abolished by chemical lesion of the PVN by kainic acid. Phase III is mediated mainly by presynaptic inhibitory CB1 receptors located on the postganglionic (although a preganglionic localization cannot be excluded) sympathetic nerve endings innervating resistance vessels and heart. The CB1 receptor antagonist-sensitive inhibitory effect of these receptors was detected after electrical stimulation of the preganglionic sympathetic nerve fibres in pithed rabbits or rats or following injection of nicotine but not phenylephrine/noradrenaline or isoprenaline (increasing blood pressure and heart rate, respectively). The prolonged hypotension might also be related to the activation of CB1 and/or vanilloid TRPV1 receptors in the spinal cord or to a direct vasodilatation via O-1918 sensitive receptors. In conscious rats anandamide and methanandamide induced a brief pressor (phase II) response connected with renal and mesenteric vasoconstriction and hindquarters vasodilatation. In addition, higher doses of anandamide elicited an initial bradycardia, hypotension and hindquarters vasoconstriction (phase I). However, unlike in anaesthetized rats, none of the cannabinoids led to a prolonged hypotension (phase III). Cardiovascular effects of anandamide are changed under pathophysiological conditions. Thus, in anaesthetized rats myocardial ischemia enhanced phase I and reduced phase III whereas hypertension enhanced phase III. Acknowledgement: B.M. and E.S. would like to express their gratitude to Professor Manfred Gothert for his continuous encouragement extending over a time period of decades.