The peripheral sympathetic nervous system is the major target of cannabinoids in eliciting cardiovascular depression

Abstract

Our objective was to identify the sites of interaction of cannabinoids with cardiovascular sympathetic regulation in the rat. Effects on sympathetic tone were first determined in anaesthetised animals following i.v. administration of the drugs. Central effects were evaluated in anaesthetised rats receiving microinjections of cannabinoids into brain stem nuclei. Peripheral effects were identified in pithed rats with electrically stimulated sympathetic outflow. In anaesthetised and artificially ventilated rats, i.v. injection of the cannabinoid agonists WIN55212-2 and CP55940 decreased mean arterial pressure, heart rate and the plasma noradrenaline concentration. These effects were antagonized by the CB(1) cannabinoid receptor antagonist SR141716A. The bradycardia was abolished by the muscarinic acetylcholine receptor antagonist methylatropine. The decreases in mean arterial pressure and heart rate caused by cannabinoids in ventilated rats were much less pronounced than in spontaneously breathing rats. Microinjection of WIN55212-2 into the nucleus tractus solitarii had no effect. Microinjected into the rostral ventrolateral medulla oblongata, WIN55212-2 lowered mean arterial pressure slightly without changing other parameters. In pithed rats, WIN55212-2 inhibited the increases in mean arterial pressure, heart rate and the plasma noradrenaline concentration evoked by electrical stimulation of the sympathetic outflow. Our results show that activation of CB(1) cannabinoid receptors induces sympathoinhibition and enhancement of cardiac vagal tone, leading to hypotension and bradycardia. Presynaptic inhibition of noradrenaline release from terminals of postganglionic sympathetic neurons is the major component of the sympathoinhibition, but an effect in the rostral ventrolateral medulla oblongata may also contribute. The cannabinoid-evoked cardiovascular depression depends strongly on the respiratory state of the animals.

The complexities of the cardiovascular actions of cannabinoids

“…In vitro studies have also confirmed that cannabinoids inhibit sympathetic regulation (see Ralevic, 2003). Cannabinoid-induced sympathoinhibition by synthetic cannabinoids has also been reported in rabbits (Niederhoffer & Szabo, 1999) and rats (Niederhoffer et al, 2003). Significantly, Niederhoffer & Szabo (1999) reported that the synthetic cannabinoid, WIN55212-2, caused depressor effects in pithed rabbits with electrically stimulated, sympathetic tone 22…”

Presynaptic cannabinoid CB1 receptors are involved in the inhibition of the neurogenic vasopressor response during septic shock in pithed rats

“…Since LPS indeed decreased the neurogenic vasopressor response, we next studied whether this effect can be overcome by selective antagonists at cannabinoid CB 1 and CB 2 receptors and at vanilloid VR1 receptors. In addition, we examined the influence of an antagonist at the presynaptic histamine H 3 receptor, which, like the CB 1 receptor Niederhoffer & Szabo, 1999;Niederhoffer et al, 2003), inhibits the neurogenic vasopressor response in pithed animals (Malinowska & Schlicker, 1991).…”

Prejunctional and peripheral effects of the cannabinoid CB1 receptor inverse agonist rimonabant (SR 141716)

“…Rimonabant-sensitive blood pressure lowering in pithed animals was typically accompanied by a reduced noradrenaline spillover into the general circulation (Niederhoffer et al 2003;Niederhoffer and Szabo 1999), indicating a possible prejunctional site of action. Further evidence for the prejunctional location comes from experiments in pithed rats and rabbits, where the cannabinoid agonist WIN 55212-2, although lowering blood pressure in animals with electrical stimulation of sympathetic nerves, i.e.…”

“…Some studies suggest that cannabinoids can cause brief pressor responses followed by longer-lasting depressor responses, of which only the latter appear to be rimonabant sensitive (Malinowska et al 2001a;Varga et al 1995). With few exceptions , the vast majority of studies in rats (Batkai et al 2004b;Garcia et al 2001;Niederhoffer et al 2003;Varga et al 1995), mice (Jarai et al 2000), rabbits (Niederhoffer and Szabo 1999), and guinea pigs (Calignano et al 1997a) reported exogenous cannabinoids to reduce blood pressure in a rimonabantsensitive manner. A cannabinoid-induced, rimonabantsensitive lowering of heart rate has been reported in mice (Jarai et al 2000), and an anandamide-induced rimonabantsensitive lowering of cardiac contractility has been shown in mice (Pacher et al 2004) and, based upon elevations of endogenous anandamide levels, proposed in doxorubicininduced cardiotoxicity .…”

“…Findings that rimonabant-sensitive cannabinoid-induced blood pressure lowering was accompanied by reduced cardiac function (Batkai et al 2004b;Malinowska et al 2001b;Niederhoffer et al 2003) and/or decreased peripheral resistance (Batkai et al 2004b;Garcia et al 2001) may suggest that some of the cannabinoid-induced cardiovascular effects may occur at the cardiac and/or vascular level, a possibility that has been directly investigated in numerous studies.…”