Cardiovascular Effects of Anandamide in Anesthetized and Conscious Normotensive and Hypertensive Rats

Abstract

We previously showed that in anesthetized rats anandamide elicits bradycardia and a triphasic blood pressure response: transient hypotension secondary to a vagally mediated bradycardia, followed by a brief pressor and prolonged depressor response, the latter two effects being similar to those of delta 9-tetrahydrocannabinol (THC). The prolonged depressor but not the pressor response was reduced after alpha-adrenergic receptor blockade or cervical spinal cord transection and was inhibited by the cannabinoid type 1 (CB1) receptor antagonist SR141716A, suggesting CB1 receptor-mediated sympathoinhibition as the underlying mechanism. Here we examined the relationship between sympathetic tone and the cardiovascular effects of anandamide by testing these effects in both conscious and anesthetized, normotensive and spontaneously hypertensive rats. In urethane-anesthetized normotensive rats, SR141716A inhibited the prolonged depressor and bradycardic effects of anandamide and THC with similar potency, whereas it did not affect the pressor response to either agent. Anadamide caused similar hypotension in spontaneously breathing and in paralyzed, mechanically ventilated rats, suggesting that the hypotension is not secondary to respiratory effects. In conscious normotensive rats, anandamide elicited transient vagal activation and a brief pressor response, but the prolonged hypotensive component was absent. SR141716A potentiated and prolonged the brief pressor response to anandamide, suggesting that the depressor response may have been masked by an increased pressor response. All three phases of the anadamide response were present in both anesthetized and conscious spontaneously hypertensive rats, and the hypotensive component, inhibited by SR141716A in both, was more prolonged in the absence (> 50 minutes) than the presence (10 to 15 minutes) of anesthesia. We conclude that anandamide causes a non-CB1 receptor-mediated pressor and a CB1 receptor-mediated prolonged depressor response. The depressor response can be elicited in both conscious and anesthetized animals, but its magnitude depends on preexisting sympathetic tone.

Blood pressure regulation by endocannabinoids and their receptors

“…All of these findings indicate the absence of an endocannabinergic 'tone' in the maintenance of normal blood pressure. In contrast, both anandamide (Lake et al, 1997b;Bátkai et al, 2004a) and THC (Kosersky, 1978) evoke larger and longer lasting hypotension in SHR than in normotensive rats, and the effect in the former does not depend on the absence or presence of anesthesia (Lake et al, 1997b). Consistent with these observations, THC inhalation was found to result in a greater and longer lasting decrease of arterial blood pressure in hypertensive as compared to normotensive individuals (Crawford and Merritt, 1979).…”

“…Treatment of normotensive rats or mice with CB 1 antagonists alone was found not to affect blood pressure (Lake et al, 1997a;Varga et al, 1995), and baseline blood pressure was similar in CB 1 knockout mice and their wild-type littermates (Járai et al, 1999;Ledent et al, 1999). Further studies demonstrated that a relatively modest hypotensive effect of anandamide was present in anesthetized (Lake et al, 1997a;Varga et al, 1995) but not in conscious normotensive rats (Stein et al, 1996;Lake et al, 1997b), and a lack of significant hypotension following inhibition of anandamide transport (Calignano et al, 1997). All of these findings indicate the absence of an endocannabinergic 'tone' in the maintenance of normal blood pressure.…”

“…It has been established that the endocannabinergic system plays a pivotal role in cardiovascular regulation under various pathophysiological conditions associated with hypotension including hemorrhagic (Wagner et al, 1997), endotoxic (Varga et al, 1998) and cardiogenic shock (Wagner et al, 2001a, and advanced liver cirrhosis (Bátkai et al, 2001;Ros et al, 2002). Additional evidence also implicates this system in the regulation of blood pressure (Lake et al, 1997b;Li et al, 2003;Bátkai et al, 2004a). The present review focuses on the in vivo hypotensive and cardiodepressant effects of cannabinoids and on the novel therapeutical strategies offered by targeting the endocannabinergic system in the treatment of hypertension.…”

Mesenteric Vasodilation Mediated by Endothelial Anandamide Receptors

“…22 The hypotensive potency of a series of agonists, including those tested in the present study, displayed a strong positive correlation with their analgesic potency or their binding K d to the brain cannabinoid receptor. 22 Furthermore, the inhibitory potency of the highly selective CB1 receptor antagonist SR141716A 23 was similar for cannabinoid-induced hypotension 33 and neurobehavioral effects. 23 Although SR141716A did inhibit the mesenteric vasodilator response to anandamide, the inhibition was unusual in that a 10-fold increase in the concentration of the antagonist resulted in a much smaller than expected increase in inhibition.…”

Hypotension associated with ingestion of cannabinoids in two children with cancer

“…In rats, intravenous administration of anandamide, an endogenous cannabinoid primarily acting on the CB1 receptor, has been found to have a triphasic effect on blood pressure, characterized by a transient drop followed by a brief rise and then a sustained period of hypotension. 5,6 The human cardiovascular system appears to be affected by THC. A placebo-controlled trial showed that, among people who used cannabis regularly, systolic blood pressure dropped with an oral THC dose of 30 mg but increased at doses greater than 75 mg. 7 A concomitant dosedependent elevation in heart rate was noted.…”