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LETTER TO THE EDITOR
Endocannabinoids and CB1 receptors have been implicated in endotoxin (LPS)-induced hypotension: LPS stimulates the synthesis of anandamide in macrophages, and the CB1 antagonist SR-141716 inhibits the hypotension induced by treatment of rats with LPS or LPS-treated macrophages. Recent evidence indicates the existence of cannabinoid receptors distinct from CB1 or CB2 that are inhibited by SR-141716 but not by other CB1 antagonists such as AM251. In pentobarbital-anesthetized rats, intravenous injection of 10 mg/kg LPS elicited hypotension associated with profound decreases in cardiac contractility, moderate tachycardia, and an increase in lower body vascular resistance. Pretreatment with 3 mg/kg SR-141716 prevented the hypotension and decrease in cardiac contractility, slightly attenuated the increase in peripheral resistance, and had no effect on the tachycardia caused by LPS, whereas pretreatment with 3 mg/kg AM251 did not affect any of these responses. SR-141716 also elicited an acute reversal of the hypotension and decreased contractility when administered after the response to LPS had fully developed. The LPS-induced hypotension and its inhibition by SR-141716 were similar in pentobarbital-anesthetized wild-type, CB1–/–, and CB1–/–/CB2–/– mice. We conclude that SR-141716 inhibits the acute hemodynamic effects of LPS by interacting with a cardiac receptor distinct from CB1 or CB2 that mediates negative inotropy and may be activated by anandamide or a related endocannabinoid released during endotoxemia.
Cannabinoids and Endotoxemia
To the Editor: The recent study by Bátkai et al. (1) demonstrated that the cannabinoid antagonist SR-141716 but not its structural analog AM251 opposed the hypotensive effect of a bolus injection of lipopolysaccharide (LPS) in anesthetised rats. They concluded that the effect of SR-141716 was due to prevention of the negative inotropic effects of LPS, mediated through a cardiac receptor distinct from the CB1 or CB2 receptor subtype.
Bátkai et al. (1) measured left ventricular systolic pressure (LVSP) and the maximal positive slope of LVSP (+dP/dt) as indexes of cardiac contractility. In addition, they monitored distal abdominal aortic blood flow (AABF), took AABF as an indicator of cardiac output (despite the fact that it did not include carotid, splanchnic, and renal blood flows), and divided mean arterial blood pressure by AABF to provide an estimate of peripheral resistance (PRI). This imprecise measure of cardiac output, and derivation therefrom, of PRI may account for the unexplained and paradoxical dissociation between the various effects of SR-141716 they report. Thus LPS injection caused hypotension, accompanied by decreases in LVSP, +dP/dt, and "cardiac output," together with an increase in PRI. SR-141716 prevented the hypotension and the negative inotropic effects of LPS but not the fall in cardiac output or the rise in PRI. It is not clear to us how a fall in pressure can be influenced without corresponding changes in cardiac output and/or peripheral resistance or how indexes of cardiac contractility can change so markedly without effects on cardiac output (particularly in the absence of opposing changes in heart rate).
Bátkai et al. (1) concluded that "the hypotensive effect of LPS is due to decreased cardiac contractility, which leads to a decrease in stroke volume and cardiac output rather than vasodilation." By inference, the effects of SR-141716 should be manifest as an inhibition of the fall in cardiac output, but their data do not show that.
The conclusion reached by Bátkai et al. (1) is notable in the context of earlier findings from some of the same group (4), where it was proposed that endogenous cannabinoids constitute "a novel paracrine mechanism of vasodilatation in endotoxic shock." Bátkai et al. (1) do not properly acknowledge the disparity between this statement and their recent findings (1) or consider the latter in relation to the prevalent view that endocannabinoids are vasodilators. However, their recent observations are more consistent with our data. Thus we have not been able to demonstrate clear cut, CB1 receptor-mediated vasodilator effects of the endocannabinoid anandamide in normal animals (2). Furthermore, in a model of endotoxemia produced by chronic infusion of LPS in conscious rats, which is characterized by widespread vasodilatation, we have been unable to demonstrate any effect of AM251 on blood pressure and only a modest effect on hindquarters vascular conductance (3). Hence, our data fit better with a non-CB1 receptor-mediated cardiac action of SR-141716 as an explanation for its ability to oppose the hypotensive effect of LPS in the hypodynamic vasoconstricted model and certainly do not support claims of an important role for endocannabinoids as vasodilators in endotoxemia (4).
REFERENCES
Regarding their second point, the present results confirm our earlier findings that SR-141716 inhibits the acute hypotensive response to LPS (8). Our additional testing of AM251 was prompted by several recent reports demonstrating that anandamide and some atypical cannabinoids can cause both vasodilation and cardiodepression via an as-yet-undefined receptor sensitive to SR-141716 but not AM251 (cited in Ref. 1), and the results are compatible with the involvement of a similar receptor rather than CB1 in the acute effects of LPS. Although the hypotensive response to exogenous anandamide is mediated exclusively by CB1 receptors (6), LPS has been shown to dramatically increase anandamide synthesis in macrophages (5), and anandamide released from such sites may interact with non-CB1 receptors. The possibility that such a receptor may have additional, noncannabinoid endogenous ligands that, like anandamide, are substrates of the enzyme fatty acid amidohydrolase has been also discussed (1). The other novelty in our study was the evidence suggesting a cardiac rather than vascular site of action of SR-141716 in reversing LPS-induced hypotension. This was not unexpected given the well-established dominance of cardiodepression rather than vasodilation in the acute response to LPS (1). However, in the absence of blood flow measurements in the coronary, cerebral, and renal vasculatures, these findings do not rule out localized vasodilation, the effect of which would be cancelled out by the vasoconstriction observed in the hindquarter. The absence of a significant vasodilator response to anandamide in the conscious rat model used by Gardiner et al. (3) doesn't help to decide this issue, given the fact that in conscious normotensive rats anandamide does not elicit hypotension (4, 7). Anandamide-induced hypotension is greatly potentiated and also present in the unanesthetized state in hypertensive animals (2, 4), which would offer a more suitable model to explore its regional hemodynamic effects. Therefore, it would be premature to rule out endocannabinoid involvement in the control of regional hemodynamics in various pathological states, as Gardiner and Bennett would like us to do.
REFERENCES
B independently of platelet-activating factor. J Biol Chem 278: 45034–45039, 2003.
Jens A. Wagner2
2Department of Medicine
University of Wuerzburg
Wuerzburg 97070
Germany
Zoltán Járai3
3First Department of Medicine
Semmelweis University
1085 Budapest
Hungary
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