Novel antagonist implicates the CB1 cannabinoid receptor in the hypotensive action of anandamide

Varga, K; Lake, Kristy D.; Martin, Billy R.; Kunos, George

doi:10.1016/0014-2999(95)00181-j

Cited by 180 publications

(192 citation statements)

References 8 publications

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“…In a recent study (Pacher et al, 2004) we have tested this possibility by analyzing the detailed hemodynamic effects of anandamide in TRPV 1 −/− and TRPV 1 +/+ mice. Similar to previous findings in the rat (Varga et al, 1995), bolus injections of anandamide (20 mg/kg i.v.) caused a triphasic effect in (Fig.…”

Section: Cardiovascular Effects Of Cannabinoids In Vivo Role Of Cb 1supporting

confidence: 90%

“…Intravenous administration of anandamide in anesthetized rats initiates a triphasic blood pressure response with a major prolonged hypotensive effect (phase III) preceded by a transient, vagally mediated fall in heart rate and blood pressure (phase I) followed by a brief, nonsympathetically mediated pressor response of unknown mechanism (phase II) (Varga et al, 1995). Capsazepine and ruthenium red, antagonists of the TRPV 1 receptor, dose-dependently inhibit the phase I bradycardic response in anesthetized rats, without affecting the phase III hypotension, which was abolished by the cannabinoid CB 1 receptor antagonist SR141716 (Malinowska et al, 2001) and was also absent in CB 1 receptor knockout mice (Ledent et al, 1999;Járai et al, 1999).…”

Section: Cardiovascular Effects Of Cannabinoids In Vivo Role Of Cb 1mentioning

confidence: 99%

“…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.…”

Section: Role Of the Endocannabinergic System In Blood Pressure Regulmentioning

confidence: 99%

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Blood pressure regulation by endocannabinoids and their receptors

2005

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Cannabinoids and their endogenous and synthetic analogs exert powerful hypotensive and cardiodepressor effects by complex mechanisms involving direct and indirect effects on myocardium and vasculature. On the one hand, endocannabinoids and cannabinoid receptors have been implicated in the hypotensive state associated with hemorrhagic, endotoxic and cardiogenic shock, and advanced liver cirrhosis. On the other hand, there is emerging evidence suggesting that the endocannabinergic system plays an important role in the cardiovascular regulation in hypertension. This review is aimed to discuss the in vivo hypotensive and cardiodepressant effects of cannabinoids mediated by cannabinoid and TRPV 1 receptors, and focuses on the novel therapeutical strategies offered by targeting the endocannabinoid system in the treatment of hypertension.

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Section: Cardiovascular Effects Of Cannabinoids In Vivo Role Of Cb 1supporting

confidence: 90%

Section: Cardiovascular Effects Of Cannabinoids In Vivo Role Of Cb 1mentioning

confidence: 99%

Section: Role Of the Endocannabinergic System In Blood Pressure Regulmentioning

confidence: 99%

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Blood pressure regulation by endocannabinoids and their receptors

2005

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“…Upon systemic administration, they can affect blood pressure regulation under both normal and pathophysiological conditions. 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.…”

Section: Cardiovascular Effectsmentioning

confidence: 99%

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

Diepen

Schlicker

Michel

2008

Naunyn-Schmied Arch Pharmacol

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Rimonabant is an inverse agonist specific for cannabinoid receptors and selective for their cannabinoid-1 (CB 1 ) subtype. Although CB 1 receptors are more abundant in the central nervous system, rimonabant has many effects in the periphery, most of which are related to prejunctional modulation of transmitter release from autonomic nerves. However, CB 1 receptors are also expressed in, e.g., adipocytes and endothelial cells. Rimonabant inhibits numerous cardiovascular cannabinoid effects, including the decrease of blood pressure by central and peripheral (cardiac and vascular) sites of action, with the latter often being endothelium dependent. Rimonabant may also antagonize cannabinoid effects in myocardial infarction and in hypotension associated with septic shock or liver cirrhosis. In the gastrointestinal tract, rimonabant counteracts the cannabinoid-induced inhibition of secretion and motility. Although not affecting most cannabinoid effects in the airways, rimonabant counteracts inhibition of smoothmuscle contraction by cannabinoids in urogenital tissues and may interfere with embryo attachment and outgrowth of blastocysts. It inhibits cannabinoid-induced decreases of intraocular pressure. Rimonabant can inhibit proliferation of, maturation of, and energy storage by adipocytes. Among the many cannabinoid effects on hormone secretion, only some are rimonabant sensitive. The effects of rimonabant on the immune system are not fully clear, and it may inhibit or stimulate proliferation in several types of cancer. We conclude that direct effects of rimonabant on adipocytes may contribute to its clinical role in treating obesity. Other peripheral effects, many of which occur prejunctionally, may also contribute to its overall clinical profile and lead to additional indications as well adverse events.

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“…The hypotensive effect of delta-9-THC is mimicked by various cannabinoids with a rank order of potency that correlates well with the affinity of the same ligands for the CB1 receptor [30]. Administration of the endocannabinoid anandamide (AEA) to anesthetized rats also produces a brief pressor response that is followed by a more prolonged decrease in blood pressure [31]. The depressor response to AEA is inhibited by coadministration of the SR141716A CB1 receptor antagonist [31] and is absent in CB1 receptor null mice [32] reinforcing the notion that the CB1 receptor is indeed the molecular target responsible for these observed cardiovascular effects.…”

Section: Acute Effectsmentioning

confidence: 99%

Cannabis and endocannabinoid modulators: Therapeutic promises and challenges

Grant

Cahn

2005

Clinical Neuroscience Research

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The discovery that botanical cannabinoids such as delta-9 tetrahydrocannabinol exert some of their effect through binding specific cannabinoid receptor sites has led to the discovery of an endocannabinoid signaling system, which in turn has spurred research into the mechanisms of action and addiction potential of cannabis on the one hand, while opening the possibility of developing novel therapeutic agents on the other. This paper reviews current understanding of CB1, CB2, and other possible cannabinoid receptors, their arachidonic acid derived ligands (e.g. anandamide; 2 arachidonoyl glycerol), and their possible physiological roles. CB1 is heavily represented in the central nervous system, but is found in other tissues as well; CB2 tends to be localized to immune cells. Activation of the endocannabinoid system can result in enhanced or dampened activity in various neural circuits depending on their own state of activation. This suggests that one function of the endocannabinoid system may be to maintain steady state. The therapeutic action of botanical cannabis or of synthetic molecules that are agonists, antagonists, or which may otherwise modify endocannabinoid metabolism and activity indicates they may have promise as neuroprotectants, and may be of value in the treatment of certain types of pain, epilepsy, spasticity, eating disorders, inflammation, and possibly blood pressure control.

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Novel antagonist implicates the CB1 cannabinoid receptor in the hypotensive action of anandamide

Cited by 180 publications

References 8 publications

Blood pressure regulation by endocannabinoids and their receptors

Blood pressure regulation by endocannabinoids and their receptors

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

Cannabis and endocannabinoid modulators: Therapeutic promises and challenges

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