Presynaptic cannabinoid and imidazoline receptors in the human heart and their potential relationship

Abstract

Segments of human right atrial appendages preincubated with [3H]noradrenaline and superfused with physiological salt solution containing desipramine and corticosterone were used to examine whether the cardiac sympathetic nerves are endowed with cannabinoid receptors and to further study pharmacological properties of presynaptic imidazoline receptors. The cannabinoid CB1 receptor agonists CP55,940, HU210 and anandamide inhibited evoked [3H]noradrenaline release. The inhibition by CP55,940 and anandamide was abolished by the CB1 receptor antagonists SR141716A (1 microM) and LY320135 (1 microM). Rauwolscine at the imidazoline receptor-blocking concentration of 30 microM abolished the inhibitory effect of CP55,940 and anandamide. After blockade of alpha2-adrenoceptors with 1 microM rauwolscine, the imidazoline binding site ligand S23230, which is the (-)-enantiomer of the racemic oxazoline derivative S22687, exhibited low potency in inhibiting electrically evoked [3H]noradrenaline release (pIC30%=4.96), whereas the (+)-enantiomer S23229 and the racemate S22687 were ineffective. In the presence of 30 microM rauwolscine, S23230 did not significantly inhibit evoked release. The imidazoline receptor-mediated inhibitory effect of BDF 6143 and aganodine on evoked [3H]noradrenaline release was abolished by 1 microM SR141716A and by 1 microM LY320135. The inhibitory effect of moxonidine on evoked [3H]noradrenaline release, which is exclusively mediated via activation of alpha2-autoreceptors, was not antagonized by 1 microM SR141716A. In conclusion, inhibitory cannabinoid CB1 receptors are present on the sympathetic axon terminals of human atrial appendages. Presynaptic imidazoline receptors share the property of other receptors in that they can be stereoselectively activated. The cross-antagonism of imidazoline receptor agonists/antagonists with CB1 receptor antagonists/agonists suggests that these receptors may have certain binding domains in common or that they interact with each other in an unknown manner.

International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid Receptors and Their Ligands: Beyond CB1and CB2

“…These putative receptors have been reported to be activated by CP55940 (300 nM) and R-(ϩ)-WIN55212 (10 and 100 M) but not by anandamide (1 M) and to be blocked by rimonabant (1 M) and LY320135 (0.1 to 10 M) (Molderings et al, 1999.…”

Acute Myocardial Infarction Inhibits the Neurogenic Tachycardic and Vasopressor Response in Rats via Presynaptic Cannabinoid Type 1 Receptor

“…This phenomenon may even have a prognostic relevance because CB 1 blockade decreased the survival rate. Functional presynaptic inhibitory CB 1 receptors sensitive to AEA have also been identified in human heart (Molderings et al, 1999). Further studies are necessary to clarify whether drug therapies directed against presynaptic inhibitory CB 1 receptors are effective in myocardial infarction.…”

Modification of Noradrenaline Release in Pithed Spontaneously Hypertensive Rats by I1-Binding Sites in Addition to α2-Adrenoceptors

“…In contrast, investigations by other authors revealed that these drugs inhibit noradrenaline release exclusively by activating prejunctional ␣ 2 -adrenoceptors (Bohmann et al, 1994;Gaiser et al, 1999). Whether imidazoline binding sites are involved (in addition to ␣ 2 -adrenoceptors) in noradrenaline release may be dependent on stimulation conditions (Molderings et al, 1999a) and/or species differences (Molderings et al, 2000).…”