Cannabinoids are known to cause coronary vasodilatation and reduce left ventricular developed pressure (LVDP) in isolated hearts although the identity of the receptor(s) mediating these responses is unknown. Our objective was to pharmacologically characterize cannabinoid receptors mediating cardiac responses to the endocannabinoid, anandamide. Dose‐response curves for coronary perfusion pressure (CPP) and LVDP were constructed to anandamide, R‐(+)‐methanandamide, palmitoylethanolamide (PEA) and JWH015 in isolated Langendorff‐perfused rat hearts. Anandamide dose‐response curves were also constructed in the presence of antagonists selective for CB₁, CB₂ or VR₁ receptors. Anandamide and methanadamide significantly reduced CPP and LVDP but the selective CB₂ receptor agonists, PEA and JWH015 had no significant effect, compared with equivalent vehicle doses. Single bolus additions of the selective CB₁‐receptor agonist, ACEA (5 nmol), decreased LVDP and CPP. When combined with JWH015 (5 nmol) these responses were not augmented. Anandamide‐mediated reductions in CPP were significantly blocked by the selective CB₁ receptor antagonists SR 141716A (1 μM) and AM251 (1 μM) and the selective CB₂ receptor antagonist SR 144528 (1 μM) but not by another selective CB₂ receptor antagonist AM630 (10 μM) nor the vanilloid VR₁ receptor antagonist capsazepine (10 μM). SR 141716A, AM281 and SR 144528 significantly blocked negative inotropic responses to anandamide that were not significantly affected by AM251, AM630 and capsazepine. One or more novel sites mediate negative inotropic and coronary vasodilatatory responses to anandamide. These sites can be distinguished from classical CB₁ and CB₂ receptors, as responses are sensitive to both SR 141716A and SR 144528. British Journal of Pharmacology (2002) 135, 1191–1198; doi:10.1038/sj.bjp.0704565

BackgroundAngiotensin II type 1 (AT₁) receptor antagonists, when given over the long term, reduce the deleterious consequences of ischemia-reperfusion injury. Whether short-term administration of AT₁or angiotensin II type 2 (AT₂) receptor antagonists is cardioprotective has not been investigated.Methods and ResultsThe effects of short-term administration of selective AT₁and AT₂receptor antagonists on the recovery of mechanical function during reperfusion after 30 minutes of global, no-flow ischemia were studied in left atrium–perfused isolated working rat hearts. Control hearts (n=8) showed incomplete recovery of left ventricular minute work (LV work) and cardiac efficiency during reperfusion to 51±15% and 61±19% of preischemic levels, respectively. Compared with control hearts, the selective AT₂receptor antagonist PD123,319 (0.3 μmol/L) given before ischemia (n=7) improved the recovery of LV work and efficiency to 82±4% and 98±7% of preischemic levels, respectively (P<.01). In contrast, the selective AT₁antagonist losartan (1 μmol/L) blocked the recovery of LV work and depressed efficiency to 0±0% and 1±0% (n=7) of preischemic levels, respectively (P<.01; n=7). Neither antagonist altered coronary vascular conductance.ConclusionsThis is the first demonstration that short-term treatment with a selective AT₁versus AT₂antagonist exerts different effects on recovery of mechanical function after ischemia-reperfusion: the AT₂antagonist was cardioprotective, whereas the AT₁antagonist was not. These data suggest that AT₂antagonists and AT₁agonists may offer novel approaches for the treatment of mechanical dysfunction after ischemia-reperfusion.

Cannabinoids include not only plant‐derived compounds (of which Δ⁹‐tetrahydrocannabinol is the primary psychoactive ingredient of cannabis), but also synthetic agents and endogenous substances termed endocannabinoids which include anandamide (2‐arachidonoylethanolamide) and 2‐arachidonoylglycerol. Cannabinoids act on specific, G‐protein‐coupled, receptors which are currently divided into two types, CB₁ and CB₂. Relatively selective agonists and antagonists for these receptors have been developed, although one agent (SR141716A) widely used as an antagonist at CB₁ receptors has non‐cannabinoid receptor‐mediated effects at concentrations which are often used to define the presence of the CB₁ receptor. Both cannabinoid receptors are primarily coupled to G_i/o proteins and act to inhibit adenylyl cyclase. Stimulation of CB₁ receptors also modulates the activity of K⁺ and Ca²⁺ channels and of protein kinase pathways including protein kinase B (Akt) which might mediate effects on apoptosis. CB₁ receptors may activate the extracellular signal‐regulated kinase cascade through ceramide signalling. Cannabinoid actions on the cardiovascular system have been widely interpreted as being mediated by CB₁ receptors although there are a growing number of observations, particularly in isolated heart and blood vessel preparations, that suggest that other cannabinoid receptors may exist. Interestingly, the currently identified cannabinoid receptors appear to be related to a wider family of lipid receptor, those for the lysophospholipids, which are also linked to G_i/o protein signalling. Anandamide also activates vanilloid VR1 receptors on sensory nerves and releases the vasoactive peptide, calcitonin gene‐related peptide (CGRP), which brings about vasodilatation through its action on CGRP receptors. Current evidence suggests that endocannabinoids have important protective roles in pathophysiological conditions such as shock and myocardial infarction. Therefore, their cardiovascular effects and the receptors mediating them are the subject of increasing investigative interest.