Cytochrome P450 pathway contributes to methanandamide-induced vasorelaxation in rat aorta.
OBJECTIVE
The generation of hyperpolarising vasorelaxant endothelial cytochrome P450 epoxygenase (CYP)-derived metabolites of arachidonic may provide beneficial effects for the treatment of cardiovascular diseases in which the bioavailability of NO is impaired. The cannabinoid methanandamide has vasodilatory properties linked to hyperpolarisation. The aim of the present work was to investigate the vasorelaxant effects of methanandamide in rat aorta, focusing on the role of cytochrome P450 pathway.


METHODS
Changes in isometric tension in response to a cumulative concentration-response curve of methanandamide (1 nM-100 μM) were recorded in aortic rings from male Wistar rats. The involvement of cannabinoid receptors, endothelial nitric oxide (NO)-, prostacyclin- and some hyperpolarising-mediated pathways were investigated. The activation of large-conductance Ca(2+)-activated K(+) (BKCa) channels have also been evaluated.


RESULTS
Methanandamide provoked an endothelium-dependent vasorelaxation in rat aorta, reaching a maximal effect (Rmax) of 67% ± 2.6%. This vasorelaxation was clearly inhibited by the combination of CB(1) and CB(2) cannabinoid antagonists (Rmax: 21.6% ± 1.3%) and by the combination of guanylate cyclase and CYP inhibitors (Rmax: 16.7% ± 1.1%). The blockade induced separately by guanylate cyclase (31.3% ± 2.8%) or CYP (36.3% ± 6.6%) inhibitors on methanandamide vasorelaxation was not significantly modified by either CB(1) or CB(2) inhibition. BKCa channels inhibition caused a partial and significant inhibition of the methanandamide vasorelaxation (Rmax: 39.9% ± 3.3%).


CONCLUSIONS
Methanandamide endothelium-dependent vasorelaxation is mediated by CB(1) and CB(2) cannabinoid receptors. The NO- and CYP-mediated pathways contribute in a concurrent manner in this vascular effect. Stimulation of both cannabinoid receptor subtypes is indistinctly linked to NO or CYP routes to cause vasorelaxation.
López-Miranda
Visitación
V
Dpto. Farmacología y Nutrición, Facultad Ciencias de la Salud, Universidad Rey Juan Carlos, Avda. Atenas s/n, 28922, Alcorcón, Madrid, Spain. visitacion.lopezmiranda@urjc.es
Dannert
M Teresa
MT
Herradón
Esperanza
E
Alsasua
Angela
A
Martín
M Isabel
MI
D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D001095:Arachidonic Acids / Q000494:pharmacology*; D001685:Biological Factors / Q000378:metabolism; D000090762:Cytochrome P-450 CYP2J2; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D011464:Epoprostenol / Q000378:metabolism; D006162:Guanylate Cyclase / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D024681:Potassium Channels, Calcium-Activated / Q000037:antagonists & inhibitors; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D043882:Receptors, Cannabinoid / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects*
D001095:Arachidonic Acids; D001685:Biological Factors; C469526:Cnr2 protein, rat; D065607:Cytochrome P-450 Enzyme Inhibitors; D024681:Potassium Channels, Calcium-Activated; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; C067410:endothelium-dependent hyperpolarization factor; C088155:methanandamide; D009569:Nitric Oxide; D003577:Cytochrome P-450 Enzyme System; D011464:Epoprostenol; D000090762:Cytochrome P-450 CYP2J2; D006162:Guanylate Cyclase