Vasodilator actions of EDHF and anandamide

Detta är en avhandling från Department of Clinical Pharmacology, Lund University Hospital, S-221 85 Lund, Sweden

Sammanfattning: Vasodilator responses to endothelium-derived hyperpolarizing factor (EDHF) and anandamide in isolated arteries were investigated. A combination of the potassium channel blockers charybdotoxin and apamin inhibits EDHF-mediated relaxations. Experiments in which charybdotoxin or apamin was substituted with other potassium channel inhibitors indicated that small- and intermediate-conductance calcium-activated potassium channels contribute to EDHF-mediated relaxations. The possibility that EDHF is potassium ions was also examined. Potassium ions failed to mimic the action of EDHF and no evidence was found for involvement of Na+/K+ ATPase and inwardly rectifying potassium channels in EDHF-mediated responses. In the presence of the Na+/K+ ATPase inhibitor ouabain, acetylcholine and KCl stimulated release of CGRP from sensory nerves. Relaxant responses to the endogenous cannabinoid anandamide were examined in isolated rat and guinea pig arteries. Cannabinoid receptors did not mediate anandamide-induced relaxations. Capsaicin pretreatment, the CGRP receptor antagonist CGRP 8-37 and the vanilloid receptor antagonist capsazepine inhibited anandamide-induced relaxations, indicating that vanilloid receptors on perivascular sensory nerves mediate the effects of anandamide. Anandamide also activated the cloned rat vanilloid receptor (VR1). Effects of anandamide and related vanilloid receptor ligands in guinea-pig mesenteric arteries and main bronchi were compared. Capsaicin was equally potent in the two tissues, while anandamide, resiniferatoxin and olvanil were more potent vasodilators than bronchoconstrictors. Schild plots for capsazepine yielded similar pA2 values in both tissues. Data simulations suggested that the differences in effects of the vanilloid receptor agonists might be explained by differences in agonist efficacies and receptor densities rather than by receptor heterogeneity.

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