Etomidate and thiopental inhibit the release of endothelium-derived hyperpolarizing factor in the human renal artery.
BACKGROUND
Endothelium-derived hyperpolarizing factor is thought to be a cytochrome P450-derived arachidonic acid metabolite that hyperpolarizes vascular smooth muscle cells by opening Ca(2+)-activated K+ channels (K+Ca channels). In the rabbit carotid artery both volatile and intravenous anesthetics inhibit the acetylcholine-stimulated release of endothelium-derived hyperpolarizing factor. Because the release of this factor may help to maintain vascular tone in humans under conditions of a failing nitric oxide synthesis, e.g., in atherosclerosis, the effects of two intravenous anesthetics, thiopental and etomidate, on the endothelium-derived hyperpolarizing factor-mediated relaxant response to acetylcholine were investigated in human isolated renal artery segments.


METHODS
The segments were suspended in Krebs-Henseleit solution (37 degrees C) containing the cyclooxygenase inhibitor diclofenac (1 microM) and preconstricted with norepinephrine (6 microM). Relaxations caused by acetylcholine (1 microM) were compared in the presence and absence of the nitric oxide synthase inhibitor N(G)-nitro-L-arginine (0.1 mM) in control segments and in segments exposed to etomidate or thiopental (0.03-0.3 mM). In addition, the effects of the two anesthetics on the relaxant response to the nitric oxide donors glyceryl trinitrate (3 microM) and sodium nitroprusside (0.1 microM) were examined.


RESULTS
The relaxant response to acetylcholine, which was resistant to both nitric oxide synthase and cyclooxygenase blockade, was markedly reduced by the K+Ca channel antagonist tetrabutyl ammonium (3 mM) and the cytochrome P450 inhibitor clotrimazole (30 microM). Both etomidate and thiopental, at a concentration of 0.3 mM, selectively attenuated the relaxant response to acetylcholine in N(G)-nitro-L-arginine-treated segments, but did not affect relaxations elicited by glyceryl trinitrate or sodium nitroprusside.


CONCLUSIONS
Etomidate and thiopental inhibit the endothelium-derived hyperpolarizing factor-mediated relaxant response to acetylcholine in the human renal artery, an effect that appears to be attributable to the cytochrome P450-inhibiting properties of these anesthetics.
Kessler
P
P
Center of Anesthesiology and Resuscitation, Johann Wolfgang Goethe University Clinic, Frankfurt am Main, Germany.
Lischke
V
V
Hecker
M
M
D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001685:Biological Factors / Q000378:metabolism*; D005045:Etomidate / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D019335:Nitroarginine; D015221:Potassium Channels / Q000187:drug effects; D011817:Rabbits; D012077:Renal Artery / Q000187:drug effects* / Q000378:metabolism; D013874:Thiopental / Q000494:pharmacology*
D018686:Anesthetics, Intravenous; D001685:Biological Factors; D015221:Potassium Channels; C067410:endothelium-dependent hyperpolarization factor; D019335:Nitroarginine; D001120:Arginine; D013874:Thiopental; D005045:Etomidate