The mechanisms of the direct action of etomidate on vascular reactivity in rat mesenteric resistance arteries.
BACKGROUND
Etomidate minimally influences hemodynamics at a standard induction dose in young healthy patients, but can cause significant systemic hypotension at higher doses for induction or electroencephalographic burst suppression (i.e., cerebral protection) in patients with advanced age or heart disease, and during cardiopulmonary bypass. However, less is known about its action on systemic resistance arteries.


METHODS
Using an isometric force recording method and fura-2-fluorometry, we investigated the action of etomidate on vascular reactivity in small mesenteric arteries from young (7-8 wk old, n = 179) and aged (96-98 wk old, n = 10) rats.


RESULTS
In the endothelium-intact strips from young rats, etomidate enhanced the contractile response to norepinephrine or KCl (40 mM) at 3 microM but inhibited it at higher concentrations (>or=10 microM). The enhancement was still observed after treatment with N(G)-nitro l-arginine, tetraethylammonium, diclofenac, nordihydroguaiaretic acid, losartan, ketanserin, BQ-123, or BQ-788, but was not observed in aged rats. In the endothelium-denuded strips from young rats, etomidate (>or=10 microM) consistently inhibited the contractile response to norepinephrine or KCl without enhancement at 3 microM. In the fura-2-loaded, endothelium-denuded strips from young rats, etomidate inhibited norepinephrine- or KCl-induced increases in both intracellular Ca(2+) concentration ([Ca(2+)]i) and force. Etomidate still inhibited the norepinephrine-induced increase in [Ca(2+)]i after depletion of the intracellular Ca(2+) stores by ryanodine, which was sensitive to nifedipine. Etomidate had little effect on norepinephrine- or caffeine-induced Ca(2+) release from the intracellular stores or Ca(2+) uptake into the intracellular stores. During stimulation with norepinephrine or KCl, etomidate had little effect on the [Ca(2+)]i-force relation at low concentrations (<or=30 microM) but caused its downward shift at 100 microM.


CONCLUSIONS
In small mesenteric arteries, etomidate influences the contractile response to norepinephrine or membrane depolarization through endothelium-dependent enhancing and endothelium-independent inhibitory actions. The enhancement is at least in part independent of nitric oxide, endothelium-derived hyperpolarizing factor, cyclooxygenase products, lipoxygenase products, angiotensin II, serotonin, or endothelin-1, but may involve some signaling pathway that is impaired by aging. The endothelium-independent inhibition is due to decreases in both the [Ca(2+)]i and myofilament Ca(2+) sensitivity in vascular smooth muscle cells. The decrease in [Ca(2+)]i would be due mainly to inhibition of voltage-gated Ca(2+) influx. The observed inability of lower concentrations (1-3 microM) of etomidate to cause significant vasodilation is consistent with minimal changes in hemodynamics during induction of anesthesia with etomidate in young subjects, whereas the observed vasodilator action of higher concentrations of etomidate might underlie systemic hypotension caused by higher doses of etomidate in the clinical setting.
Shirozu
Kazuhiro
K
Department of Anesthesiology and Critical Care Medicine, Faculty of Medicine, Kyushu University, Fukuoka 812-8582, Japan.
Akata
Takashi
T
Yoshino
Jun
J
Setoguchi
Hidekazu
H
Morikawa
Keiko
K
Hoka
Sumio
S
D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular; D005045:Etomidate / Q000494:pharmacology*; D005456:Fluorescent Dyes; D016257:Fura-2; D005905:Glyburide / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D007293:Inosine Triphosphate / Q000494:pharmacology; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects*; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009638:Norepinephrine / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014655:Vascular Resistance / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D018686:Anesthetics, Intravenous; D005456:Fluorescent Dyes; D007004:Hypoglycemic Agents; D014662:Vasoconstrictor Agents; D007293:Inosine Triphosphate; D011189:Potassium Chloride; D005905:Glyburide; D002118:Calcium; D016257:Fura-2; D009638:Norepinephrine; D005045:Etomidate