The mechanisms of the direct action of etomidate on vascular reactivity in rat mesenteric resistance arteries

Kazuhiro Shirozu, Takashi Akata, Jun Yoshino, Hidekazu Setoguchi, Keiko Morikawa, Sumio Hoka

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

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 μM but inhibited it at higher concentrations (≥ 10 μM). The enhancement was still observed after treatment with N-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 (≥ 10 μM) consistently inhibited the contractile response to norepinephrine or KCl without enhancement at 3 μM. In the fura-2-loaded, endothelium-denuded strips from young rats, etomidate inhibited norepinephrine- or KCl-induced increases in both intracellular Ca concentration ([Ca]i) and force. Etomidate still inhibited the norepinephrine-induced increase in [Ca]i after depletion of the intracellular Ca stores by ryanodine, which was sensitive to nifedipine. Etomidate had little effect on norepinephrine- or caffeine-induced Ca release from the intracellular stores or Ca uptake into the intracellular stores. During stimulation with norepinephrine or KCl, etomidate had little effect on the [Ca]i-force relation at low concentrations (≤30 μM) but caused its downward shift at 100 μM. 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]i and myofilament Ca sensitivity in vascular smooth muscle cells. The decrease in [Ca]i would be due mainly to inhibition of voltage-gated Ca influx. The observed inability of lower concentrations (1-3 μM) 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.

Original languageEnglish
Pages (from-to)496-507
Number of pages12
JournalAnesthesia and Analgesia
Volume108
Issue number2
DOIs
Publication statusPublished - Jan 1 2009

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Etomidate
Mesenteric Arteries
Blood Vessels
Norepinephrine
Endothelium
Fura-2
Hypotension
Hemodynamics
Masoprocol
Ryanodine
Ketanserin
Fluorometry
Tetraethylammonium
Losartan
Lipoxygenase
Myofibrils
Diclofenac
Endothelin-1
Nifedipine
Prostaglandin-Endoperoxide Synthases

All Science Journal Classification (ASJC) codes

  • Anesthesiology and Pain Medicine

Cite this

The mechanisms of the direct action of etomidate on vascular reactivity in rat mesenteric resistance arteries. / Shirozu, Kazuhiro; Akata, Takashi; Yoshino, Jun; Setoguchi, Hidekazu; Morikawa, Keiko; Hoka, Sumio.

In: Anesthesia and Analgesia, Vol. 108, No. 2, 01.01.2009, p. 496-507.

Research output: Contribution to journalArticle

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AU - Hoka, Sumio

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N2 - 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 μM but inhibited it at higher concentrations (≥ 10 μM). The enhancement was still observed after treatment with N-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 (≥ 10 μM) consistently inhibited the contractile response to norepinephrine or KCl without enhancement at 3 μM. In the fura-2-loaded, endothelium-denuded strips from young rats, etomidate inhibited norepinephrine- or KCl-induced increases in both intracellular Ca concentration ([Ca]i) and force. Etomidate still inhibited the norepinephrine-induced increase in [Ca]i after depletion of the intracellular Ca stores by ryanodine, which was sensitive to nifedipine. Etomidate had little effect on norepinephrine- or caffeine-induced Ca release from the intracellular stores or Ca uptake into the intracellular stores. During stimulation with norepinephrine or KCl, etomidate had little effect on the [Ca]i-force relation at low concentrations (≤30 μM) but caused its downward shift at 100 μM. 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]i and myofilament Ca sensitivity in vascular smooth muscle cells. The decrease in [Ca]i would be due mainly to inhibition of voltage-gated Ca influx. The observed inability of lower concentrations (1-3 μM) 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.

AB - 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 μM but inhibited it at higher concentrations (≥ 10 μM). The enhancement was still observed after treatment with N-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 (≥ 10 μM) consistently inhibited the contractile response to norepinephrine or KCl without enhancement at 3 μM. In the fura-2-loaded, endothelium-denuded strips from young rats, etomidate inhibited norepinephrine- or KCl-induced increases in both intracellular Ca concentration ([Ca]i) and force. Etomidate still inhibited the norepinephrine-induced increase in [Ca]i after depletion of the intracellular Ca stores by ryanodine, which was sensitive to nifedipine. Etomidate had little effect on norepinephrine- or caffeine-induced Ca release from the intracellular stores or Ca uptake into the intracellular stores. During stimulation with norepinephrine or KCl, etomidate had little effect on the [Ca]i-force relation at low concentrations (≤30 μM) but caused its downward shift at 100 μM. 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]i and myofilament Ca sensitivity in vascular smooth muscle cells. The decrease in [Ca]i would be due mainly to inhibition of voltage-gated Ca influx. The observed inability of lower concentrations (1-3 μM) 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.

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