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Anesthesiology 2003; 98:104–13 © 2003 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Inhibitory Effects of Etomidate and Ketamine on Adenosine Triphosphate–Sensitive Potassium Channel Relaxation in Canine Pulmonary Artery Ju-Tae Sohn, M.D.,* Paul A. Murray, Ph.D.† Background: The authors recently demonstrated that etomi- diseases, including essential hypertension, angina pecto- date and ketamine attenuated endothelium-dependent pulmo- ris, myocardial ischemia, and cerebral vascular disease.4 -nary vasorelaxation mediated by nitric oxide and Ca2؉-acti -؉ Investigators in our laboratory and others have demon vated K channels. In the current study, they tested the ϩ hypothesis that these intravenous anesthetics inhibit pulmo- strated that K ATP channel agonists can cause marked Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/98/1/104/405921/0000542-200301000-00019.pdf by guest on 24 September 2021 nary vasorelaxation mediated by adenosine triphosphate–sen- pulmonary vasodilation, which is reversed by gliben- sitive potassium (K؉ ) channel activation. ϩ 5–13 ATP clamide, a specific K ATP channel inhibitor. More- Methods: Endothelium intact and denuded pulmonary arte- over, endogenous Kϩ channel–induced vasodilation rial rings were suspended in organ chambers for isometric ATP tension recording. The effects of etomidate (5 ؋ 10؊6 and 5 ؋ is functionally significant, because it has been shown to ؊ ؊ ؊ M) and ketamine (5 ؋ 10 5 and 10 4 M) on vasorelaxation modulate the pulmonary vasoconstrictor response to 5 10 ؉ 14 7 responses to lemakalim (K ATP channel activator), prostacy- hypoxia and systemic hypotension. clin, and papaverine were assessed in phenylephrine-precon- Kϩ channels are present not only in vascular smooth tracted rings. The effect of cyclooxygenase inhibition with in- ATP domethacin was assessed in some protocols. muscle cells, but also have been demonstrated in systemic ϩ ؊6 15,16 Results: Etomidate (5 ؋ 10 M) only inhibited the vasorelax- vascular endothelial cells. In endothelial cells, K ATP ant response to lemakalim in endothelium intact rings, whereas channel activation results in hyperpolarization, an increase ؋ ؊5 ϩ a higher concentration of etomidate (5 10 M) inhibited in Ca2 influx, and the production of endothelium-derived relaxation in both intact and endothelium-denuded rings. Pre- 17,18 treatment with indomethacin abolished the endothelium-de- vasodilators, such as nitric oxide and prostacyclin. We pendent attenuation of lemakalim-induced relaxation caused by have recently demonstrated that lemakalim-induced pulmo- ؊ ؊ etomidate. Ketamine (5 ؋ 10 5 and 10 4 M) inhibited the relax- nary vasorelaxation involves both endothelium-dependent ation response to lemakalim to the same extent in both endo- and vascular smooth muscle components.19 The endothe- thelium-intact and -denuded rings, and this effect was not pre- lium-dependent component of lemakalim-induced vasore- vented by indomethacin pretreatment. Etomidate and ketamine had no effect on the relaxation responses to prostacyclin or laxation is mediated by a vasodilator metabolite of the 19 ϩ papaverine. cyclooxygenase pathway. Moreover, K ATP channels me- Conclusions: These results indicate that etomidate, but not diate a synergistic interaction between nitric oxide and ketamine, attenuates the endothelium-dependent component of prostacyclin in response to some endothelium-dependent lemakalim-induced pulmonary vasorelaxation via an inhibitory 20 effect on the cyclooxygenase pathway. Both anesthetics inhibit agonists (e.g., bradykinin). ؉ K ATP-mediated pulmonary vasorelaxation via a direct effect on Etomidate and ketamine are intravenous anesthetics pulmonary vascular smooth muscle. that are recognized to have minimal effects on clinically measured endpoints of cardiovascular function. Thus, ϩ ADENOSINE triphosphate-sensitive potassium (K ATP) they are often used as induction agents in patients with channels have been identified in pulmonary arterial hemodynamic instability. Our laboratory has recently 1 ϩ smooth muscle. K ATP channel activation results in demonstrated that etomidate and ketamine attenuated ϩ membrane hyperpolarization and a decrease in Ca2 pulmonary vasorelaxant responses to bradykinin and ϩ influx through voltage-dependent Ca2 channels, which acetylcholine by inhibiting both nitric oxide and Ca2ϩ- in turn reduces vascular smooth muscle tone. Kϩ ϩ ATP activated potassium channel (K Ca)-mediated compo- channels are known to be activated by hyperpolarizing nents of the response.21 However, the effects of these agonists, such as diazoxide, pinacidil, cromakalim, and anesthetics on Kϩ -mediated pulmonary vasorelax- 2,3 ϩ ATP its enantiomer, lemakalim. K ATP channel agonists are ation have not been investigated. An anesthesia-induced used as therapeutic agents in a variety of cardiovascular attenuation of pulmonary vasodilator mechanisms could increase right ventricular afterload, which could ad- * Research Fellow. † Carl E. Wasmuth Endowed Chair and Director. versely affect patients with right ventricular dysfunction. Received from the Center for Anesthesiology Research, Division of Anesthe- The first goal of this in vitro study was to investigate siology and Critical Care Medicine, The Cleveland Clinic Foundation, Cleveland, the effects of etomidate and ketamine on the pulmonary Ohio. Submitted for publication May 9, 2002. Accepted for publication August ϩ 15, 2002. Supported by grants No. HL-38291 and HL-40361 from the National vasorelaxant response to the K ATP agonist lemakalim. Heart, Lung and Blood Institute, Bethesda, Maryland. Presented in part at the Based on our previous results,19,21 we tested the hypoth- annual meeting of the American Society of Anesthesiologists, New Orleans, Louisiana, October 16, 2001. esis that these anesthetics would attenuate the endothe- Address reprint requests to Dr. Murray: Center for Anesthesiology Research, lium-dependent component of lemakalim-induced relax- FF40, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio ation. We also tested the hypothesis that the inhibitory 44195. Address electronic mail to: [email protected]. Individual article reprints may be purchased through the Journal Web site, www.anesthesiology.org. effects of etomidate and ketamine involved a decrease in Anesthesiology, V 98, No 1, Jan 2003 104 ϩ ETOMIDATE AND KETAMINE INHIBIT K ATP RELAXATION 105 the production or activity of vasodilator metabolites of Isometric Tension Experiments the cyclooxygenase pathway. Pulmonary arterial rings were vertically mounted be- tween two stainless steel hooks in organ baths filled with 25 ml Krebs-Ringer bicarbonate solution (37°C) gassed with 95% O and 5% CO . One of the hooks was an- Material and Methods 2 2 chored and the other was connected to a strain gauge to measure isometric force. The rings were stretched at All experimental procedures and protocols were ap- 10-min intervals in increments of 0.5 g to achieve opti- proved by the Institutional Animal Care and Use Com- mal resting tension. Optimal resting tension was defined mittee of the The Cleveland Clinic Foundation. as the minimum amount of stretch required to achieve the largest contractile response to 40 mM KCl and was Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/98/1/104/405921/0000542-200301000-00019.pdf by guest on 24 September 2021 Preparation of Pulmonary Arterial Rings determined in preliminary experiments to be 5 g for the Thirty healthy mongrel dogs weighing 20–30 kg were size of the arteries used in these experiments. After the anesthetized with intravenous pentobarbital sodium arterial rings had been stretched to their optimal resting (30 mg/kg) and intravenous fentanyl citrate (15 ␮g/kg). tension, the contractile response to 60 mM KCl was After tracheal intubation, the lungs were mechanically measured. After washing out KCl from the organ bath ventilated. A catheter was placed in the right femoral and the return of isometric tension to prestimulation artery, heparin (8,000 units) was administered intrave- values, a cumulative concentration–response curve to nously, and the dogs were exsanguinated by controlled phenylephrine was performed in each ring. This was hemorrhage. A left lateral thoracotomy was performed achieved by increasing the concentration of phenyleph- Ϫ8 Ϫ5 through the fifth intercostal space, and the heart was rine in half-log increments (from 10 M to 3 ϫ 10 M) arrested with induced ventricular fibrillation (Grass In- after the response to each preceding concentration had strument Co., Quincy, MA). The heart and lungs were reached a steady state. This allowed us to calculate the removed from the thorax en bloc, and the lower right dose required to achieve 50% of the maximum response and left lung lobes were dissected free. Intralobar pul- to phenylephrine (ED50) in each ring. All rings were ␤ monary arteries (2–4 mm ID) were carefully dissected pretreated with the -adrenoreceptor antagonist pro- ϫ Ϫ6 and immersed in cold modified Krebs-Ringer bicarbon- pranolol (5 10 M, incubated for 30 min) before ate solution composed of 118.3 mM NaCl, 4.7 mM KCl, phenylephrine administration in all protocols to avoid the ␤-agonist effect of phenylephrine. 1.2 mM MgSO4, 1.2 mM KH2PO4, 2.5 mM CaCl2,25mM NaHCO3, 0.016 mM Ca-EDTA, and 11.1 mM glucose. The arteries were cleaned of connective tissue and cut into Experimental Protocols ring segments 4–5 mm in length with special care taken After washout of phenylephrine from the organ bath not

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