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Propofol-Induced Depression of Cultured Rat Ventricular Myocytes Is Related to the M2

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Propofol-Induced Depression of Cultured Rat Ventricular Myocytes Is Related to the M2 1712 m LABORATORY INVESTIGATIONS Anesthesiology 1999; 91:1712–9 © 1999 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Propofol-induced Depression of Cultured Rat Ventricular Myocytes Is Related to the M2- acetylcholine Receptor–NO–cGMP Signaling Pathway Shuji Yamamoto, M.D., Ph.D.,* Shin Kawana, M.D., Ph.D.,† Atsushi Miyamoto, M.P., Ph.D.,‡ Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/91/6/1712/399327/0000542-199912000-00024.pdf by guest on 30 September 2021 Hideyo Ohshika, M.D., Ph.D.,§ Akiyoshi Namiki, M.D., Ph.D.i Background: It is well-known that propofol sometimes causes of the enhancement of nitrite production induced by propofol bradycardia or asystole during anesthesia; however, the direct (IC50) stimulation was abolished by pretreatment with atropine, effect of propofol on the myocardium remains unclear. Previ- methoctramine, or NG-monomethyl-L-arginine acetate (L- ous reports showed the contribution of muscarinic acetylcho- NMMA). The negative chronotropy induced by propofol (IC50) line receptors to propofol-induced bradycardia. Conversely, it stimulation was reduced to 40–50% by pretreatment with atro- was suggested recently that nitric oxide (NO) plays an impor- pine, methoctramine, L-NMMA, or 1H[1,2,4]oxadiazolo[4,3- tant role in mediating the effect of vagal stimulation in the a]quanoxalin-1-one, a selective inhibitor of guanylyl cyclase. 3 autonomic regulation of the heart. Therefore, the authors in- Propofol displaced [ H]QNB binding to the cell membrane of vestigated the effects of propofol on spontaneous contraction myocytes in a concentration-dependent manner. and NO production in cultured rat ventricular myocytes. Conclusion: These results suggest that the negative chronot- Methods: The authors measured chronotropic responses of ropy induced by propofol is mediated in part by M2-acetylcho- cultured rat ventricular myocytes induced by propofol stimula- line receptor activation, which involves the enhancement of NO tion with a sensor, a fiber-optic displacement measurement production in cultured rat ventricular myocytes. (Key words: Anesthetics; beating rate; high-performance liquid chromatog- instrument. The authors also quantitatively analyzed NO metab- raphy reaction system; M -acetylcholine receptor; nitrite; ni- olite production in cultured myocytes by measuring the levels 2 trate; sensor. of nitrite and nitrate in a high-performance liquid chromatog- raphy reaction system. The influence of propofol on musca- rinic acetylcholine receptors of myocyte membranes was also PROPOFOL (2,6-diisopropylphenol) is an intravenous measured with a competitive binding assay using [3H]quinu- anesthetic agent commonly used for general anesthesia. 3 clidinyl benzilate ([ H]QNB). There have been many reports of profound bradycardias Results: Propofol caused negative chronotropy in a dose- associated with its use, including sinus bradycardia1 and dependent manner. Propofol (IC50) also caused the enhance- 2 ment of nitrite production in cultured myocytes. Eighty percent even fetal asystole, in clinical use. Although modulation of the tone of the autonomic nervous system3 or alter- ation of baroreflex sensitivity4 would be included in the * Instructor, Department of Anesthesiology. mechanisms of bradydysrhythmic effects, the direct ef- † Assistant Professor, Department of Anesthesiology. fects of propofol on the myocardium remain unclear. ‡ Associate Professor, Department of Pharmacology. Recently, Alphin et al.5 reported that propofol slowed § Professor and Chairman, Department of Pharmacology. the atrial rate and depressed atrioventricular nodal con- i Professor and Chairman, Department of Anesthesiology. duction in the isolated guinea pig heart. The negative Received from the Departments of Anesthesiology and Pharmacol- dromotropic effect of propofol was shown to be pre- ogy, Sapporo Medical University School of Medicine, Sapporo, Japan. dominantly mediated by muscarinic acetylcholine recep- Submitted for publication December 11, 1998. Accepted for publica- tors (mAChRs). Results showed the contribution of tion April 12, 1999. Supported in part by Grants-in-Aid for Scientific Research (08838021 and 09557212 to Dr. Miyamoto) from the Ministry mAChRs to propofol-induced bradycardia. of Education, Science, Sports, and Culture of Japan, Tokyo, Japan; and In the autonomic regulation of cardiac contractility, by the Department of Anesthesiology, Sapporo Medical University, nitric oxide (NO) has been reported to play a significant Sapporo, Japan. Presented in part at the Annual Meeting of the Amer- role.6–8 We previously demonstrated the enhancement ican Society of Anesthesiologists, New Orleans, Louisiana, October of NO production with negative chronotropy induced by 19–23, 1996. carbachol, a muscarinic receptor agonist, in cultured rat Address reprint requests to Dr. Kawana: Department of Anesthesi- 9,10 ology, Sapporo Medical University School of Medicine, South-1, West- ventricular myocytes. These effects of carbachol 16, Chuo-ku, Sapporo, 060-8543 Japan. Address electronic mail to: were abolished by atropine, an mAChR antagonist, G [email protected] methoctramine, an M2-AChR antagonist and N -mono- Anesthesiology, V 91, No 6, Dec 1999 1713 PROPOFOL-INDUCED NEGATIVE CHRONOTROPY AND NO PRODUCTION methyl-L-arginine acetate (L-NMMA), an NO synthase beat regularly and synchronously. All experiments were 11 (NOS) inhibitor. Our results indicated that M2-AChR performed at 6 to 7 days of culture. mediated the activation of the NO-signaling pathway in cultured rat ventricular myocytes, which contributed to Measurement of Contraction of Myocytes the depression of myocardial contractility. These results Spontaneous contraction of cultured myocytes was are consistent with those that Balligand et al.6,8 reported measured using a Fotonic Sensor, a fiber-optic displace- for spontaneously beating neonatal rat cardiac myocytes. ment measurement instrument (MTI 1000; MTI Co., Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/91/6/1712/399327/0000542-199912000-00024.pdf by guest on 30 September 2021 We hypothesized that the NO signaling pathway medi- Latham, NY) in a multigas incubator.9–11,14–17 The prin- ated by M2-AChR also plays an important role in the ciple of measurement is to detect changes in the dis- cardiac depressant effect of propofol. tance between the probe and myocytes vertically ex- Few reports indicate that propofol stimulates NO pro- truded by contraction. The fiber-optic probe consists of duction in any tissues. Petros et al.12 found that propofol adjacent pairs of light-transmitting and light-receiving stimulated the production and release of NO from cul- fibers. The ratio of reflected light to transmitted light tured porcine aortic endothelial cells. Park et al.13 re- changes in proportion to the distance between the ported that propofol caused a direct vasodilative effect probe and an object at a certain range shown by a on distal coronary arteries in rats, which was primarily calibration curve specific to each probe. We used a endothelium-dependent and was mediated by multiple needle-type probe (MTI- 3806R; MTI Co.) 0.7-mm in substances, including NO and a vasodilative prostanoid. diameter, which could cover approximately 100–150 However, no evidence indicates that propofol stimulates myocytes. The serum-containing medium was replaced NO production in the myocardium. by 2,000 ml serum-free Dulbecco modified Eagle mini- In this study, we evaluated propofol-induced direct mum essential medium buffered with HEPES (SFD) 2 h negative chronotropy in cultured rat ventricular myo- before measurement, and the cells were stabilized in a cytes and enhancement of NO production. We also eval- multigas incubator (Sanyo, Tokyo, Japan) at 37°C in a uated M2-AChRs and other components in the NO sig- humidified atmosphere of 95% air and 5% CO2. The naling pathway that contribute to the negative probe was set perpendicular to the myocytes in the dish. chronotropy induced by propofol stimulation. They were analyzed after being agitated on a horizontally rotating shaker after 15 min in an incubator for stabili- zation. Two hundred microliters of vehicle or a 10-fold Materials and Methods concentrated solution of propofol was added to 1,800 ml SFD in the dish and then mixed with the shaker for 15 s Preparation of Cultured Rat Ventricular Myocytes at 60 rpm. The resultant concentrations of propofol All experiments were performed during the supervi- (Aldrich, Milwaukee, WI) were 100 nM to 100 mM.We sion of the Animal Care Committee of Sapporo Medical measured the changes in spontaneous beating rates of University. Primary cultured cardiac myocytes were pre- myocytes with the Fotonic Sensor for 5 min after vehicle pared from ventricles of neonatal Wistar rats (1–3 days or propofol addition. The IC50 value of propofol was old) by collagenase (Wako Chemical, Osaka, Japan) di- obtained from the dose–response curve. We also mea- 14 gestion, as described previously. Briefly, neonatal rat sured the effects of pretreatment with 1 mM atropine for ventricles were removed and incubated with collagenase 10 min; 1 mM methoctramine (RBI, Natick, MA), an M2- (200 U/ml) in Ca21- and Mg21-free Hank salt-balanced acetylcholine receptor subtype antagonist, for 10 min; solution (HBSS, pH 7.4) during 95% O2 and 5% CO2 gas 300 mML-NMMA (RBI), an NOS inhibitor, for 60 min; or bubbling at 37°C. The isolated ventricular myocytes 100 mM 1H-[1,2,4]oxadiazolo[4,3-a]quanoxalin-1-one were seeded at a density
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