Anesth Analg 2004;98:30-36
© 2004 International Anesthesia Research Society
CARDIOVASCULAR ANESTHESIA
The Interaction of MCI-154, a Calcium Sensitizer, and Isoflurane on Systemic and Coronary Hemodynamics in Chronically Instrumented Dogs
Shunji Takahashi, MD,
Sungsam Cho, MD,
Tetsuya Hara, MD,
Hiroyuki Ureshino,
Shiro Tomiyasu, MD, and
Koji Sumikawa, MD
Department of Anesthesiology, Nagasaki University School of Medicine, Nagasaki, Japan
Address correspondence and reprint requests to Sungsam Cho, MD, Department of Anesthesiology, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan. Address e-mail to chos{at}net.nagasaki-u.ac.jp
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Abstract
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We conducted this study to determine the interaction of MCI-154, 6-[4-(4'-pyridylamino)phenyl]-4,5-dihydro-3(2H)-pyridazinone hydrochloride, a calcium sensitizer, and isoflurane on myocardial contractility as well as systemic and coronary hemodynamics in chronically instrumented dogs after pharmacological autonomic nervous system activity blockade. MCI-154 increased heart rate and left ventricular function with no change in rate pressure product, pressure work index, and coronary blood flow, with a decrease in coronary vascular resistance (CVR) in the conscious state. Isoflurane decreased heart rate and left ventricular function, with a decrease in rate pressure product and pressure work index. Isoflurane also decreased CVR, but not coronary blood flow. The cardiovascular actions of MCI-154 during isoflurane anesthesia were qualitatively similar to those observed in the conscious state. In contrast to the finding in the conscious state, MCI-154 reversed the decrease in cardiac output and preload recruitable stroke work caused by isoflurane, but these are not significantly different from the effects of isoflurane alone. These results indicate that MCI-154 increases myocardial contractility and decreases CVR without changing calculated myocardial oxygen consumption during both the conscious state and isoflurane anesthesia.
IMPLICATIONS: MCI-154, a calcium sensitizer, restores the myocardial contractility depressed by isoflurane and enhances the coronary vasodilating effect of isoflurane in chronically instrumented dogs.
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Introduction
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MCI-154, 6-[4-(4'-pyridylamino)phenyl]-4,5-di- hydro-3(2H)-pyridazinone hydrochloride (Mitsubishi Chemical Corp.), is a new positive inotropic drug with peripheral vasodilating properties (1–6). MCI-154 exerts positive inotropic effects without the involvement of 
- and ß-adrenergic, histaminergic, and muscarinic receptors (1,2). Concerning the positive inotropic mechanisms, it has been reported that MCI-154 increased the myofibrillar sensitivity to Ca2+ and the maximal Ca2+ activated force and facilitated the interaction between actin and myosin (3–5). MCI-154 increased cardiac output (CO) and decreased myocardial oxygen consumption (MvO2), and the oxygen cost during MCI-154 was significantly smaller compared with dobutamine, phosphodiesterase III (PDE III) inhibitors, and pimobendan in dogs and in patients with ischemic heart disease (7–10). The vasodilator effects of MCI-154 may decrease ventricular volume and, hence, offset the increase in myocardial oxygen demand associated with an augmentation of the contractile state. Although the Ca2+ sensitizing action may adversely affect diastolic function, MCI-154 not only improved the left ventricular (LV) systolic function, but also accelerated LV relaxation in dogs with pacing-induced heart failure (11). MCI-154 was also reported to increase coronary blood flow (CBF) in a dose-dependent manner (12). Concerning the coronary vasodilating mechanisms, MCI-154 can modulate the Ca2+ sensitivity of the Ca2+-activated K+ channel in vascular smooth muscle cells (13). Thus, MCI-154 would be useful in the management of heart failure with or without reduced coronary reserve because of the oxygen-saving effect and coronary vasodilating property.
Isoflurane reduces myocardial contraction by mechanisms involving the depression of intracellular calcium transient via inhibition of Ca2+ release from sarcoplasmic reticulum (14). Isoflurane also has a coronary vasodilating effect mediated through the decrease in intracellular Ca2+ by inhibition of the voltage-operated Ca2+ channel (15) and activation of the adenosine triphosphate-sensitive K channel (16). This study was conducted to test the following hypotheses: 1) MCI-154 could restore myocardial contractility depressed by isoflurane without changing MvO2 through an increase in the myofibrillar sensitivity to Ca2+ and the maximal Ca2+ activated force, and 2) MCI-154 might enhance coronary vasodilation induced by isoflurane through the interaction of different mechanisms. We used the slope (Mw) of the regional preload recruitable stroke work (PRSW) relationship to determine myocardial contractility, because the PRSW relationship is minimally influenced by heart rate (HR), preload, or afterload, as previously described by Pagel et al. (17). In this study, the pharmacological blockade of autonomic nervous system (ANS) activity was used to avoid the influence of ANS activity on systemic and coronary hemodynamics during the administration of MCI-154 or isoflurane (17). Therefore, the interaction of MCI-154 and isoflurane on myocardial contractility and systemic and coronary hemodynamics in this study was independent of ANS activity.
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Methods
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All experimental procedures and protocols described in this study were approved by the Animal Care and Use Committee of Nagasaki University School of Medicine. Fourteen healthy mongrel dogs of either sex weighing 12–15 kg were fasted overnight and then anesthetized with pentobarbital sodium (20 mg/kg IV) and fentanyl citrate (15 µg/kg IV). After intubation of the trachea, anesthesia was maintained by isoflurane 1.5 minimum alveolar anesthetic concentration (MAC) end-tidal in 100% oxygen with mechanical ventilation (Harvard Apparatus Co., South Natick, MA). A thoracotomy was performed in the left fifth intercostal space. Heparin-filled catheters (Argyle; Unitika Co., Hyogo, Japan) were inserted into the descending thoracic aorta, the LV at the apex, and the right atrium to measure the aortic blood pressure (AOP) and LV pressure (LVP) and to infuse fluids and drugs, respectively. The peak rates of positive and negative changes in LVP (+dP/dtmax and -dP/dtmin, respectively) were obtained by electronic differentiation of the LVP wave form. Ultrasonic flowprobes (HPD 120-10S and 20-20S; Crystal Biotech, Hopkinton, MA) were positioned around the ascending aorta and the proximal left circumflex coronary artery for measurement of CO and CBF. A pair of miniature ultrasonic segment-length crystals (5 MHz) for measurement of changes in regional contractile function (segment shortening; %SS) was implanted within the LV subendocardium in the area perfused by the left circumflex artery. A catheter fitted with a 10- to 20-mL inflatable latex balloon was inserted into the left femoral vein and advanced so that the balloon was just below the right atrium. After chest closure, the pneumothorax was evacuated, and the instrumentation wires and catheters were exteriorized into a pouch sewn to the posterior cervical region. The dogs were nursed carefully and treated with an IV antibiotic—cefodizime sodium (Taiho Pharmaceutical Co. Ltd., Tokyo, Japan)—0.5 g daily after surgery for 10 days.
AOP and LVP were measured with a pressure transducer-tipped catheter (PC500; Millar Instruments, Houston, TX). HR was derived from the AOP pulse. Formula-derived variables included total systemic vascular resistance (SVR), diastolic coronary vascular resistance (DCVR), %SS, rate pressure product (RPP), and pressure work index (PWI) (Appendix 1). We measured RPP and PWI to estimate MvO2, because PWI has been reported to reflect the change in MvO2 over wide ranges of HR, ventricular loading conditions, and contractile states (18,19). All hemodynamic data were continuously monitored on a polygraph and digitized via a computer interfaced with an analog-to-digital converter (HEM; Physio-Tech, Tokyo, Japan).
We used the PRSW relationship to determine myocardial contractility, as previously described (17). Briefly, a series of LVP-segment length diagrams were obtained after the inferior vena cava was transiently occluded to produce an approximately 30 mm Hg decline in LV systolic pressure over 10 to 15 cardiac cycles. The area of segmental stroke work was plotted against the corresponding end-diastolic segment length for each loop. Linear regression analysis was used to determine Mw, and the length intercept of the PRSW relation was calculated (Appendix 1).
The experimental protocol is shown in Figure 1. Dogs were allowed to recover from the surgery for at least 10 days before the experimentation. Each dog was fasted overnight, and fluid deficits were replaced with lactated Ringer’s solution (3 mL · kg-1 · h-1). Dogs were randomly assigned to one of two groups. With dogs lying quietly, the first measurement was performed for baseline data in the conscious state. The next measurement was performed after the pharmacological blockade of ANS activity in both groups. Pharmacological blockade of the ANS activity consisted of IV propranolol hydrochloride (2 mg/kg), atropine methylnitrate (3 mg/kg), and hexamethonium bromide (20 mg/kg) (17). Adequate blockade of the ANS activity was established by lack of reflex change in HR by the inferior vena cava occlusion before, during, and after each experiment. Subsequently, dogs in Group CM (n = 7) were treated with two consecutive infusions of MCI-154 (0.5 and 1.0 µg · kg-1 · min-1), and the measurements were performed 15 min after infusion of each dose of MCI-154 in the conscious state was started. The dose and the steady-state infusion time of MCI-154 were chosen on the basis of previous studies (11,12). In Group IM (n = 7), anesthesia was induced with isoflurane alone via a mask, and the lungs were mechanically ventilated through endotracheal intubation. Anesthesia was maintained by isoflurane, 1.5 MAC end-tidal (1.92%), and other anesthetics and muscle relaxant drugs were not used. After 30 min of steady state, measurements were obtained with isoflurane alone. Dogs were then treated with two consecutive infusions of MCI-154, and measurements were performed. End-tidal CO2 and isoflurane concentrations were measured continuously by a gas analyzer (Capnomac Ultima; Datex, Helsinki, Finland), and the end-tidal CO2 concentration, calibrated by using the PaCO2 values, was maintained at levels of 35–40 mm Hg by adjusting the respiratory rate. The PaCO2 and the arterial oxygen tension were 37–42 mm Hg and 180–340 mm Hg, respectively; these were verified before the measurements in the isoflurane-alone state and after the experiments. A heating lamp and electrical blanket were used to maintain the esophageal temperature at 37.0°C–38.5°C.
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Figure 1. Experimental protocol. T1 = conscious baseline; T2 = autonomic nervous system (ANS) blockade; T3 = isoflurane; T4 and T5 = the dose of MCI-154 0.5 and 1.0 µg · kg-1 · min-1, respectively. MAC = minimum alveolar anesthetic concentration.
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MCI-154 was dissolved in 0.9% normal saline using ultrasound immediately before use. Propranolol hydrochloride, atropine methylnitrate, and hexamethonium bromide (Sigma, St. Louis, MO) were dissolved in 0.9% normal saline.
All data are expressed as mean ± SEM. Data within and among groups were analyzed with analysis of variance for repeated measures followed by the Scheffé F test. A P value <0.05 was considered statistically significant.
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Results
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Table 1 shows the systemic and coronary hemodynamic data, and Table 2 shows LV function data. There were no significant differences in the baseline hemodynamic data with or without ANS blockade among groups. MCI-154 dose-dependently increased HR and CO and decreased end-diastolic segment length and end-systolic segment length. A significant increase in diastolic CBF (DCBF) with a decrease in DCVR was observed in the conscious state (Table 1, Fig. 2). Mw, PRSW, %SS, +dP/dtmax, and -dP/dtmin increased significantly, with no change in RPP or PWI, indicating that MCI-154 has an inotropic effect without changing calculated MvO2 (Tables 1 and 2, Fig. 2).
Isoflurane decreased HR, mean aortic pressure, LV systolic pressure, DCVR, and CO (Table 1, Fig. 2). Isoflurane also significantly reduced Mw, PRSW, %SS, +dP/dtmax, -dP/dtmin, RPP, and PWI (Tables 1 and 2 , Fig. 2). The cardiovascular actions of MCI-154 during isoflurane anesthesia were qualitatively similar to those observed in the conscious state (Tables 1 and 2, Figs. 1 and 2). MCI-154 increased HR, Mw, %SS, +dP/dtmax, and -dP/dtmin, with no change in RPP or PWI, compared with the isoflurane-alone state. In contrast to the finding in the conscious state, MCI-154 restored the decrease in CO and PRSW caused by isoflurane, but these variables are not significantly different from those measured with isoflurane alone. MCI-154 increased diastolic coronary blood flow (DCBF), with a decrease in DCVR and SVR.
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Discussion
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We investigated the interaction of MCI-154, a calcium sensitizer, and isoflurane on myocardial contractility and on systemic and coronary hemodynamics in chronically instrumented dogs after pharmacological ANS blockade. We found that MCI-154 increases myocardial contractility and decreases coronary vascular resistance (CVR) without changing calculated MvO2 in the conscious state and during isoflurane anesthesia.
In contrast to the finding in the conscious state, MCI-154 restored the decrease in CO caused by isoflurane, but this was not significantly different than with isoflurane alone. There are several possible explanations for these results. First, Korvald et al. (20) reported that MCI-154 has a minimal effect on myocardial contractility, such as Mw, but that it increases CO by an increase in HR with a concomitant decrease in SVR in intact pigs. In our other investigation, which used chronically instrumented dogs without the pharmacological ANS blockade, MCI-154 significantly increased HR and CO and decreased SVR during isoflurane anesthesia (data not shown). Thus the vasodilating effect of MCI-154 might increase CO with a concomitant increase in HR. However, MCI-154 increases Mw and HR with and without pharmacological ANS blockade (data not shown). MCI-154 also decreases SVR during isoflurane anesthesia, but not in the conscious state. Second, isoflurane would attenuate an increase in myocardial contractility of MCI-154. In this study, MCI-154 increased Mw by 71% from control at 1.0 µg · kg-1 · min-1 in the conscious state and by 48% during isoflurane anesthesia. The mechanisms of MCI-154-induced increases in myocardial contractility are increased myofibrillar sensitivity to Ca2+ and maximal Ca2+ activated force (3–5). In contrast, the mechanisms of isoflurane-induced reduction in myocardial contraction involve a depression of intracellular calcium transient (14). Thus, the effect of MCI-154 on myocardial contractility might be altered by intracellular Ca2+ concentration.
Inotropic stimulation by catecholamines increases MvO2 and may often exacerbate myocardial ischemia, especially in patients with coronary artery disease. Thus, an inotropic drug able to increase CO with less MvO2 would be advantageous. PDE III inhibitors, such as amrinone and olprinone, were reported to increase CO and LV contractility without increasing MvO2 (21,22). Takaoka et al. (10) reported that MCI-154 increased CO and decreased MvO2 and that the oxygen cost with MCI-154 was significantly smaller compared with dobutamine and olprinone in patients with LV dysfunction after myocardial infarction. Abe et al. (7) also reported that MCI-154 significantly improved the depressed %SS and myocardial acidosis without an increase in myocardial blood flow in dogs with coronary stenosis, as compared with dobutamine, milrinone, and pimobendan. MCI-154 may be useful in the management of heart failure, especially with reduced coronary reserve, compared with catecholamines or PDE III inhibitors.
Ca2+ sensitizers might prolong relaxation by shifting the relationship between pCa and force to the left on the pCa axis (23). EMD 57033, a relatively pure Ca2+ sensitizer, was reported to impair relaxation in the beating heart (24). Pagel et al. (17) observed that levosimendan did not alter the time constant of isovolumic relaxation and -dP/dtmin, indicating that LV relaxation was unaltered by levosimendan in conscious or isoflurane- or halothane-anesthetized dogs. In contrast, MCI-154 not only improved LV systolic function, but also accelerated LV relaxation in dogs with pacing-induced heart failure (11). These results show that MCI-154 increases -dP/dtmin both in the conscious state and during isoflurane anesthesia. MCI-154 might therefore have a property of enhancing LV relaxation.
MCI-154 dose-dependently increased HR both in the conscious state and during isoflurane anesthesia in this study. Previously, MCI-154 was reported to increase HR dose-dependently in both conscious and anesthetized dogs without ANS block (8,12). Hosono and Taira (25) reported that MCI-154 dose-dependently increased the sinus rate but not the ventricular rate and shortened atrioventricular conduction time in an isolated dog heart preparation. Lakhe et al. (26) reported that EMD 53998, a Ca2+ sensitizer with PDE inhibitory action, increased the sinus rate dose-dependently but that EMD 57033, a relatively pure Ca2+ sensitizer, did not have this effect. MCI-154 also has PDE III-inhibitory properties (27), so it is likely that MCI-154 directly increases the sinus rate by the increase in cyclic adenosine monophosphate content and Ca2+ entry. Although the increase in HR induced by MCI-154 might worsen myocardial ischemia, MCI-154 caused no change in MvO2 and tended to decrease RPP in dogs with and without coronary stenosis (8). Our results also show that MCI-154 increased HR but did not affect RPP or PWI, either in the conscious state or during isoflurane anesthesia.
Isoflurane has a coronary vasodilating effect. CBF is regulated by multiple factors, including coronary perfusion pressure, MvO2, HR, preload, afterload, and inotropic state. The mechanisms of isoflurane-induced coronary vasodilation include the decrease in intracellular Ca2+ through inhibition of voltage-operated Ca2+ channels (15) and activation of the adenosine triphosphate-sensitive K channel (16). Our results show that the administration of isoflurane with pharmacological blockade of the ANS activity causes no change in DCBF, whereas it decreases DCVR. These results are concordant with those reported by Pagel et al. (17). MCI-154 dose-dependently decreased DCVR and concomitantly increased DCBF both in the conscious state and during isoflurane anesthesia. These results are supported by reports that MCI-154 produced an increase in DCBF and a reduction in DCVR in conscious dogs (12). Other Ca2+ sensitizers, levosimendan and pimobendan, also decreased DCVR and concomitantly increased DCBF without increasing MvO2 (17,28). This suggests that MCI-154 would have a direct coronary vasodilating effect.
In summary, our results indicate that MCI-154 directly increases myocardial contractility and decreases CVR without changing calculated MvO2 in the conscious state and during isoflurane anesthesia. In contrast to the finding in the conscious state, MCI-154 restored the decrease in CO caused by isoflurane, but this was not significantly different from isoflurane alone. MCI-154 augmented LV function in heart failure, as evidenced by greater increases in the CO and LV end-systolic pressure-volume ratio than in normal heart (11), and further studies are needed to elucidate the interaction of MCI-154, a calcium sensitizer, and isoflurane in diseased heart.
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Appendix 1:
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Formulas Used to Derive Hemodynamic Variables
where MAP = mean aortic pressure (mm Hg); LVEDP = left ventricular end-diastolic pressure (mm Hg); 80 = transformation factor of Wood units (mm Hg · L-1 · min-1) to standard metric units (dynes · s · cm-5); CO = cardiac output (L/min); CBF = coronary blood flow (L/min); AOP = aortic blood pressure (mm Hg); DCBF = diastolic coronary blood flow (L/min); EDL = end-diastolic segment length (mm); ESL = end-systolic segment length (mm); HR = heart rate (bpm); SV = stroke volume (mL); BW = body weight (kg); and Mw = the slope of the regional preload recruitable stroke work relationship.
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Acknowledgments
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This work was supported in part by Grant-in-Aid B 10470319 for Scientific Research from the Ministry of Education, Science and Culture, Japan.
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References
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Accepted for publication August 13, 2003.
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Abstract
Introduction
significantly (P < 0.05) different from isoflurane alone; #significantly (P < 0.05) different from a 0.5 µg · kg-1 · min-1 MCI-154 infusion; 
significantly (P < 0.05) different between Groups CM and IM.
