Anesth Analg 2001;92:602-608
© 2001 International Anesthesia Research Society
CARDIOVASCULAR ANESTHESIA
Morphine Enhances Myofilament Ca2+ Sensitivity in Intact Guinea Pig Beating Hearts
Yuri Nakae, MD, PhD*,
Satoshi Fujita, MD, PhD , and
Akiyoshi Namiki, MD, PhD*
*Department of Anesthesiology, Sapporo Medical University School of Medicine; and Department of Anesthesia, Hokkaido Keiaikai Minami 1-jyo Hospital, Sapporo, Japan
Address correspondence and reprint requests to Yuri Nakae, MD, PhD, Department of Anesthesiology, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226-0509. Address e-mail to ynakae{at}mcw.edu
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Abstract
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We investigated whether morphine alters intracellular Ca2+ concentration ([Ca2+]i), left ventricular pressure (LVP), and myofilament Ca2+ sensitivity under physiologic conditions in intact guinea pig beating hearts and whether  1, 2, and  opioid stimulations are related to the direct cardiac effects of morphine. Transmural LV phasic [Ca2+]i was measured from fluorescence signals at 385 nm and 456 nm. The Ca2+ transients during each contraction were defined as available [Ca2+]i. The hearts were perfused with modified Krebs-Ringer solution containing morphine in the absence and presence of 1 (BNTX), 2 (NTB), and (nor-BNI) antagonists, while developed LVP and available [Ca2+]i were recorded. Morphine (1 µM) decreased available [Ca2+]i by 44 ± 12 nM without decreasing developed LVP at 2.5 mM of [CaCl2]e (P < 0.05). Morphine (1 µM) caused a leftward shift in the curve of developed LVP as a function of available [Ca2+]i (P < 0.05). BNTX (1 µM), but not nor-BNI (1 µM) or NTB (0.1 µM) blocked morphine (1 µM) effects to decrease available [Ca2+]i. Morphine decreases available [Ca2+]i but not LVP, and it enhances myofilament Ca2+ sensitivity under physiologic conditions at clinical concentrations in intact isolated beating guinea pig hearts. The 1 opioid stimulation modifies the effects of morphine on Ca2+ transients and myofilament Ca2+ sensitivity.
Implications: Morphine modifies myofilament Ca2+ sensitivity and Ca2+ transients in guinea pig hearts at concentrations that are clinically relevant.
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Introduction
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Morphine is a mixed opioid agonist, and it mainly binds to cardiac and  receptors because µ receptors are not present in the heart (1,2). The stimulation of the and opioid receptors causes negative inotropic effects as the result of a decrease in intracellular Ca2+ concentration ([Ca2+]i) transients in isolated cardiac myocytes from adult rats (3). However, the direct cardiac effect of morphine on [Ca2+]i transients and contraction is controversial. Morphine decreases myocyte shortening without a decrease in the Ca2+ transients in rat ventricular myocytes (4), whereas it causes an increase in [Ca2+]i and Ca2+ influx on cultured ventricular myocytes from neonatal rats (5,6).
These results from previous in vivo studies were obtained under the conditions of low temperatures and low stimulus frequencies. However, the change of Ca2+ transients may be underestimated in these conditions. We used an intact guinea pig beating heart model under physiologic conditions, i.e., a temperature of 37°C and beating rates of more than 200 bpm, and we simultaneously measured [Ca2+]i and left ventricular pressure (LVP) to determine the effect of myofilament Ca2+ sensitivity. We investigated whether morphine alters [Ca2+]i transients, LVP, and myofilament Ca2+ sensitivity in intact guinea pig beating hearts and whether 1, 2, and opioid receptor stimulations are related to the direct cardiac effects of morphine.
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Methods
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Langendorff Heart Preparation
Approval from the Institutional Animal Care Committee of Sapporo Medical University was obtained before initiation of this study. English short-haired guinea pigs weighing 250–300 g were injected intraperitoneally with 20 mg of ketamine (Sigma-Aldrich, Tokyo, Japan) and 1,000 U of heparin (Sigma-Aldrich) and were decapitated after they became unresponsive to noxious stimulation. All hearts were isolated and perfused at 55 mm Hg by the method reported previously (7–9). The perfusate, a modified Krebs-Ringer (KR) solution (in mM: 137 Na+, 5 K+, 1.2 Mg2+, 2.5 Ca2+, 134 Cl-, 15.5 HCO3-, 1.2 H2PO4-, 11.5 glucose, 2 pyruvate, 16 mannitol, and 0.05 EDTA, with 5 U/L insulin), was equilibrated with a gas mixture of 97% oxygen (O2) and 3% carbon dioxide (CO2) at a flow rate of 1 L/min, resulting in a pH of 7.4. Perfusate and bath temperatures were maintained at 37° ± 0.1°C by a thermostatically controlled water circulator (Thermo pumpTM; Taitec CO., Koshiya, Japan). Isovolemic developed (systolic-diastolic) LVP, maximum rates of increase and decrease in LVP (+dP/dtmax and -dP/dtmax), spontaneous atrial heart rate (HR), and aortic inflow, which indicates coronary inflow (CF), were measured continuously. LVP was measured by a pressure transducer (DTX plus pressTM; Ohmeda, Madison, WI) connected to a thin, saline-filled latex balloon (LB-3TM; MARS, Inc., Sapporo, Japan) inserted into the LV through the left atrium. The volume of the balloon was adjusted to obtain a diastolic LVP of 0 mm Hg. CF was measured at constant temperature and constant perfusion pressure (55 mm Hg) by using a self-calibrating, in-line, ultrasonic flowmeter (Transonic T106, Tokyo, Japan) placed directly into the aortic inflow line. To determine maximal CF, adenosine (0.2 mL of 200 µM stock solution) was injected into the aortic root cannula during the initial control period and after the last control reading. To study the effects of drugs under physiologic conditions, HR pacing was not applied. Coronary inflow and outflow (coronary sinus) O2 tensions were measured together with pH and CO2 tension by using a blood gas analyzer (ABL 505TM; Radiometer, Copenhagen, Denmark). Percent O2 extraction, O2 delivery (DO2), O2 consumption (MVO2), and relative cardiac efficacy (LVP · HR/MVO2), which reflects the O2 supply-to-demand ratio, were calculated as previously reported (7,8). After all experiments were completed, the weight of each heart was measured for the calculation of DO2 and MVO2.
Measurements of [Ca2+]i in Intact Beating Hearts
Transmural LV phasic [Ca2+]i was measured by the fluorescence ratio of indo-1 emission at 385 nm and 456 nm (F385/F456) by using a fiber bundle (FB-50; Japan Spectroscopic, Tokyo, Japan) connected to a luminescence spectrometer (CAF-110; Japan Spectroscopic). Our methods have been described in detail previously (8). After perfusion for 15 min by using the standard perfusate, the hearts were loaded in an ambient light-free room at 25° ± 0.5°C for 20–30 min with 166 mL of recirculating standard perfusate containing free Ca2+ fluorescent indicator indo-1 AM (6 µM, cell-permeable ester form of indo-1, Sigma-Aldrich). Loading of indo-1 was stopped when F385/F456 intensities had increased by approximately 10 fold. Residual indo-1 was washed out by perfusing the heart with standard perfusate for at least 20 min, and then each heart was rewarmed to 37° ± 0.2°C before initiating the study. To avoid blanching of indo-1, the arc lamp shutter was opened only for 2.5-s recording intervals for a total exposure of <125 s for each indo-1-loaded heart. Fluorescence of the indo-1 dye is independent of the tissue oxygenation state at these two isobestic wavelengths (10–12).
After correcting for autofluorescence and noncytosolic uptake, F385/F456 was calibrated to [Ca2+]i transients (in nM) by the standard equation for fluorescent indicators: [Ca2+]i = S456•Kd([R-Rmin]/[Rmax-R]), where Kd is the indo-1 dissociation constant for Ca2+, S456 is the ratio between the fluorescence intensities measured at 456 nm in the absence of Ca2+ and in the presence of saturating Ca2+, R is the ratio of detected indo-1 fluorescence intensities, Rmin and Rmax are the fluorescence ratios in the absence of Ca2+ and in the presence of saturating Ca2+, respectively (10,12). In the present study (n = 5), the Kd of indo-1 for Ca2+ was calculated to be 236.6 ± 28.8 nM at 37°C. Rmax was calculated to be 5.04, and Rmin was calculated to be 0.05. Noncytosolic fluorescence was measured at the end of each experiment by perfusing hearts with 17.5 µM MnCl2 to quench fluorescence derived from the cytosolic compartment (13). Background autofluorescence was corrected at each wavelength at 37°C after the initial perfusion and equilibration and before indo-1 loading. In pilot studies (n = 5), the drugs used in this study did not alter basal autofluorescence and Mn2+-corrected noncytosolic Ca2+, and autofluorescence was unaffected over the 3-h testing period with normal oxygenation. Also, the drugs used did not interact with the fluorescence of indo-1 AM. The [Ca2+]i transients during each contraction were defined as available [Ca2+]i (systolic-diastolic, s-d[Ca2+]i). The [Ca2+]i transients can be measured reliably for at least 4 h at 37°C after washout of extracellular indo-1 AM. The data were digitized by a MacLabTM system (AD Instruments, NSW, Australia) and stored in a personal computer.
Experimental Protocol
Sixty hearts were used during this investigation. At first, we studied the effects of morphine on cardiac metabolic and functional variables. Initial control measurements were obtained during perfusion of KR solution (CaCl2 2.5 mM) after a 30-min stabilization period. Ten hearts were perfused with KR solution (vehicle, CaCl2 2.5 mM) containing morphine chloride (morphine; Sankyo, Tokyo, Japan; 0.01, 0.1, 1, and 10 µM) for 4 min, respectively. The HR, CF, developed LVP, +dP/dtmax, -dP/dtmax, and inflow and outflow O2 tensions were measured after a 4-min equilibration period. After control measurements, different concentrations of morphine were tested in random fashion in the same heart with a 20-min washout period.
Next, we studied the effects of morphine on the available [Ca2+]i and developed LVP. After loading and residual washout of indo-1 AM, 10 hearts were perfused with KR solution (vehicle) and KR solution containing morphine (0.1 and 1 µM). At the same time, the concentration of extracellular Ca2+ ([CaCl2]e) was increased incrementally from 0.3 to 4.5 mM for an 11-min period, during which all cardiac variables and [Ca2+]i were measured at 1-min intervals until, under any drug protocol, LVP reached its maximal value. Concentrations were tested in random fashion in the same heart with a 20-min washout period. Five hearts had an additional control (postcontrol) to examine for any time related changes. The developed LVP (mm Hg) and s-d[Ca2+]i (in nM) were plotted as functions of [CaCl2]e (in mM), and normalized developed LVP was plotted as a function of s-d[Ca2+]i.
Finally, we examined the effects of morphine on available [Ca2+]i and developed LVP in the presence of opioid receptor antagonists. Forty hearts were perfused with KR solution (vehicle), KR solution containing either naloxone (naloxone hydrochloride; Sigma-Aldrich; 1 µM), nor-BNI (-antagonist, 1 µM), BNTX (1-antagonist, 1 µM), or NTB (2-antagonist, 0.1 µM), and KR solution containing morphine (1 µM) with either naloxone, nor-BNI, BNTX, or NTB, respectively (in each 10 hearts). At the same time, [CaCl2]e was increased incrementally as described above. Drugs were given in random fashion in the same heart with a 20-min washout period. Each heart underwent a change in [CaCl2]e three times, once in the absence of drugs (vehicle), so that each heart served as its own control. Postcontrol values (n = 5) were measured in the same heart after a Ca2+-dose response was repeated 3 times. Altering extracellular [CaCl2]e did not significantly alter noncytosolic compartment Ca2+ for a 20-min period as previously reported (14). All drug effects were maximal within 3 min, stable during drug perfusion, and reversible on washout within 15 min of stopping the drug infusion. We determined the concentrations of opioid antagonists that equivalently inhibited the effects of each agonist. The nor-BNI, BNTX, and NTB were supplied by H. Nagase and T. Endoh (Basic Research Laboratories, Toray Industries, Inc., Kamakura, Japan).
All data are expressed as means ± SD. Cardiac functional and metabolic data were compared by using Tukey’s comparison of means test after analysis of variance for repeated measures. Curves of developed LVP and s-d[Ca2+]i as functions of [CaCl2]e, and curves of LVP as a function of s-d[Ca2+]i were compared by using nonlinear regression analyses sigmoidal dose-response (variable slope, PrismTM; GraphPad Software, Inc., CA), where all correlation coefficients (R) exceeded 0.98. Slopes, 95% confidence intervals (CI95), and slope comparisons were determined for each curve. Differences between means were considered significant when P was <0.05.
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Results
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Table 1 summarizes the effects of morphine on cardiac functional and metabolic variables at 2.5 mM of [CaCl2]e. Morphine (0.01, 0.1, 1, and 10 µM) did not alter any cardiac functional and metabolic variables.
Morphine (0.1 and 1 µM) did not change developed LVP at 2.5 mM of [CaCl2]e while [CaCl2]e was increased incrementally from 0.3 to 4.5 mM (Table 2 and Fig. 1A). Morphine (1 µM) decreased systolic [Ca2+]i and s-d[Ca2+]i by 46 ± 8 nM and 44 ± 12 nM, but not diastolic [Ca2+]i, at 2.5 mM of [CaCl2]e (Table 2 and Fig. 1B, P < 0.05). Figure 2 shows changes in normalized developed LVP (%) with increases in s-d[Ca2+]i (nM) obtained while [CaCl2]e was increased incrementally from 0.3 to 4.5 mM in the perfusate of vehicle and morphine (1 µM). Morphine (1 µM) did not alter maximum developed LVP (LVPmax). Morphine (1 µM) caused a significant leftward shift in the developed LVP and s-d[Ca2+]i relation curve by 49 ± 4 nM (CI95) at 50% LVPmax (P < 0.05). Morphine (0.1 µM) did not shift the curve. Postcontrol data are shown in Table 2, and Figure 1. There were no differences between vehicle (baseline) and postcontrol values on developed LVP, s[Ca2+]i, d[Ca2+]i, and s-d[Ca2+]i.
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Table 2. Changes in Developed LVP, s[Ca2+]i, d[Ca2+]i, and s-d[Ca2+]i at 2.5 mM of [CaCl2]e in the Perfusate of Morphine (0.1 µM and 1 µM)
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Figure 1. A. Changes in developed left ventricular pressure (LVP [mm Hg]) while [CaCl2]e was increased incrementally from 0.3 to 4.5 mM in the perfusate of vehicle, morphine (0.1 and 1 µM), and postcontrol. Morphine did not decrease developed LVP. B. Changes in s-d[Ca2+]i (nM) while [CaCl2]e was increased incrementally from 0.3 to 4.5 mM in the perfusate of vehicle, morphine (0.1 and 1 µM), and postcontrol. Morphine (1 µM) decreased s-d[Ca2+]i at 2.5 mM of [CaCl2]e. Data are presented as mean ± SD (n = 10, postcontrol data obtained in 5 experiments.) Baseline values present during vehicle administration before morphine. Postcontrol presents values measured after the final washout of morphine.
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Figure. 2. Changes in normalized developed left ventricular pressure (LVP [%]) with increases in s-d[Ca2+]i (nM) while [CaCl2]e was increased incrementally from 0.3 to 4.5 mM in the perfusate of vehicle, morphine (1 µM), and morphine (1 µM) with BNTX (1 µM). Morphine (1 µM) shifted the curve to the left. Data are presented as mean ± SD (n = 10). Baseline values present during vehicle administration before morphine. BNTX = 1 antagonist. *P < 0.05 versus vehicle.
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Morphine (1 µM) with naloxone (1 µM) did not decrease developed LVP, s[Ca2+]i, d[Ca2+]i, nor s-d[Ca2+]i at 2.5 mM of [CaCl2]e ( Table 3). Morphine (1 µM) with nor-BNI (1 µM) decreased s[Ca2+]i by 36 ± 11 nM and s-d[Ca2+]i by 57 ± 11 nM at 2.5 mM of [CaCl2]e ( Table 4, P < 0.05). Morphine (1 µM) with BNTX (1 µM) did not change developed LVP, s[Ca2+]i, d[Ca2+]i, nor s-d[Ca2+]i at 2.5 mM of [CaCl2]e ( Table 5). Morphine (1 µM) with BNTX (1 µM) did not cause a leftward shift in the developed LVP and s-d[Ca2+]i relation curve (Fig. 2). Morphine (1 µM) with NTB (0.1 µM) decreased s[Ca2+]i by 45 ± 6 nM and s-d[Ca2+]i by 41 ± 7 nM at 2.5 mM of [CaCl2]e ( Table 6, P < 0.05). Naloxone (1 µM), nor-BNI (1 µM), BNTX (1 µM), and NTB (0.1 µM) individually did not change developed LVP, s[Ca2+]i, d[Ca2+]i, and s-d[Ca2+]i at 2.5 mM of [CaCl2]e (Tables 3–6). There were no differences between vehicle (baseline) and postcontrol values in each protocol (Tables 3–6). The maximal CF after the administration of adenosine was increased 22 ± 3 mL/min compared with before adenosine (17 ± 1 mL/min) during the initial control period and 19 ± 2 mL/min compared with before adenosine (16 ± 2 mL/min) after the last control reading, respectively, for all experimental protocols (P < 0.05).
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Table 3. Changes in Developed LVP, s[Ca2+]i, d[Ca2+]i, and s-d[Ca2+]i at 2.5 mM of [CaCl2]e in the Perfusate of Naloxone (1 µM) and Morphine (1 µM) with Naloxone (1 µM)
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Table 4. Changes in Developed LVP, s[Ca2+]i, d[Ca2+]i, and s-d[Ca2+]i at 2.5 mM of [CaCl2]e in the Perfusate of nor-BNI (1 µM) and Morphine (1 µM) with nor-BNI (1 µM)
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Table 5. Changes in Developed LVP, s[Ca2+]i, d[Ca2+]i, and s-d[Ca2+]i at 2.5 mM of [CaCl2]e in the Perfusate of BNTX (1 µM) and Morphine (1 µM) with BNTX (1 µM)
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Table 6. Changes in Developed LVP, s[Ca2+]i, d[Ca2+]i, and s-d[Ca2+]i at 2.5 mM of [CaCl2]e in the Perfusate of NTB (0.1 µM) and Morphine (1 µM) with NTB (0.1 µM)
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Discussion
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In the present study, morphine (1 µM) decreased Ca2+ transients without causing a decrease of LVP. Previous studies have reported that morphine caused an increase in Ca2+ transients without altering the amplitude of systolic cell motion in cultured ventricular myocytes from neonatal rats (5,6), whereas it decreased myocytes shortening with no change in the Ca2+ transients in freshly isolated adult rat ventricular myocytes (4). These differences can be explained by experimental preparations and conditions. Most studies have been conducted in isolated myocytes. Neonatal and adult ventricular myocytes differ in the developmental stage of sarcoplasmic reticulum (15). In addition, previous results have been obtained under low temperature or a low frequency of stimulus, or both. In our preliminary study, when the HR decreased naturally because of low temperature (27°C), LVP, s[Ca2+]i, and d[Ca2+]i were increased by 18%, 6%, and 9%, respectively, more than those in studies obtained at 37°C. Thus, the change of Ca2+ transients may have been underestimated under low temperature because the available [Ca2+]i was decreased less than that under physiologic conditions. Our present findings were obtained under physiologic conditions; i.e., a temperature of 37°C and beating rates of more than 200 bpm.
Because morphine alters Ca2+ transients without altering cardiac function, this finding may suggest that it induces other effects that counterbalance its effect on Ca2+ transients. We assessed myofilament Ca2+ sensitivity by evaluating the relationship between available Ca2+ and developed LVP. Morphine (1 µM) caused a leftward shift in the curve of developed LVP as a function of available [Ca2+]i. On the basis of previously published work on isolated tissue and cells (16–19), this finding suggests that morphine (1 µM) enhances myofilament Ca2+ sensitivity, indicating that it increases the affinity for Ca2+ binding to regulatory proteins, especially troponin C. Mechanisms of inotropic effect are explained by the alterations of available [Ca2+]i, time course of Ca2+ transients, myofilament Ca2+ sensitivity, and efficacy or rate of individual cross-bridge cycle formation (16–19). As described above, morphine might have no direct negative inotropic effect as a result of enhancement of myofilament Ca2+ sensitivity despite decreasing available [Ca2+]i.
The 1 opioid antagonist, but not 2 and opioid antagonists, inhibits the decrease of Ca2+ transients by morphine in whole perfused guinea pig hearts. The overall cardiac effect of morphine may be a composite effect of and receptors. A previous study has demonstrated that the and opioid agonists cause negative inotropic effects with a decrease of Ca2+ transients in isolated rat ventricular myocytes (3). Our preliminary studies showed that the 1 opioid agonist (TAN-67, 1 µM) decreased Ca2+ transients more than the 2 (deltorphine, 1 µM) and agonists (ICI-199441, 1 µM) in intact guinea pig hearts (20,21). The 1 opioid stimulation would be the predominant effect of morphine on Ca2+ transients in intact guinea pig beating heart. Moreover, the 1 antagonist inhibited the enhancement of myofilament Ca2+ sensitivity by morphine. This finding indicates that the 1 opioid stimulation modifies the changes of myofilament Ca2+ sensitivity induced by morphine.
We used a modified KR solution as a perfusate. Previous studies have demonstrated that oxygen supply provided by buffer solutions may be insufficient for oxygen demands compared with blood solution in certain experimental conditions (22), and that buffer solutions may not provide the best conditions to study the direct effect of a drug on coronary circulation and myocardial performance (23). The MVO2 under the conditions we conducted, i.e., high frequencies (more than 200 bpm) and high temperature (37°C), may increase more than under those of low frequencies and low temperature. However, the oxygen content in our study would be sufficient considering the counterbalance of DO2 and MVO2 that we calculated. Moreover, we performed the studies with a high fraction of inspired oxygen. Increased partial pressure of oxygen is known to modify coronary vasoconstriction mediated through potassium channels (24). In the present study, adenosine was injected to determine maximal CF during the initial control period and after the last control reading. Because the CF significantly increased compared with the initial value after the administration of adenosine, we confirmed that coronary vasoreactivity was preserved under increased partial pressure of oxygen.
Differences in species are associated with a different presence of receptor subtypes. The µ receptor is present in adult rat heart, but not guinea pig (25). There are also differences reported in the Na+/Ca2+ exchange mechanism between the rat and guinea pig (26). Similarly, there are differences in drug concentrations between the previous studies and the current study. Plasma morphine concentrations after oral administration exceed 1 µM (27). It is likely that the concentrations of morphine in this study that decreased Ca2+ transients include the concentrations encountered in clinical use.
In conclusion, morphine decreases Ca2+ transients but not cardiac contraction, and it enhances myofilament Ca2+ sensitivity under physiologic conditions in intact isolated beating guinea pig hearts at concentrations that are clinically relevant. Our data suggest that 1 opioid stimulation modifies the effects of morphine on Ca2+ transients and myofilament Ca2+ sensitivity.
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Acknowledgments
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This work was supported in part by a Grant-in-Aid for Scientific Research (No. 10671434) from the Ministry of Education, Japan.
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Footnotes
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A preliminary report of this work was presented in part at the annual meeting of the American Society of Anesthesiologists, October 9–13, 1999, Dallas, TX.
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Accepted for publication November 20, 2000.
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Y. Nakae, S. Fujita, and A. Namiki
Modulation of Myofilament Ca2+ Sensitivity by {delta}- and {kappa}-Opioid Agonists in Intact Guinea Pig Hearts
Anesth. Analg.,
March 1, 2003;
96(3):
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[Full Text]
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Abstract
Introduction
