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CARDIOVASCULAR ANESTHESIA

Propofol Inhibits Ca²⁺ Transients but Not Contraction in Intact Beating Guinea Pig Hearts

Yuri Nakae, MD^*, 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, Department of Anesthesiology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo 060-8543, Japan. Address e-mail to yurinaka{at}sapmed.ac.jp

	Abstract

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We investigated whether propofol inhibits Ca²⁺ transients and left ventricular pressure (LVP) in intact beating guinea pig hearts at clinical concentrations and whether an inhibition of Ca²⁺ transients by propofol results from an impairment of sarcolemmal or of sarcoplasmic reticulum (SR) function. By using a Langendorff’s preparation, transmural left ventricular phasic intracellular Ca²⁺ concentration ([Ca²⁺]_i) was measured by the fluorescence ratio of indo-1 emission at 385 nm and 456 nm and was calibrated to Ca²⁺ transients (in nM). The Ca²⁺ transients during each contraction were defined as available [Ca²⁺]_i. Sixty hearts were perfused with modified Krebs-Ringer’s solution containing lipid vehicle and propofol (1 and 10 µM) in the absence and presence of ryanodine, thapsigargin, and nifedipine, while developed LVP and available [Ca²⁺]_i were recorded. Propofol (10 µM) decreased available [Ca²⁺]_i by 11.0% ± 1.3% without decreasing developed LVP (% of control, P < 0.05). Propofol (10 µM) caused a leftward shift in the curve of developed LVP as a function of available [Ca²⁺]_i. Propofol (10 µM) with nifedipine (1 µM), but not with ryanodine (1 µM) or thapsigargin (1 µM), decreased available [Ca²⁺]_i by 15.5% ± 1.7% (P < 0.05). Propofol decreases available [Ca²⁺]_i without decreasing cardiac contraction, and it enhances myofilament Ca²⁺ sensitivity in intact beating hearts at clinical concentrations. The inhibition of available [Ca²⁺]_i by propofol may be mainly mediated by an impairment of sarcoplasmic reticulum Ca²⁺ handling rather than the sarcolemmal L-type Ca²⁺ current.

Implications: This is the first study of the effects of propofol on intracellular Ca²⁺ concentration and myofilament Ca²⁺ sensitivity under physiologic conditions in intact isolated beating guinea pig hearts.

	Introduction

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Acute cardiovascular changes after the induction of anesthesia with propofol, such as systemic hypotension and reduced cardiac output, have been reported in patients with or without intrinsic cardiac disease (1,2). In animal experiments, the direct cardiac effect of propofol is controversial. Propofol exerts a direct negative inotropic effect, which is mediated by a decrease in available intracellular Ca²⁺ concentration ([Ca²⁺]_i), in the isolated ferret ventricular myocardium and rat ventricular myocytes at supraclinical concentrations (3,4). However, it remains to be determined whether this decrease in [Ca²⁺]_i results from an impairment of sarcolemmal (3) activity or the function of sarcoplasmic reticulum (SR) (4). However, propofol does not have a negative inotropic effect at clinical plasma concentrations in isolated guinea pig ventricular muscle, rat myocardium, and rabbit heart (5–7). However, these results from previous in vivo studies were obtained at low temperatures and low stimulus frequencies, and the effects of SR function on the Ca²⁺ transient might 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 over 200 bpm, and we simultaneously measured [Ca²⁺]_i and cardiac contraction to determine the effect of myofilament Ca²⁺ sensitivity.

We hypothesized that propofol has a negative inotropic effect with a decrease in [Ca²⁺]_i at the relevant clinical blood concentration in the intact guinea pig beating heart. We investigated whether propofol inhibits Ca²⁺ transients and left ventricular pressure (LVP) and alters myofilament Ca²⁺ sensitivity in intact guinea pig beating hearts at clinical concentrations and whether an inhibition of Ca²⁺ transient by propofol results from an impairment of sarcolemmal activity or of SR function.

	Methods

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Langendorff Heart Preparation
Approval from our institutional animal care committee was obtained before initiation of this study. English short-haired guinea pigs, weighing 250–300 g, were injected intraperitoneally with 20 mg of ketamine and 1,000 U of heparin and were decapitated after they became unresponsive to noxious stimulation. The heart was isolated and perfused by the method reported previously (8). The perfusate, a modified Krebs-Ringer’s (KR) solution (Ca²⁺, 2.5 mM) as described before (8), 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 pump^TM; Taitec CO., Koshiya, Japan). Isovolemic developed (systolic-diastolic) LVP, maximum rates of rise and decrease in LVP (+dP/dt_max and -dP/dt_max), spontaneous atrial heart rate (HR), and aortic inflow, which indicates coronary inflow (CF), were measured continuously. LVP was measured by using a pressure transducer (DTX plus press^TM; Ohmeda, WI) connected to a thin, saline-filled latex balloon (LB-3^TM; MARS, Inc., Sapporo, Japan) inserted into the left ventricle (LV) through the left atrium. The volume of the balloon was adjusted to obtain a diastolic LVP of 0 mm Hg. To study the effects of drugs under physiologic conditions, heart rate pacing was not applied. CF and coronary outflow (coronary sinus) O₂ tensions were measured together with pH and CO₂ tension by using a blood gas analyzer (ABL 505^TM; Radiometer, Copenhagen, Denmark). Percent O₂ extraction, O₂ delivery (DO₂), O₂ consumption (MVO₂), and relative cardiac efficiency (LVP x HR/MVO₂), which defines the O₂ supply-to-demand ratio, were calculated as previously reported methods (8).

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^TM; Japan Spectroscopic, Tokyo, Japan) connected to a luminescence spectrometer (CAF-110^TM; Japan Spectroscopic) by the techniques previously reported by Brandes et al. (9–11). The excitation light was derived from a 75-watt xenon arc lamp through a 350-nm filter, an interference filter (bandwidth, 12 nm), and a visible light-blocking filter, and it penetrated transmurally (5 mm). The light emitted from the heart was collected by the outgoing fiber bundle and filtered at 385 nm and 456 nm. The end of the fiberoptic cable (tip surface area, 38.5 mm2) was placed against the LV epicardial surface through a hole in the bath. To reduce cardiac motion artifacts, the heart was held to the fiberoptic tip with nylon mesh.

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). Indo-1 AM was initially dissolved in 6.0 mL of dimethylsulfoxide containing 16% (wt/vol) pluronic F-127. 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 less than 125 s for each indo-1-loaded heart. Fluorescence of the indo-1 dye has been shown to be independent of the tissue oxygenation state at these two isobestic wavelengths (9–11).

After correcting for autofluorescence and noncytosolic uptake, F385/F456 was calibrated to [Ca²⁺]_i transients (in nM) by the standard equation for fluorescent indicators:

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, and R_min and R_max are the fluorescence ratios in the absence of Ca²⁺ and in the presence of saturating Ca²⁺, respectively (9,11). 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. R_max was calculated to be 5.04, and R_min 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 (12). Background autofluorescence was corrected at each wavelength at 37°C after 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. 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. In the present study, because the changes in [Ca²⁺]_i did not always parallel those in LVP in systolic and diastolic phases, available [Ca²⁺]_i was independent of developed LVP. The data were digitized by a MacLab^TM system (AD Instruments, NSW, Australia) and stored in a personal computer (Power Macintosh 7600/132^TM; Apple Japan, Tokyo, Japan).

At first, we studied the effects of propofol 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. Five hearts were perfused with KR solution (control, CaCl₂ 2.5 mM) containing propofol (0.1, 1, 10, and 100 µM) and intralipid (lipid vehicle, 0.0001%) for 2 min, respectively. The HR, CF, developed LVP, +dp/dt_max, -dp/dt_max, and inflow and outflow O₂ tensions were measured after a 4-min equilibration period with a 20-min washout period. Propofol was dissolved in 10% lipid vehicle and further diluted with distilled deionized water. The 10% lipid vehicle (10% Intralipid^TM; Ohtsuka, Tokyo, Japan) is a solvent of commercially available propofol, and the concentration of lipid vehicle (0.0001%) was determined as the concentration equivalent to that obtained in the heart perfused with a propofol (100 µM)-lipid vehicle combination.

Next, we studied the effects of propofol on the available [Ca²⁺]_i and developed LVP. After loading and the residual washout of indo-1, 15 hearts were randomly perfused with KR solution (control), and with KR solution containing either lipid vehicle (0.0001%) or propofol (1 and 10 µM). At the same time, the concentration of extracellular calcium ([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 each drug protocol, LVP reached its maximal value. 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, to differentiate the potential sites of propofol’s effect on available [Ca²⁺]_i, 45 hearts were randomly perfused with KR solution (control), KR solution containing either nifedipine (an L-type Ca²⁺ channel antagonist, 1 µM), ryanodine (which activates Ca²⁺-induced Ca²⁺ release from the SR, 1 µM), or thapsigargin (an SR Ca²⁺ adenosine triphosphatase inhibitor, 1 µM), and KR solution containing lipid vehicle (0.0001%) and propofol (10 µM) with nifedipine, ryanodine, or thapsigargin, respectively. At the same time, [CaCl₂]_e was increased incrementally as described above. Stock solutions of nifedipine were made by dissolving nifedipine in an absolute ethanol, polyethylene glycol, and saline vehicle (1:1:8, vol/vol).

Each heart underwent a change in [CaCl₂]_e twice, once in the absence of drugs (control), so that each heart served as its own control. Altering extracellular CaCl₂ did not significantly alter noncytosolic compartment Ca²⁺ for a 20-min period as previously reported (13). Five hearts had an additional control (postcontrol) to examine for any time related changes. All drug effects were maximal within 3 min, stable during drug perfusion, and reversible on washout within 15 min of stopping the drug infusion.

All data were 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, Prism^TM; GraphPad Software, Inc., CA), where all correlation coefficients (R2) were >0.98. Slopes, 95% confidence intervals (CI₉₅), and slope comparisons were determined for each curve. Differences between means were considered statistically significant when P was less than 0.05.

	Results

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Table 1 summarizes the effects of propofol on cardiac functional and metabolic variables at 2.5 mM CaCl₂. Propofol (100 µM) decreased developed LVP (P < 0.05). Propofol (10 and 100 µM) decreased +dp/dt_max, -dp/dt_max, and HR (P < 0.05). Propofol (100 µM) decreased %O₂ extraction and MVO₂ (P < 0.05). Propofol (10 and 100 µM) reduced cardiac efficiency (P < 0.05). Lipid vehicle (0.0001%) did not alter any functional or metabolic variables (Table 1).

View larger version (45K): [in this window] [in a new window]   Figure 1. Calibrated tracings from one heart showing simultaneous phasic changes in available [Ca2+]i (s-d[Ca2+]i, nM, bold line) and developed left ventricular pressure (LVP [mm Hg] thin line) before (control) and after infusion of propofol (10 µM) at 2.5 mM of [CaCl2]e. Although s-d[Ca2+]i was decreased in the presence of propofol, there was no alteration in developed LVP.

View larger version (18K): [in this window] [in a new window]   Figure 2. Changes in developed left ventricular pressure (LVP [mm Hg]) and s-d[Ca2+]i (nM) while [CaCl2]e was increased incrementally from 0.3 to 4.5 mM in the perfusate of the control, propofol (1 and 10 µM), and lipid vehicle (0.0001%). Propofol and lipid vehicle did not decrease developed LVP (A). Propofol (10 µM) decreased s-d[Ca2+]i at 2.5 mM of [CaCl2]e (B). Data are presented as mean ± SD. * Significantly different from control (P < 0.05).

View larger version (16K): [in this window] [in a new window]   Figure 3. 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 the control, propofol (1 and 10 µM), and lipid vehicle (0.0001%). Propofol (10 µM) shifted the curve to the left. Data are presented as mean ± SD. * Significantly different from control (P < 0.05).

	Discussion

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Our most important finding is that propofol decreases available [Ca²⁺]_i without producing an intrinsic myocardial depression when studied at clinically relevant concentrations in whole perfused guinea pig hearts. In clinical use, the peak plasma concentration of propofol after an IV induction dose is as high as 44 µM, whereas stable plasma levels of approximately 10–20 µM are observed during a maintenance infusion (14). The free plasma concentration of propofol does not exceed 10 µM because its mean protein binding rates are 77% and 87% in normal patients and in patients with cirrhosis, respectively (15). Propofol decreased the available [Ca²⁺]_i at lower concentrations than previously reported (3,4). This difference can be explained by variations in species studied, experimental models, and experimental conditions. The results from previous studies were obtained at temperatures of 28°–30°C and stimulus frequencies of 0.25–0.3 Hz. In contrast, our findings were obtained under physiologic conditions, i.e., a temperature of 37°C and beating rates exceeding 200 bpm.

We also assessed the relationship between available [Ca²⁺]_i and developed LVP to examine the effect of propofol on myofilament Ca²⁺ sensitivity. Mechanisms of negative 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 (16–21). Propofol (10 µM) caused a leftward shift in the curve of developed LVP as a function of s-d[Ca²⁺]_i. This finding suggests that propofol (10 µM) enhances myofilament Ca²⁺ sensitivity, indicating that it increases the affinity for Ca²⁺ binding to regulatory proteins, especially Troponin C. Thus, propofol might have no negative inotropic effect, despite a decrease in available [Ca²⁺]_i caused by the enhancement of myofilament Ca²⁺ sensitivity.

We investigated whether the decrease in available [Ca²⁺]_i by propofol results mainly from the impairment of sarcolemmal activity or of SR function. Propofol decreased available [Ca²⁺]_i in the presence of nifedipine (1 µM). Because nifedipine (1 µM) completely inhibits Ca²⁺ influx through the sarcolemmal L-type Ca²⁺ channel, it decreased developed LVP, s[Ca²⁺]_i and s-d[Ca²⁺]_i. In addition, a previous study has shown that propofol inhibits transsarcolemmal Ca²⁺ influx (22). Propofol in the presence of nifedipine decreased d[Ca²⁺]_i, although nifedipine alone did not reduce it. This finding indicates that propofol does not only inhibit L-type Ca²⁺ current, but also blocks SR Ca²⁺ handling.

Furthermore, we examined the effects of propofol on cardiac contraction and Ca²⁺ transients in the presence of ryanodine and thapsigargin, i.e., when intracellular Ca²⁺ stores were exhausted. Ryanodine or thapsigargin increased d[Ca²⁺]_i. This finding indicates that the intracellular Ca²⁺ store was depleted by different mechanisms, that ryanodine increases SR Ca²⁺ release and thapsigargin inhibits SR Ca²⁺ re-uptake (23,24), because d[Ca²⁺]_i reflects Ca²⁺ modulation through SR. In addition, ryanodine or thapsigargin were found to decrease developed LVP and available [Ca²⁺]_i, indicating that both drugs exert a negative inotropic action. Changes in cardiac contraction and Ca²⁺ transients caused by propofol that occur over and above those produced by ryanodine and thapsigargin reflect the action on sarcolemmal function. Our results showed that propofol, with either ryanodine or thapsigargin, did not inhibit developed LVP and available [Ca²⁺]_i. Therefore, a decrease in available [Ca²⁺]_i by propofol would be mainly mediated by an impairment of the SR Ca²⁺ handling rather than by an inhibition of transsarcolemmal L-type Ca²⁺ current.

The effects of SR function on the Ca²⁺ transient are underestimated at a low temperature and low stimulation in previous studies (4,8). In our preliminary study, when the HR was kept at 220 bpm under the condition of a low temperature (17°C), LVP decreased by 8% and d[Ca²⁺]_i increased by 19% more than in studies performed at physiological temperature (37°C). When the HR decreased naturally because of low temperature (17°C), LVP and s[Ca²⁺]_i were increased by 75% and 23%, respectively. As described above, we found that propofol does have an effect on the SR function under physiologic conditions.

In the present study, lipid vehicle alone did not reduce LVP, s[Ca²⁺]_i, d[Ca²⁺]_i, or available [Ca²⁺]_i, as previously reported (3–7). Lipid vehicle also did not alter the effects of nifedipine, ryanodine, or thapsigargin on developed LVP and available [Ca²⁺]_i. These findings indicate that, unlike propofol, lipid vehicle does not exert a negative inotropic effect, nor does it decrease available [Ca²⁺]_i.

Our study demonstrated that propofol (100 µM) decreased %O₂ extraction and MVO₂ and that propofol (10 and 100 µM) reduced relative cardiac efficiency, which defines the O₂ supply-to-demand ratio. Percent O₂ extraction was used to assess direct vasodilatory responses, as differentiated from those caused by autoregulatory response (25). Our results suggest that propofol causes the direct dilation of coronary resistance vessels only at the concentration of 100 µM.

In conclusion, propofol decreases available [Ca²⁺]_i without causing a decrease in cardiac contraction, and it enhances myofilament Ca²⁺ sensitivity in intact beating hearts isolated from guinea pigs at clinically relevant blood concentrations. The inhibition of available [Ca²⁺]_i by propofol may be mediated mainly by an impairment of SR Ca²⁺ handling rather than an affect on the sarcolemmal L-type Ca²⁺ current.

	Acknowledgments

 
This work was supported in part by a Grant-in-Aid for Scientific Research (No. 10671434) from the Ministry of Education, Japan.

	Footnotes

 
A preliminary report of this work was presented in part at the annual meeting of the American Society of Anesthesiologists, October 17–21, 1998, Orlando, FL.

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