Effects of halothane on contraction and intracellular calcium in ventricular myocytes from streptozotocin-induced diabetic rats

A. Rithalia1, M. A. Qureshi2, F. C. Howarth2 and S. M. Harrison*,1

1 School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, UK. 2 Department of Physiology, Faculty of Medicine & Health Sciences, United Arab Emirates University, PO Box 17666, Al Ain, United Arab Emirates

*Corresponding author. E-mail: S.M.Harrison@Leeds.ac.uk

Accepted for publication: July 30, 2003


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Background. Some of the cellular targets affected by volatile anaesthetics (e.g. halothane) which contribute to the negative inotropic effects of these agents are also affected during the progression of diabetic cardiomyopathy. A previous report suggested that halothane inhibited contraction to a lesser extent in papillary muscle from diabetic animals and so the aim of this study was to investigate possible mechanisms underlying this effect.

Methods. Contractility and cytosolic calcium ion (Ca2+) transients were measured (fura-2) in ventricular myocytes isolated from control and streptozotocin (STZ)-induced diabetic rats in the absence and presence of halothane 0.6 mmol litre–1 at 1 Hz stimulation. Sarcoplasmic reticulum (SR) Ca2+ content was assessed by rapid application of caffeine. All experiments were carried out at 36–37°C.

Results. The amplitude of shortening, the electrically evoked Ca2+ transient, SR Ca2+ content and myofilament Ca2+ sensitivity, though not altered by STZ treatment, were significantly reduced by halothane to a similar extent in control and STZ myocytes. The time course of contraction and Ca2+ transient were prolonged in myocytes from STZ-treated rats compared with controls but this was not altered further by halothane. STZ treatment appeared to reduce Ca2+ efflux from the cell, an effect reversed by halothane.

Conclusions. In contrast to a previous report, we could find no evidence of amelioration of the negative inotropic effect of halothane in myocytes from the STZ-induced diabetic rat. Contractility, the cytosolic Ca2+ transient, SR Ca2+ content and myofilament Ca2+ sensitivity were qualitatively similar in control and STZ myocytes and were all depressed to the same extent by halothane.

Br J Anaesth 2004; 92: 246–53

Keywords: anaesthetics volatile, halothane; antibiotics, streptozotocin; complications, diabetes; heart, ventricular myocytes


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Previous investigations have reported that the volatile general anaesthetic halothane induces a sustained negative inotropic effect on the heart,16 which is thought to result from altered mechanisms of cytosolic calcium ion (Ca2+) transport, including reduced L-type Ca2+ current,711 reduced sarcoplasmic reticulum (SR) Ca2+ content,1214 and depressed myofilament Ca2+ sensitivity.6 14 15 These experiments to investigate the mechanisms of action of halothane have been carried out in normal mammalian tissue but it is likely that the responses of the myocardium to halothane may differ in myopathic conditions, where disease-induced changes in the expression of proteins involved in Ca2+ regulation occur.

One such condition is diabetic cardiomyopathy, where cardiac dysfunction has been well documented.16 17 For example, in experimental models of type I diabetes, a variety of alterations in the amplitude and time course of contraction and the intracellular Ca2+ ([Ca2+]i) transient have been reported in single ventricular myocytes.18 Changes in contractile proteins,19 intracellular Ca2+ homeo stasis20 secondary to altered gene and protein expression17 and cardiac electrophysiology21 have all been suggested to contribute to the alterations in contractile function in the diabetic heart. It is interesting to note that diabetic patients are reported to be more prone to intraoperative cardiovascular morbidity than non-diabetic patients.22

A routinely used experimental model of type I diabetes is that induced following the injection of streptozotocin (STZ), which effectively destroys pancreatic beta cell function,23 decreasing insulin secretion and elevating blood glucose. The cardiac defects observed with this model are consistent with those seen in the clinical condition of type I diabetes in that cardiomyopathy is induced independent of other complicating factors such as atherosclerosis or vascular disease.2426

Hattori and colleagues27 reported that the negative inotropic effect of halothane was blunted in papillary muscles isolated from the left ventricle of rats with STZ-induced diabetes. Amelioration of the halothane-induced negative inotropic effect in diabetic ventricle could only result from a reduced impact of halothane on the cytosolic Ca2+ transient and/or myofilament Ca2+ sensitivity. In this study we have investigated the effect of halothane on contraction amplitude, the cytosolic Ca2+ transient, SR Ca2+ content, fractional release of Ca2+ from the SR and myofilament Ca2+ sensitivity, in order to identify which mechanisms contribute to the previously reported27 reduced negative inotropic effect of halothane in diabetic rats.


    Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Induction of diabetes
Approval for this project was obtained from the Faculty of Medicine & Health Sciences Ethics Committee. Diabetes was induced in young male Wistar rats (200–250 g; bred in house) by a single i.p. injection of STZ (Sigma) 60 mg kg–1. STZ was dissolved in a citrate buffer solution (citric acid 0.1 mmol litre–1, sodium citrate 0.1 mmol litre–1; pH 4.5). Age-matched controls received citrate buffer solution alone. Both groups of animals were maintained on the same diet with water ad libitum until they were used 8–12 weeks later. Principles of laboratory animal care were followed throughout.

Ventricular myocyte isolation
Single ventricular myocytes were isolated according to previously described techniques28 with minor modifications. In brief, rats were killed humanely by stunning followed by cervical dislocation (schedule 1 procedure, UK Home Office), the heart removed quickly and mounted on a Langendorff perfusion apparatus. Hearts were perfused retrogradely at a constant flow of 8 ml g heart–1 min–1 with a HEPES-based salt solution (isolation solution – see below) containing Ca2+ 0.75 mmol litre–1. Perfusion flow rate was adjusted to allow for differences in heart weight between STZ-treated and control animals. When the coronary circulation had cleared of blood, perfusion was continued for 4 min with Ca2+-free isolation solution containing EGTA 0.1 mmol litre–1, and then for 6 min with solution containing Ca2+ 0.05 mmol litre–1, collagenase 0.75 mg ml–1 (type 1; Worthington, NJ, USA) and protease (type XIV; Sigma) 0.075 mg ml–1. After this time, the ventricles were excised from the heart, minced and gently shaken in collagenase-containing isolation solution supplemented with bovine serum albumin 1%. Cells were filtered from this solution at 4 min intervals and resuspended in isolation solution containing Ca2+ 0.75 mmol litre–1.

Measurement of shortening
Ventricular myocytes were allowed to settle on the glass bottom of a Perspex chamber mounted on the stage of an inverted microscope (Axiovert 35, Zeiss, Germany). Myocytes were superfused (3–5 ml min–1) with a HEPES-based normal Tyrode (NT) solution containing Ca2+ 1 mmol litre–1 at 36–37°C. Myocyte contraction was induced by field stimulation (at 1 Hz) via platinum electrodes situated in the sides of the chamber. Unloaded shortening was used as an index of contractility.29 Shortening was followed using a video edge detection system (VED-114, Crystal Biotech, USA). The degree of shortening (expressed as a percentage of resting cell length (RCL)), the time to peak shortening (TPK) and time from peak to half relaxation (THALF) were recorded.

Measurement of the Ca2+ transient
Myocytes were loaded with the fluorescent indicator fura-2 AM (F-1221, Molecular Probes, USA) as described previously.30 In brief, 6.25 µl of a 1.0 mmol litre–1 stock solution of fura-2 AM (dissolved in dimethylsulphoxide (DMSO)) was added to 2.5 ml of cells (final fura-2 concentration of 2.5 µmol litre–1) and shaken gently for 10 min. Fura-2 loading was carried out at room temperature (24°C) to reduce compartmentation of the dye into intracellular organelles. After loading, myocytes were centrifuged, washed with NT to remove extracellular fura-2 and then left for 30 min to ensure complete hydrolysis of the intracellular ester. Following de-esterification, cells were superfused (as above) with NT at 36–37°C. To measure [Ca2+]i, myocytes were alternately illuminated by 340 nm and 380 nm light using a monochromator (Cairn Research, UK) which changed the excitation light every 2 ms. The resultant fluorescent emission at 510 nm was recorded by a photomultiplier tube and the ratio of the emitted fluorescence at the two excitation wavelengths (340/380 ratio) was calculated to provide an index of [Ca2+]i.

SR Ca2+ release was assessed using previously described techniques.30 After establishing steady-state Ca2+ transients in electrically stimulated (1 Hz) myocytes loaded with fura-2, stimulation was stopped for a period of 5 s. Caffeine 20 mmol litre–1 was then rapidly applied for 10 s using a solution switcher device.31 Electrical stimulation was restarted and the Ca2+ transients were allowed to recover to steady state. Fractional release of Ca2+ from the SR was assessed by comparing the amplitude of the steady-state electrically evoked Ca2+ transients with that of the caffeine-evoked Ca2+ transient.14

Solutions
The isolation solution was composed of NaCl 130 mmol litre–1, KCl 5.4 mmol litre–1, MgCl2 1.4 mmol litre–1, NaH2PO4 0.4 mmol litre–1, HEPES 5 mmol litre–1, glucose 10 mmol litre–1, taurine 20 mmol litre–1, creatine 10 mmol litre–1, pH 7.1 (NaOH) at 37°C. After dissociation, myocytes were perfused with NT solution of the following composition: NaCl 140 mmol litre–1, KCl 5 mmol litre–1, MgCl2 1 mmol litre–1, glucose 10 mmol litre–1, HEPES 5 mmol litre–1, CaCl2 1 mmol litre–1, pH 7.4. Halothane 0.6 mmol litre–1 was added to the NT solution from a 0.5 mol litre–1 stock solution made up in DMSO. The DMSO concentration in halothane-containing solutions was 0.12%, a concentration that had no significant effect on contractions (not shown).

Statistical analysis
Results are expressed as the mean (SEM) of n observations. Statistical comparisons were performed using independent t-test, paired t-test or two-way analysis of variance (ANOVA) as appropriate. P values less than 0.05 were considered significant.


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
General characteristics of the STZ-treated rat
The general characteristics of STZ-treated rats compared with their age-matched controls are shown in Table 1. Diabetes was confirmed in STZ- treated rats by a significant, 4.5-fold elevation of blood glucose, similar to that observed previously.27 STZ-treated rats had significantly lower body and heart weights compared with controls.


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Table 1 General characteristics of control and streptozotocin (STZ)-treated rats. Data are mean (SEM). All differences between the groups were statistically significant (P<0.01; independent samples t-test)
 
General characteristics of ventricular myocytes from STZ-treated rats
There were no clear visual differences between rod-shaped myocytes from control and STZ-treated animals. RCL of control myocytes was 117 (5) µm (n=21) and was not significantly altered by STZ-treatment (RCL of STZ myocytes was 113 (3) µm, n=30).

Characteristics of myocyte shortening
Typical fast-time base recordings of shortening in control and STZ-treated myocytes, before and after application of halothane 0.6 mmol litre--1 are shown in Figure 1A. The amplitude of shortening, expressed as a percentage of RCL, was not significantly altered by STZ treatment (Fig. 1B). Halothane induced a significant sustained negative inotropic effect; however, contrary to an earlier report,27 the magnitude of this effect was not altered by STZ treatment (Fig. 1B). In the absence of halothane, the time course of contraction was significantly prolonged by STZ treatment (P<0.05); mean TPK shortening in control and STZ myocytes was 94 (3) ms (n=21) and 113 (4) ms (n=30), respectively (P<0.001 vs control). THALF relaxation in control and STZ myocytes was 41 (3) ms (n=21) and 51 (4) ms (n=30), respectively (P<0.05 vs control). However, exposure to halothane did not lead to any further significant changes in the time course of contraction (Fig. 1C and D).



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Fig 1 (A) Representative fast-time base recordings of unloaded shortening in control and streptozotocin (STZ) ventricular myocytes superfused with either normal Tyrode (NT) or NT containing halothane 0.6 mmol litre--1 for 2 min. Mean data showing amplitude of shortening (B), time to peak shortening (TPK) (C) and time from peak to half relaxation (THALF) (D) in control and STZ myocytes in the absence (black bars) and presence (white bars) of halothane. Values are mean and SEM of 9–19 observations from myocytes derived from four control and five STZ-treated animals. RCL, resting cell length; +++P<0.001 for NT vs halothane (paired t-test); *P<0.05; ***P<0.001 for control vs STZ (unpaired t-test).

 
Ca2+ transient characteristics and SR Ca2+ content
Figure 2A shows a slow-time base record of electrically evoked Ca2+ transients under control conditions. After a 5 s cessation of stimulation, caffeine 20 mmol litre–1 was rapidly applied to estimate SR Ca2+ content. Once the caffeine-evoked Ca2+ transient had declined, stimulation was resumed and the recovery of Ca2+ transient amplitude monitored. These experiments were repeated in STZ cells and in the presence of halothane. Figure 2B illustrates that electrically evoked Ca2+ transient magnitude was not significantly different between control and STZ cells and that halothane led to a significant reduction in amplitude of the Ca2+ transient but the extent of inhibition did not differ between control and STZ cells. STZ treatment prolonged the Ca2+ transient time course; TPK and THALF of the Ca2+ transient were increased by 35% and 15%, respectively, values similar to the prolongation of contraction (27% and 11%, respectively) in this group of cells.



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Fig 2 (A) A typical chart recording showing the experimental protocol used to investigate sarcoplasmic reticulum (SR) calcium ion (Ca2+) content. Cells were electrically stimulated at 1 Hz, stimulation was then stopped for 5 s and caffeine 20 mmol litre--1 was applied for 10 s. Electrical stimulation was restarted following washout of caffeine. The graphs show amplitude of Ca2+ transient (B), SR Ca2+ content (C) and fractional release (D) in ventricular myocytes superfused with either normal Tyrode (NT) or NT containing halothane. Values are mean and SEM of 9–12 observations from myocytes derived from three control and three streptozotocin (STZ)-treated animals. +P<0.05; ++P<0.01; +++P<0.001 for NT vs halothane (paired t-test).

 
STZ treatment did not significantly affect SR Ca2+ content, as assessed from the caffeine-induced Ca2+ transient amplitude (0.53 (0.06) and 0.49 (0.05) ratio units in control and STZ myocytes, respectively; Fig. 2C). Expressing the magnitude of electrically evoked Ca2+ transients as a fraction of caffeine-induced transient amplitude gives a measure of fractional release of Ca2+ from the SR. Figure 2D illustrates that fractional release was 0.63 (0.04) in controls and was unaltered in STZ myocytes (0.62 (0.05)).

Halothane significantly decreased the caffeine-induced Ca2+ transient in both control and STZ myocytes (to 0.39 (0.05) and 0.34 (0.04) ratio units, respectively; Fig. 2C); however, fractional release of Ca2+ from the SR was significantly increased by halothane in both control and STZ myocytes (to 0.69 (0.06) and 0.67 (0.07), respectively; Fig. 2D).

Figure 3 illustrates the effect of STZ treatment and halothane on the rate of decay of the caffeine-evoked Ca2+ transient, which is primarily determined by the activity of the Na+/Ca2+ exchanger (NCX). This was significantly slower in STZ myocytes (Fig. 3A), the rate constant being 0.69 (0.04) fura-2 fluorescence units (FU) s–1 compared with 0.89 (0.07) FU s–1 in control myocytes. Halothane significantly increased the rate of decay of the caffeine transient in both control and STZ myocytes (to 1.08 (0.12) and 0.87 (0.09) FU s–1, respectively; Fig. 3A).



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Fig 3 Mean data describing the rate of decay of the caffeine transient (A) and the rate of recovery of the magnitude of electrically evoked calcium ion (Ca2+) transients after washout of caffeine (B). Values are mean and SEM of 9–12 observations from myocytes derived from three control and three streptozotocin (STZ)-treated animals. +P<0.05, ++P<0.01 for normal Tyrode (NT) vs NT containing halothane (paired t-test); *P<0.05 for control vs STZ (unpaired t-test).

 
The recovery of electrically evoked Ca2+ transients after caffeine exposure (an index of the rate of refilling of the SR with Ca2+) was also altered by STZ treatment; in control myocytes the transient recovered at a rate of 2.8 (0.4)% s–1, significantly slower than the recovery rate of 4.3 (0.8)% s–1 in STZ myocytes. Halothane tended to slow the recovery of electrically evoked Ca2+ transients following caffeine exposure (Fig. 3B) but this was only significant in control myocytes (reduced to 2.2 (0.4)% s–1).

Characteristics of myofilament Ca2+ sensitivity
Figure 4A and B illustrates plots of cell length vs fura-2 ratio for representative control and STZ myocytes in the absence and presence of halothane. The gradient of the late phase of relaxation (right panels), when the myofilaments are in dynamic equilibrium with cytosolic Ca2+, gives an index of myofilament Ca2+ sensitivity.32 Figure 4C shows that this gradient was unaffected by STZ treatment (6.4 (1.5) and 7.8 (0.9) µm FU–1 in 9 control and 12 STZ myocytes, respectively); however, halothane significantly decreased this gradient (P<0.05) in both control and STZ myocytes (to 4.3 (1.1) and 5.9 (0.6) µm FU–1, respectively).



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Fig 4 (A, B) (left panels) Complete plots of shortening vs fura-2 fluorescence ratio in the absence (black) and presence (grey) of halothane in control and streptozotocin (STZ)-treated myocytes, respectively. The right panels show the final phase of shortening from the plots displayed in the panels on the left. The solid lines are the result of linear regression of these data, the slope of which provides an index of myofilament calcium (Ca2+) sensitivity. (C) shows the mean data (with SEM) describing myofilament Ca2+ sensitivity in the absence (black bars) and presence (white bars) of halothane in 9 control and 12 STZ myocytes derived from three control and six STZ animals. +P<0.05 for normal Tyrode (NT) vs NT containing halothane (paired t-test).

 

    Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The data presented here illustrate that STZ-induced diabetes leads to prolongation of TPK and THALF of the cytosolic Ca2+ transient and contraction, as observed in other studies.17 18 The effect of STZ treatment on contractility in previous studies is mixed with some studies reporting no change27 33 34 and other studies reporting a decrease in contractility.17 18 We found that contraction tended to be smaller than that recorded in control cells but this did not reach statistical significance (Fig. 1B).

The main conclusion from this study is that we could find no evidence of an amelioration of the negative inotropic effect of halothane on contractile activity in myocytes from diabetic animals, in contrast to an earlier report.27 In the present study, halothane had qualitatively the same effect in control and STZ cells on a variety of parameters such as the magnitude of contraction and the Ca2+ transient, SR Ca2+ content, fractional release of Ca2+ from the SR and myofilament Ca2+ sensitivity.

Many similarities exist between the earlier27 and the current study, such as the dose of STZ administered to induce diabetes, resultant plasma glucose levels, the age of the animals at induction of diabetes and the period of time following induction before the animals were used. Furthermore, qualitatively similar effects of diabetes on the magnitude and time course of contraction were observed in this compared with other reports. Therefore, the reason for this disparity is not evident, but could reflect different experimental conditions employed in the two studies (e.g. papillary muscles vs isolated myocytes or the temperature at which the two studies were carried out: 36–37°C in the present study vs 30°C27).

Figure 3 illustrates that the rate of decay of the caffeine-evoked Ca2+ transient, which primarily reflects Ca2+ extrusion from the cell via NCX, was reduced in STZ myocytes. This result is consistent with decreased NCX function in STZ myocytes.17 This could contribute to the significantly faster recovery of the Ca2+ transient after washout of caffeine (Fig. 3B) as Ca2+ efflux from the cell would be reduced in STZ myocytes, which would accelerate recovery of the SR Ca2+ content. Halothane significantly enhanced the rate of decay of the caffeine-evoked Ca2+ transient in both control and STZ myocytes and slowed the refilling of the SR with Ca2+. These results are consistent with halothane-induced enhancement of Ca2+ extrusion from the cell in both cell types. This result is intriguing as the major pathway for extrusion of Ca2+ from the cell in the presence of caffeine is via NCX, which others have reported to be inhibited by halothane.35 36 These conflicting data suggest that further studies are required to assess the direct effect of halothane (and other volatile anaesthetics) on NCX function. For example, the effects of volatile anaesthetics on whole-cell NCX currents under voltage-clamp conditions or the measurement of NCX current induced during the decline of a caffeine-evoked Ca2+ transient would help elucidate these discrepancies. It should also be noted that in contrast to the results observed here, halothane was found to have no effect on the decline of caffeine-induced Ca2+ transients in ferret ventricular myocytes at room temperature.37 However, NCX is temperature dependent and its activity is reduced at 23°C compared with 37°C.38

In conclusion, we could find no evidence that halothane had a less potent negative inotropic effect in ventricular myocytes from STZ-treated rats. Furthermore, a number of parameters describing Ca2+ regulation were studied but halothane had a similar effect in control and STZ myocytes. Some of the experimental results found in the present study differ from those in the literature, but these may well result from different experimental conditions between studies.


    Acknowledgements
 
This study was supported by grants from the Faculty of Medicine & Health Sciences, United Arab Emirates University, Al Ain, UAE. Amber Rithalia was supported by a travel bursary from the British Council, Abu Dhabi, UAE and by the British Heart Foundation.


    References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
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