Effects of intracoronary calcium chloride on regional oxygen balance and mechanical function in normal and stunned myocardium in dogs

K. Y. Yoo*,1, J. U. Lee2, S. H. Kwak1, W. M. Im1, C. Y. Jeong1, S. S. Chung1, M. H. Yoon1, S. W. Jeong1 and J. T. Park2

1Department of Anesthesiology, Chonnam National University Medical School, 8 Hak-dong, Kwangju 501-746, Korea. 2Chonnam University Research Institute of Medical Sciences, 5 Hak-dong, Kwangju 501-746, Korea*Corresponding author

Accepted for publication: August 3, 2001


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Background. Brief myocardial ischaemia has been demonstrated to result in mechanical and coronary endothelial dysfunction, in which calcium may play a role. We examined whether the mechanical and vascular responses to calcium are altered in postischaemic, reperfused myocardium.

Methods. Regional myocardial oxygen consumption (MV·O2), mechanical function and coronary blood flow (CBF) in response to calcium chloride (0.10, 0.25, 0.50 and 0.75 mg ml–1 of CBF) directly infused into the left anterior descending (LAD) artery were determined before (normal) and 30 min after a 15-min-period of LAD occlusion (stunned) in an open-chest canine model. Percentage segment shortening (%SS) and percentage postsystolic shortening (%PSS) in the LAD territory were determined using ultrasonic crystals and CBF using a Doppler transducer. Myocardial extraction of oxygen (EO2) and lactate (Elac) was calculated.

Results. The infusion of calcium chloride resulted in dose-dependent increases in %SS and MV·O2 but did not affect %PSS in normal myocardium. These changes were accompanied by parallel increases in CBF, resulting in no change in EO2. In stunned myocardium, the responses to calcium chloride were not significantly altered, with the exception of a reduction in %PSS. However, ischaemia and reperfusion itself significantly reduced %SS and Elac and increased %PSS.

Conclusions. These data suggest that calcium chloride improves regional systolic and diastolic function both in normal and stunned myocardium. Calcium chloride is unlikely to cause direct coronary vasoconstriction or to deteriorate regional mechanical function in postischaemic myocardium.

Br J Anaesth 2002; 88: 78–86

Keywords: heart, coronary circulation; ions, calcium; drugs, inotropic; dog


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
A brief ischaemic episode followed by reperfusion results in ‘stunned’ myocardium, in which the myocardial contractile function is impaired for a prolonged period in the absence of cell necrosis.1 Myocardial stunning per se usually requires no therapy at all, as blood flow is normal and contractile function recovers spontaneously. However, if it is severe or involves parts of the left ventricle large enough to cause impairment of global ventricular function, it can be reversed with inotropic agents.25

Clinically, calcium is frequently used as an initial therapeutic agent to reverse acute postischaemic ventricular dysfunction during separation from cardiopulmonary bypass.6 However, calcium has been observed to reduce coronary blood flow (CBF) in an isolated beating heart.7 A recent in vivo study also demonstrated that intracoronary calcium chloride caused direct coronary vasoconstriction, in addition to its inotropic action, in normal canine heart.8

On the other hand, the stunned myocardium is associated with decreased coronary flow reserve and vasodilator responsiveness.9 10 Furthermore, it shows normal oxygen consumption (MV·O2), despite depressed contractile function, i.e. increased oxygen cost of contractility.11 It is speculated that calcium may exaggerate the vasoconstrictor response and hence impair myocardial oxygen balance in the stunned myocardium. Indeed, it has been demonstrated that mechanical function is not as tightly coupled as CBF and MV·O2, and thus oxygen extraction (EO2) increased during inotropic stimulation with dobutamine in postischaemic canine myocardium.5

In addition, intracellular Ca2+ overloading during ischaemia and reperfusion has been implicated in the pathogenesis of myocardial stunning.12 In an isolated rat heart, postischaemic myocardium was susceptible to Ca2+ influx and subsequent injury.13 Administration of calcium may therefore deteriorate rather than improve regional function, by augmenting calcium overload in postischaemic myocardium. The seeming paradox of the clinical use and known pathophysiological effects of calcium remains to be explained. In the present work we studied the effects of calcium chloride on regional oxygen balance and mechanical function in the stunned myocardium.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The study was approved by the Institutional Review Board of Experimental Animal Research. Mongrel dogs of either sex, weighing 17–35 kg, were anaesthetized with thiopental sodium (10–15 mg kg–1 i.v.). After tracheal intubation, anaesthesia was maintained with enflurane (1.4% end-tidal; Datex, Helsinki, Finland) in 100% oxygen by positive-pressure ventilation. In eight dogs, anaesthesia was induced with an i.v. bolus injection of fentanyl 100 µg kg–1 and midazolam 0.6 mg kg–1 and maintained by continuous infusion at rates of 20.0 µg kg–1 h–1 and 0.6 mg kg–1 h–1 respectively. Tidal volume and respiratory rate were adjusted to maintain end-tidal carbon dioxide concentration between 4.5 and 5.5%. To obtain muscle relaxation, vecuronium bromide 0.1 mg kg–1 was used initially as a bolus and thereafter infused at 0.05 mg kg–1 h–1. Body temperature and electrocardiogram were monitored continuously. Ringer’s lactate solution was administered i.v. at 5 ml kg–1 h–1.

A left thoracotomy was performed via the fifth intercostal space and the heart was suspended in a pericardial cradle. Instruments were implanted in and around the heart as shown in Fig. 1. A Doppler transit time flow probe (Transonic Systems, Ithaca, NY, USA) was placed around the main pulmonary artery to measure cardiac output, and another flow probe was placed around the left anterior descending coronary artery (LAD) distal to the first diagonal branch for continuous blood flow measurement. A rubber band was placed around the LAD immediately distal to the flow probe to serve as an occluder. For the infusion of drugs, a 24-gauge catheter was inserted into the proximal LAD. A pair of ultrasonic dimension transducers (Medical Research Technology, Gaithersburg, MD, USA) were implanted approximately 10 mm apart in the subendocardium of a region of anterior wall that demonstrated myocardial cyanosis during a brief test occlusion of the LAD. A catheter-tipped micromanometer (SPR-524; Millar Instruments, Houston, TX, USA) was inserted directly into the left ventricle via an apical incision for the measurement of left ventricular pressure (LVP). The first derivative of LVP (+dP/dtmax and –dP/dtmin) was obtained by electronic differentiation. The right femoral artery was cannulated for measurement of aortic pressure with a catheter-tipped micromanometer and for blood sampling to measure arterial oxygen and lactate contents. An 18-gauge catheter was inserted into the left atrium for the measurement of luminal pressure (Datex, Helsinki, Finland) and a 24-gauge catheter into the anterior interventricular vein at the same level as the LAD occluder for measurement of coronary venous oxygen and lactate concentrations.14



View larger version (31K):
[in this window]
[in a new window]
 
Fig 1 Schematic presentation of the experimental preparation. LAD=left anterior descending coronary artery; LCX=left circumflex coronary artery; IVC=intravenous catheter; IAC=intra-arterial catheter; UDT=ultrasonic dimension transducers.

 
Oxygen (Gem Premier; Instrumentation Laboratory, Lexington, MS, USA) and lactate concentrations (Vitros 950; Ortho-Clinical Diagnostics, Rochester, NY, USA) were measured in blood drawn simultaneously from the coronary vein and artery. MV·O2 of the anterior myocardial wall was calculated by multiplying the arteriovenous oxygen difference by total LAD flow. EO2 and myocardial lactate extraction (Elac) (as a percentage) were calculated by dividing the arteriovenous difference by the arterial content. Plasma Ca2+ concentrations were also measured from the anterior interventricular venous blood with a blood gas analyser (Gem Premier; Instrumentation Laboratory, Lexington, MS, USA).

After a stabilization period of 60 min, pre-infusion mechanical and haemodynamic data were collected in one group of 16 dogs (series 1). Simultaneous measurements were obtained of arterial and coronary venous oxygen and lactate concentrations (metabolic data). The animals then received intracoronary infusions of calcium chloride with a syringe pump (STC 524; Terumo, Japan). Calcium chloride was infused in incremental concentrations of 0.10, 0.25, 0.50 and 0.75 mg ml–1 LAD flow for 3–5 min, each administered 8–10 min apart. The infusion rate was calculated by multiplying the desired concentration by LAD blood flow, resulting in a rate between 0.3 and 2.0 ml min–1. All measurements except metabolic data at 0.50 mg ml–1 were repeated at the end of each dose and 5 min after calcium chloride infusion was stopped. Because mechanical and CBF responses to calcium chloride at 0.50 mg ml–1 did not differ significantly from those at 0.75 mg ml–1 and myocardial oxygen balance was well maintained, metabolic data at 0.50 mg ml–1 were not obtained. After one series of experiments in normal myocardium, all dogs were subjected to a 15-min LAD occlusion and subsequent reperfusion to stun the myocardium. Approximately 30 min after the onset of reperfusion, when haemodynamic and flow values were stable, the same calcium chloride infusion protocol was repeated.

In eight dogs (series 2), experiments were performed to evaluate whether preischaemic administration of calcium chloride altered postischaemic contractile responsiveness (preconditioning against postischaemic contractile dysfunction) and whether volatile anaesthetics affected postischaemic myocardial responsiveness. To address the first issue, calcium chloride was infused only in the postischaemic myocardium. To address the second issue, fentanyl–midazolam instead of enflurane was used to maintain anaesthesia. The responses to intracoronary infusions of calcium chloride (0.10, 0.25, 0.50 and 0.75 mg ml–1 of LAD flow) were assessed using a protocol similar to that used for series 1.

Data acquisition and analysis
Blood flow (main pulmonary artery and LAD), the segmental dimension of the anterior wall and pressures (LVP and mean aortic pressure) were monitored continuously and recorded on a polygraph (TA 5000; Gould, Cleveland, OH, USA). End-systolic segment length (ESL) was determined approximately 20 ms before peak –dP/dtmin and end-diastolic segment length (EDL) was determined at the onset of left ventricular isovolumetric contraction.15 Steady beat data were obtained from three to five cardiac cycles. Regional myocardial contractility was determined using percentage segment shortening (%SS), calculated from the equation %SS=[(EDL–ESL)/EDL]x100. Percentage postsystolic shortening (%PSS), as a regional diastolic function, was calculated from the equation %PSS=[(ESL–LminD)/(Lmax–LminD)]x100, where LminD and Lmax are minimum length during diastole and maximum length in an overall contraction, respectively. Coronary perfusion pressure was calculated as aortic diastolic pressure minus left atrial pressure.

At the end of the experiment, the heart was stopped by intra-atrial injection of concentrated potassium chloride solution. The area supplied by the LAD artery was defined by injection of Evans blue into the vessel at the site of the flow transducer. Weighing of the stained muscle allowed calculation of mean flow in ml min–1 per 100 g of muscle. The LAD perfusion territory was 24.3 (5.6)% of the total left ventricular mass.

Statistical analysis
All data are presented as mean (SD). They were analysed using StatView software version 4.0 (Abacus Concepts, Berkeley, CA, USA) on a Macintosh computer. Statistical analysis of the calcium chloride responses in normal and stunned myocardium was performed by two-way analysis of variance for repeated measures followed by Dunnett’s t test. Comparisons between the pre-infusion values of normal and stunned myocardium were made with the paired Student’s t-test. Enflurane- and fentanyl–midazolam-anaesthetized groups were compared using the Mann–Whitney U-test. Linear regression analysis was used to examine the relationship between CBF and MV·O2 at all doses of calcium chloride in series 1. Significance was assumed when P<0.05.


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Two of 18 dogs anaesthetized with enflurane produced lactate before the experiment and three died of ventricular fibrillation immediately after the onset of reperfusion, whereas three of eight dogs anaesthetized with fentanyl–midazolam developed ventricular fibrillation during coronary occlusion or immediately after the onset of reperfusion. These were excluded from data analysis.

Table 1 shows systemic haemodynamics in normal and stunned myocardium in enflurane-anaesthetized dogs. Calcium chloride was without significant effects on these variables in normal myocardium. However, there was a dose-dependent increase in +dP/dtmax. LAD occlusion produced a small increase in heart rate and left atrial pressure and decreased mean aortic pressure, +dP/dtmax, –dP/dtmin and cardiac index. They quickly returned towards baseline values at the onset of reperfusion, with the exception of +dP/dtmax and –dP/dtmin, which remained lower than their baseline values. In stunned myocardium, the effects of calcium chloride were similar to those in normal myocardium.


View this table:
[in this window]
[in a new window]
 
Table 1 Effects of increasing infusion rate of intracoronary calcium chloride on systemic haemodynamics before (normal) and 30 min after a 15-min coronary occlusion (stunned) in enflurane-anaesthetized dogs. HR = heart rate; MAP = mean aortic pressure; +dP/dtmax= maximum positive left ventricular pressure derivative; –dP/dtmin= minimum negative left ventricular pressure derivative; LAP = left atrial pressure; CI = cardiac index; CPP = coronary perfusion pressure; CBF = coronary blood flow. Results are mean (SD) of data from 13 dogs. *P<0.05 compared with pre-infusion values; {dagger}P<0.05 compared with normal myocardium
 
Table 2 shows the effects of calcium chloride on regional mechanical function in normal and stunned myocardium in enflurane-anaesthetized dogs. Calcium chloride caused dose-dependent increases in %SS and decreases in ESL but did not affect %PSS in normal myocardium. LAD occlusion rapidly increased EDL [from 10.0 to 10.8 (0.38), P<0.01] and %PSS [from 5.9 (2.9) to 76 (10)%, P<0.01], systolic bulging apparent within 1–3 min. Subsequent reperfusion produced a transient increase in %SS followed by a gradual decline to 7.4 (4.5)% (44% of preischaemic baseline) at 30 min of reperfusion. In stunned myocardium, the responses to calcium chloride were not altered compared with those in normal myocardium, except for a progressive reduction in %PSS. When calcium chloride was stopped, %SS rapidly returned towards, but not below, pre-infusion values in stunned myocardium (data not shown).


View this table:
[in this window]
[in a new window]
 
Table 2 Effects of increasing infusion rate of intracoronary calcium chloride on regional mechanical function before (normal) and 30 min after a 15-min coronary occlusion (stunned) in enflurane-anaesthetized dogs. %SS = percentage systolic shortening; EDL = end-diastolic segment length; ESL = end-systolic segment length, %PSS = percentage postsystolic shortening. All length measures are normalized to an initial end-diastolic length of 10 mm at baseline. Results are mean (SD) of data from 13 dogs. *P<0.05 compared with pre-infusion values; {dagger}P<0.05 compared with normal myocardium
 
Table 3 shows the effects of calcium chloride on CBF and metabolic data in normal and stunned myocardium in enflurane-anaesthetized dogs. Calcium chloride caused dose-dependent increases in MV·O2 and CBF in normal myocardium. After LAD occlusion and reperfusion, metabolic and CBF responses to calcium chloride were not altered significantly, while there was a slight decrease in MV·O2 from preischaemic baseline values of normal myocardium (P<0.05), despite severely impaired contractile function. During calcium chloride infusion, CBF increased linearly in relation to MV·O2 in normal and stunned myocardium (Fig. 2), such that that EO2 remained unchanged. Plasma Ca2+ concentrations in the anterior interventricular vein were dose-dependently increased by the administration of calcium chloride to a similar extent in normal and stunned myocardium, implying that coronary veins draining the LAD region were correctly cannulated.


View this table:
[in this window]
[in a new window]
 
Table 3 Effects of increasing infusion rate of intracoronary calcium chloride on coronary blood flow (CBF) and metabolism before (normal) and 30 min after a 15-min coronary occlusion (stunned) in enflurane anaesthetized dogs. MV·O2 = myocardial oxygen consumption; EO2 = myocardial oxygen extraction. Results are mean (SD) of data from 13 dogs. *P<0.05 compared with pre-infusion values; {dagger}P<0.05 compared with normal myocardium
 


View larger version (17K):
[in this window]
[in a new window]
 
Fig 2 Relationship between myocardial oxygen consumption (MV·O2) and coronary blood flow (CBF) during intracoronary calcium chloride infusion in normal and stunned myocardium in enflurane anaesthetized dogs (n=13). In both normal and stunned myocardium, CBF increased in parallel with MV·O2.

 
Figure 3 shows the effects of calcium chloride on lactate extraction in enflurane-anaesthetized dogs. Although significantly reduced by the ischaemia and reperfusion insult itself, Elac was not affected by calcium chloride either in normal or stunned myocardium. However, four of 13 animals anaesthetized with enflurane showed lactate production with the highest dose of calcium chloride in stunned myocardium.



View larger version (15K):
[in this window]
[in a new window]
 
Fig 3 Effects of calcium chloride on lactate extraction (Elac) in normal and stunned myocardium in enflurane-anaesthetized dogs (n=13). Elac was not significantly affected by calcium chloride either in normal or stunned myocardium. Data are skewed and therefore presented as a dot plot with mean (SD). The ischaemia and reperfusion insult itself significantly reduced Elac. {dagger}P<0.05 compared with normal myocardium.

 
Figure 4 compares the effects of calcium chloride on %SS, MV·O2, CBF and EO2 in stunned myocardium in enflurane- and fentanyl–midazolam-anaesthetized dogs. Calcium chloride produced similar increases in %SS and MV·O2. The increase in CBF was proportional to MV·O2, and therefore EO2 remained unchanged in both groups. In addition, systemic haemodynamic variables, including cardiac index, +dP/dtmax and heart rate, did not differ significantly between enflurane- and fentanyl–midazolam-anaesthetized dogs (data not shown).



View larger version (15K):
[in this window]
[in a new window]
 
Fig 4 Changes [mean (SD)] from preischaemic baseline values of %SS, MV·O2, CBF and EO2 during calcium chloride infusion in stunned myocardium in dogs anaesthetized with enflurane (n=13) or fentanyl–midazolam (n=5). Changes were similar in the two groups. {dagger}P<0.05 compared with preischaemic baseline values; *P<0.05 compared with postischaemic baseline values (indicated as dose 0 of calcium chloride).

 

    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The present study demonstrated that calcium chloride improved regional contractile and diastolic function in stunned canine myocardium. In addition, %SS returned to the postischaemic baseline value after discontinuation of inotropic stimulation with calcium chloride. Indeed, restoration of normal contractile capability during infusion of calcium has been observed in isolated globally ischaemic rat hearts16 and in vivo regionally ischaemic hearts in dogs3 12 and pigs.4 17 These findings are contradictory to the previous notion that Ca2+ overloading occurring during ischaemia and reperfusion is causally related to the pathogenesis of myocardial stunning.12 Moreover, calcium chloride administered early during reperfusion has been shown to elicit a dose-dependent deterioration in ventricular function in the isolated postischaemic rat heart.13 Viable cells may restore control of cytoplasmic Ca2+ rapidly after ischaemia, and hence intracellular Ca2+ levels return to a baseline value after 20 min of reperfusion.18 Collectively, the data suggest that calcium chloride may improve rather than deteriorate regional function if administered after, but not during, the early reperfusion period.

Vascular dysfunction may occur even after a short period of ischaemia.9 10 The vascular response to endothelium-dependent dilators (e.g. acetylcholine) was reduced, whereas that to constrictors (e.g. the thromboxane mimic U46619) was enhanced after 15 min of regional ischaemia in canine hearts in situ.10 Therefore, the vascular response to calcium chloride may differ between normal and stunned myocardium. However, the response to calcium chloride, increased CBF with no significant changes in coronary venous oxygen tension and EO2, did not differ significantly between normal and stunned myocardium (Table 3). Similarly, Buffington and Rothfield4 observed an appropriate increase in CBF when regional contractility was stimulated by calcium chloride in stunned porcine myocardium. These findings suggest that, in stunned myocardium, calcium chloride does not interfere with normal metabolic vasoregulation but maintains CBF in proportion to the myocardial oxygen demand.

In contrast, Crystal and colleagues8 demonstrated that intracoronary calcium chloride produced direct vasoconstriction and impaired coupling of CBF to the augmented myocardial oxygen demand in normal myocardium of dogs anaesthetized with fentanyl–midazolam. The discrepancy between these studies is not readily explained. It has been shown that volatile anaesthetics decrease Ca2+ sensitivity in rat aortic vascular smooth muscle in vitro19 and produce coronary vasodilation directly in in situ canine hearts.20 However, the vascular responses to calcium chloride were similar in fentanyl–midazolam- and enflurane anaesthetized dogs in the present study (Fig. 4). It is unlikely that anaesthetics are responsible for the discrepancy between these studies. Another possible explanation may include different experimental methods. Crystal and colleagues8 used an extracorporeal perfusion system with a pressurized reservoir to keep coronary perfusion pressure constant, whereas we administered calcium chloride directly into the LAD. However, the coronary perfusion pressure was not affected by calcium chloride in either study.

The markedly reduced contractile function has been associated with an unaltered MV·O2 in stunned myocardium.11 If contractile function increases at a higher energy cost in stunned myocardium, an elevated CBF would be expected for a given level of function (assuming unchanged EO2). However, the CBF response in relation to segment shortening was similar in normal and stunned myocardium in the present study. Chiu and colleagues21 have demonstrated that regional inotropic stimulation with isoproterenol restores synchrony and regional work in stunned myocardium without greatly affecting MV·O2 in dogs. They speculated that myocardial stunning produced asynchrony between force development and segment shortening, thereby decreasing systolic regional work (but not total work) to a greater extent than MV·O2. It is likely that inotropic drugs, including calcium chloride, do not increase total mechanical work but restore the synchrony, resulting in no greater increases in CBF relative to regional mechanical work in stunned myocardium.

Although systolic function associated with the use of inotropic drugs has been studied extensively in stunned myocardium, the diastolic function has been overlooked. In the present study, calcium chloride did not affect peak –dP/dtmin but produced a progressive reduction in %PSS (Table 2). Similarly, Schlack and colleagues22 observed that intracoronary norepinephrine did not affect peak –dP/dtmin but reduced postejection wall thickening in an open-chest canine model. It is also likely that calcium chloride improves early diastolic function. On the other hand, peak –dP/dtmin has been demonstrated to reflect changes in contractility (i.e. peak ventricular pressure) rather than relaxation in regionally ischaemic canine hearts.23 The unaltered aortic pressure during the infusion of calcium chloride in the present study may be related to the unaltered peak –dP/dtmin. There has been debate about whether calcium chloride increases chamber stiffness (late diastolic dysfunction) in postischaemic myocardium. Gao and colleagues24 observed that, in response to supraphysiological increases in [Ca2+]o, diastolic [Ca2+]i and tone increased in stunned trabeculae, with frequent occurrence of aftercontractions in the isolated rat heart. They speculated that increased susceptibility to Ca2+ results in increased diastolic tone under conditions that favour cellular Ca2+ accumulation. DeHert and colleagues25 also found an increase in ventricular stiffness when calcium chloride was given early after cardiopulmonary bypass, suggesting temporary diastolic dysfunction. In contrast, Eberli and colleagues26 observed that increased [Ca2+]i was not causally related to the increase in diastolic chamber stiffness in isolated rat hearts.

The effect of calcium chloride on myocardial function is transient, despite persistent elevation of the plasma concentration of ionized calcium, whereas the effect on systemic vascular resistance is more prolonged.27 We therefore chose to infuse calcium chloride continuously rather than use a single bolus injection to produce steady-state changes in myocardial contractility (and hence myocardial oxygen demand), as shown previously by Crystal and colleagues.8 In general, calcium chloride at doses of 5–15 mg kg–1 body weight is given i.v. to improve haemodynamics while the patient is weaned from cardiopulmonary bypass.28 An i.v. bolus administration of calcium chloride at a dose of 15 mg kg–1 caused a maximal increase of approximately 0.8 mmol litre–1.29 Therefore, our data with the lowest rate of calcium chloride (0.1 mg ml–1=0.9 mmol litre–1) appears to be clinically relevant.

Lactate production has been a reliable sign of a mismatch between myocardial oxygen demand and supply.30 In the present study, a progressive reduction in lactate extraction was observed during the infusion of calcium chloride in stunned myocardium, albeit statistically insignificant. Moreover, lactate was produced in four of 13 animals anaesthetized with enflurane during calcium chloride infusion at 0.75 mg ml–1 in stunned myocardium (Fig. 3). Stahl and colleagues31 observed increased heterogeneity of oxygen extraction with very low venous oxygen saturation in stunned myocardium despite patent microvasculature and normal perfusion, implying either focally impaired perfusion or increased metabolic activity. Calcium chloride would have induced focal microcirculatory changes with localized areas of tissue hypoxia and anaerobic metabolism, leading to lactate production, despite unaltered coronary venous oxygen tension. In addition, increased susceptibility to Ca2+ load in stunned myocardium has been demonstrated in isolated rat hearts.13 24 Indeed, functional deterioration has been reported after intense inotropic stimulation with high-dose dobutamine in many reperfused segments that respond positively to low-dose dobutamine infusion, probably because of impaired intracellular Ca2+ handling.32 Likewise, calcium chloride may have a deleterious long-lasting effect that differs from an immediate functional and metabolic effect, as in the present study. Therefore, caution should be exercised in extrapolating our results, showing that the postischaemic dysfunction was effectively improved by calcium chloride without impairing myocardial oxygen balance, to the clinical situation.

The present study has several limitations. First, enflurane was used to maintain anaesthesia. Volatile anaesthetics have been shown to enhance recovery of postischaemic myocardium33 and to produce coronary vasodilation directly in vivo.20 Enflurane may have protected the myocardium against ischaemia and reperfusion injury, altering the response to calcium chloride. However, we observed that responses to calcium chloride in postischaemic myocardium were similar in enflurane- and fentanyl–midazolam-anaesthetized groups (Fig. 4). Secondly, it has been demonstrated that calcium chloride has a preconditioning effect against postischaemic contractile dysfunction.34 However, the responses to calcium chloride in the stunned myocardium were similar in series 1 and series 2 (Fig. 4). It is unlikely that a preconditioning effect was exerted in our experimental protocol. Thirdly, the present study did not evaluate the time course of recovery of postischaemic, reperfused myocardium during the period corresponding to drug infusion (30–70 min of reperfusion). However, an open-chest canine model has shown constant regional contractile function (%SS) between 30 and 90 min of reperfusion.35 Furthermore, %SS returned to the pre-infusion values after cessation of calcium chloride infusion. Finally, changes in heart rate and systemic blood pressure during calcium chloride infusion may result in increases in MV·O2 and CBF. However, calcium chloride did not affect aortic pressure, heart rate or coronary perfusion pressure at any time during the study.

In summary, calcium chloride improved regional systolic and diastolic functions both in normal and stunned myocardium. However, the metabolic control of CBF is unlikely to be impaired in stunned myocardium, as shown by an enhanced regional function in association with proportional increases in CBF. In addition, calcium chloride is unlikely to deteriorate regional mechanical function in postischaemic myocardium.


    Acknowledgement
 
This work was supported by KOSEF through the Hormone Research Centre (Project no. 2001G0301).


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
1 Braunwald E, Kloner RA. The stunned myocardium: prolonged, postischemic ventricular dysfunction. Circulation 1982; 66: 1146–9

2 Patel B, Kloner RA, Przyklenk K, Braunwald E. Postischemic myocardial ‘stunning’: a clinically relevant phenomenon. Ann Intern Med 1988; 108: 626–8

3 Ito BR, Tate H, Kobayashi M, Schaper W. Reversibly injured, postischemic canine myocardium retains normal contractile reserve. Circ Res 1987; 61: 834–46

4 Buffington CW, Rothfield KP. Effects of intracoronary calcium chloride on the postischemic heart in pigs. Ann Thorac Surg 1995; 59: 1448–55

5 Hashimoto T, Buxton DB, Krivokapich J, Hansen HW, Phelps ME, Schelbert HR. Responses of blood flow, oxygen consumption, and contractile function to inotropic stimulation in stunned canine myocardium. Am Heart J 1994; 127: 1250–62

6 Royster RL, Butterworth JF IV, Prielipp RC, et al. A randomized, blinded, placebo-controlled evaluation of calcium chloride and epinephrine for inotropic support after emergence from cardiopulmonary bypass. Anesth Analg 1992; 74: 3–13

7 Gruber CM, Roberts SJ. The effect of adrenaline upon the coronary circulation. Am J Physiol 1926; 76: 508–24

8 Crystal GJ, Zhou X, Salem MR. Is calcium a coronary vasoconstrictor in vivo? Anesthesiology 1998; 88: 735–43

9 Dauber IM, Van Benthuysen KM, McMurtry IF. Functional coronary microvascular injury evident as increased permeability due to brief ischemia and reperfusion. Circ Res 1990; 66: 986–98

10 Kim YD, Fomsgaard JS, Heim KF, et al. Brief ischemia–reperfusion induces stunning of endothelium in canine coronary artery. Circulation 1992; 85: 1473–82

11 Ohgoshi Y, Goto Y, Futaki S, Yaku H, Kawaguchi O, Suga H. Increased oxygen cost of contractility in stunned myocardium of dog. Circ Res 1991; 69: 975–88

12 Kusuoka H, Porterfield JK, Weisman HF, Weisfeldt ML, Marban E. Pathophysiology and pathogenesis of stunned myocardium: depressed Ca2+ activation of contraction as a consequence of reperfusion induced cellular calcium overload in ferret hearts. J Clin Invest 1987; 79: 950–61

13 Abbott A Jr, Hill R, Shears L, Beamer K, Gustafson R, Murray G. Effects of calcium chloride administration on the postischemic isolated rat heart. Ann Thorac Surg 1991; 51: 705–10

14 Vinten-Johannsen J, Johnston WE, Crystal GJ, Mills SA, Santamore WP, Cordell AT. Validation of local venous sampling within the at risk left anterior vascular bed in the canine left ventricle. Cardiovasc Res 1987; 21: 646–51

15 Theroux P, Ross J Jr, Franklin D, Covell JW, Bloor CW, Sasayama S. Regional myocardial function and dimensions early and late after myocardial infarction in the unanesthetized dog. Circ Res 1977; 40: 158–65

16 Hoffmeister HM, Ströbele M, Beyer ME, et al. Inotropic response of stunned hypertrophied myocardium: responsiveness of hypertrophied and normal postischemic isolated rat hearts to calcium and dopamine stimulation. Cardiovasc Res 1998; 38: 149–57

17 Heusch G, Rose J, Skyschally A, et al. Calcium responsiveness in regional myocardial short-term hibernation and stunning in the in situ porcine heart: inotropic responses to postextrasystolic potentiation and intra-coronary calcium. Circulation 1996; 93: 1556–66

18 Carrozza JP Jr, Bentivegna LA, Williams CP, Kuntz RE, Grossman W, Morgan JP. Decreased myofilament responsiveness in myocardial stunning follows transient calcium overload during ischemia and reperfusion. Circ Res 1992; 71: 1334–40

19 Kakuyama M, Nakamura K, Mori K. Halothane decreases calcium sensitivity of rat aortic smooth muscle. Can J Anaesth 1999; 46: 1164–71

20 Gurevicius J, Holmes CB, Salem MR, et al. The direct effects of enflurane on coronary blood flow, myocardial oxygen consumption, and myocardial segmental shortening in in situ canine hearts. Anesth Analg 1996; 83: 68–74

21 Chiu WC, Kedem J, Scholz PM, Weiss HR. Regional asynchrony of segmental contraction may explain the ‘oxygen consumption paradox’ in stunned myocardium. Basic Res Cardiol 1994; 89: 149–62

22 Schlack W, Ebel D, Thämer V. Effect of inotropic stimulation on the synchrony of left ventricular wall motion in a dog model of myocardial stunning. Acta Anaesthesiol Scand 1996; 40: 621–30

23 Dalmas S, Marsch SCU, Philbin DM, et al. Effects and interactions of myocardial ischaemia and alterations in circulating blood volume on canine left ventricular diastolic function. Br J Anaesth 1996; 76: 419–27

24 Gao WD, Atar D, Backx PH, et al. Relationship between intracellular calcium and contractile force in stunned myocardium: direct evidence for decreased myofilament Ca2+ responsiveness and altered diastolic function in intact ventricular muscle. Circ Res 1995; 76: 1036–48

25 DeHert SG, Ten Broecke PW, De Mulder PA, et al. Effects of calcium on left ventricular function early after cardiopulmonary bypass. J Cardiothorac Vasc Anesth 1997; 11: 864–9

26 Eberli FR, Strömer H, Ferrell MA, et al. Lack of direct role for calcium in ischaemic diastolic dysfunction in isolated hearts. Circulation 2000; 102: 2643–9

27 Shapira N, Schaff HV, White RD, Pluth JR. Hemodynamic effects of calcium chloride injection following cardiopulmonary bypass: response to bolus injection and continuous infusion. Ann Thorac Surg 1984; 37: 133–40

28 Drop LJ. Ionized calcium, the heart, and hemodynamic function. Anesth Anal 1985; 64: 432–51

29 Eriksen C, Sorensen MB, Bille-Braha NE, Skovsted P, Lunding M. Hemodynamic effects of calcium chloride administered intravenously to patients with and without cardiac disease during neurolept anaesthesia. Acta Anaesthesiol Scand 1983; 27: 13–7

30 Gertz EW, Wisneski JA, Neese R, Houser A, Korte R, Bristow JD. Myocardial lactate extraction: multidetermined metabolic function. Circulation 1980; 61: 256–61

31 Stahl LD, Weiss HR, Becker LC. Myocardial oxygen consumption, oxygen supply/demand heterogeneity, and microvascular patency in regionally stunned myocardium. Circulation 1988; 77: 865–72

32 Smart SC, Sawada S, Ryan T, et al. Low-dose dobutamine echocardiography detects reversible dysfunction after thrombolytic therapy of acute myocardial infarction. Circulation 1993; 88: 405–15

33 Warltier DC, Al-Wathiqui MH, Kampine JP, Schmeling WT. Recovery of contractile function of stunned myocardium in chronically instrumented dogs is enhanced by halothane or isoflurane. Anesthesiology 1988; 69: 552–65

34 Cain BS, Meldrum DR, Meng X, Shames BD, Banerjee A, Harken AH. Calcium preconditioning in human myocardium. Ann Thorac Surg 1998; 65: 1065–70

35 Belo SE, Mazer CD. Effects of halothane and isoflurane on postischemic ‘stunned’ myocardium in the dog. Anesthesiology 1990; 73: 1243–5





This Article
Abstract
Full Text (PDF)
E-Letters: Submit a response to the article
Alert me when this article is cited
Alert me when E-letters are posted
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Search for citing articles in:
ISI Web of Science (1)
Disclaimer
Request Permissions
Google Scholar
Articles by Yoo, K. Y.
Articles by Park, J. T.
PubMed
PubMed Citation
Articles by Yoo, K. Y.
Articles by Park, J. T.