Beta-adrenergic blockers as well as alpha 2-adrenergic agonists have the potential to decrease myocardial ischaemia and the risk of cardiac death in certain groups of patients . The American College of Cardiology/American Heart Association guidelines recommend the use of either of these two classes of sympatholytic drugs to be considered in selected patients perioperatively . While the beneficial effects of beta-blockers and alpha 2-agonists on outcome measures of myocardial ischaemia have been studied intensively in clinical studies, the pathophysiological mechanisms involved in these anti-ischaemic effects have received less attention. From these clinical studies, it can be inferred that beta-blockers and alpha 2-agonists reduce myocardial ischaemia mainly in patients having significant coronary artery disease . Since such patients have reduced capacity to increase coronary blood flow in response to an increased myocardial oxygen demand, it is likely that a high myocardial oxygen demand is an important cause of myocardial ischaemia in these patients. Therefore, attenuation of haemodynamic indices associated with increased myocardial oxygen demand may be an important anti-ischaemic mechanism of beta-blockers and alpha 2-agonists. This is in accordance with the findings that the postoperative use of the short-acting beta-blocker esmolol [3,4] and of the most specific alpha 2-agonist, dexmedetomidine [5,6] is associated with reduced hyperdynamic responses. However, the effects of these drugs on directly measured myocardial oxygen demand are unknown, probably because of the invasive nature of the measurements involved. Also, possible differences between the effects of beta-blockers and alpha 2-agonists on myocardial oxygen demand have not been described yet.
The aim of this study was to determine and compare the effects of the beta 1-blocker esmolol and the alpha 2-agonist dexmedetomidine on measured myocardial oxygen consumption and indirect haemodynamic indices of myocardial oxygen demand. Due to the invasiveness of the direct measurement of myocardial oxygen consumption, these studies were performed in chloralose anaesthetized dogs .
Animal preparation and instrumentation
Eleven adult mongrel dogs (30 ± 1.8 kg) were studied with the approval of the Animal Care Committee of the University of Maastricht. Anaesthesia was induced with sodium thiopental, 25 mg kg−1 intravenously (i.v.); the dogs were intubated and ventilated with oxygen 30% in nitrous oxide. Halothane (inspired concentration 1-1.5%) was added to suppress somatic responses and to maintain haemodynamic stability during thoracotomy and instrumentation. The chest was opened through the left fifth intercostal space and the heart was suspended in a pericardial cradle. Instrumentation was performed in a warmed operating room (24°C). The rectal temperature of the dogs was kept between 37°C and 39°C by means of a thermostatically regulated heating mattress. Heart rate (HR) and rhythm were monitored using electrocardiogram (ECG) lead II. Catheters were inserted for arterial and left anterior descending (LAD) coronary venous blood sampling. The venous catheter was assumed to drain precisely the region of the myocardium supplied by the LAD artery. Pressure sensors (Sentron 180 S, Cordis, Roden, The Netherlands) were inserted through the right femoral artery into the ascending aorta and left ventricle. Ultrasonic transit-time flow probes (Transonic Systems, Ithaca, NY, USA) were placed around the aortic root and around the LAD artery just proximal to the first diagonal branch. A pulmonary artery catheter (Baxter) was introduced via the left jugular vein and connected to a thermodilution cardiac output computer (Baxter Edwards SAT 2) for cardiac output determinations. The cardiac output measurements, obtained by averaging triplicate thermodilution values, were compared at regular predetermined intervals with the ultrasonic aortic flow measurements. Three inductive coils were sutured to the left lateral epicardium in an equilateral triangle configuration to measure epicardial area changes.
As soon as instrumentation was completed, nitrous oxide and halothane were discontinued. A chloralose loading dose of 40 mg kg−1 was administered, followed by a maintenance infusion of 8 mg kg−1 h−1. The dogs were ventilated with 45% oxygen in air to normocarbia. After a stabilization period of at least 60 min, the following four successive experimental conditions were studied in each dog:
(a) Control 1.
(b) Esmolol: 20 min after starting esmolol infusion (Ohmeda Inc., NJ, USA).
(c) Control 2: 20 min after stopping the esmolol infusion.
(d) Dexmedetomidine: 20 min after starting dexmedetomidine infusion (Orion Corporation, Farmos Research, Turku, Finland).
After Control 1 measurements had been performed, a dose of isoprenaline necessary to increase HR by more than 20% was determined as the tachycardic dose in each dog. After HR and other haemodynamic variables had returned to Control 1 values, esmolol was given as a loading dose of 0.5 mg kg−1 min−1 for 2 min, followed by a continuous infusion of 0.3 mg kg−1 min−1. To check that the beta 1-adrenergic blockade from esmolol was adequate, the response to the tachycardic dose of isoprenaline was tested before stopping the esmolol infusion.
Dexmedetomidine was given as a loading dose of 1 μg kg−1 over 20 min, followed by a continuous infusion of 1.5 μg kg−1 h−1. We aimed for a target plasma concentration of dexmedetomidine of 0.5 ng mL−1, because this concentration reduces sympathetic tone effectively in dogs  and in human beings . As the pharmacokinetics of esmolol in dogs was unknown at the time of the study, we used an infusion regimen advised by Orion Corporation (Turku, Finland) and based on the pharmacokinetic set in the STANPUMP software .
During each experimental condition the following variables were measured:
(a) Haemodynamic indices: HR, systolic and diastolic aortic pressure (DAP), left ventricular pressure, aortic flow and myocardial wall thickening.
(b) Variables related to myocardial oxygen metabolism: LAD coronary arterial and LAD coronary venous blood-gas tensions, coronary flow and haemoglobin content.
To measure LAD flow relative to myocardial weight, the perfusion area of the LAD was delineated by injecting methylene blue dye in the LAD at the end of each experiment. Then the dogs were euthanized by a pentobarbital overdose and their hearts were excised. The methylene blue stained portion of the heart was dissected and weighed.
All haemodynamic and coronary flow signals were preamplified and then digitized with a 16 channel, 12-bit A/D interface in an IBM-compatible PC. Sampling frequency was 200 Hz for each channel. The signals were continuously displayed on the computer screen. During each experimental period beat-to-beat values were stored on the hard disk. The average of each variable was calculated over a stable haemodynamic period of 2 min, i.e. less than 5% HR variation. Peak of first derivative of left ventricular pressure (left ventricular dP/dtmax) was derived from the left ventricular pressure signal. Systemic vascular resistance (SVR) was calculated as the quotient of mean aortic pressure and mean aortic blood flow. Coronary vascular resistance was calculated as the quotient of mean aortic pressure and mean coronary blood flow.
The following haemodynamic indices of myocardial oxygen demand were measured:
where HR in beats min−1; SV, the stroke volume in mL; SAP and DAP in mmHg; and BW, the body weight in kg. C1: 1.63 × 10−4 and C2: 1.30 × 10−4.
To study the effects of esmolol and dexmedetomidine on the relation between haemodynamic indices of myocardial oxygen demand (in terms of myocardial oxygen volume, MVO2) and measured myocardial oxygen consumption, percentage changes in RPP and PWI were plotted against percentage changes in measured MVO2.
To measure epicardial deformation, three inductive coils were sutured to the left lateral epicardium. This method for measuring epicardial deformation and its ability to detect changes in regional contractility has been validated in our laboratory [11,12]. The coils were sutured in an equilateral triangle configuration to measure area decrease, e.g. the reduction in area of the epicardial region enclosed by the coils during the systolic ejection period. Onset and end of the ejection phase were determined from the crossover of the left ventricular pressure and the ascending aortic pressure and from the dicrotic notch in the aortic pressure signal, respectively. Since the volume of a certain part of the ventricular wall does not change significantly throughout the cardiac cycle, surface area decrease during the ejection phase is related to wall thickening, and thus regional myocardial contractility. All blood samples were collected on ice. Those to be analysed afterwards were centrifuged at 4°C within 15 min after sampling and stored as plasma at −70°C. Blood-gas tensions were assessed with a blood-gas analyser (ABL 3, Radiometer, Copenhagen, Denmark). Haemoglobin and oxygen saturation were assessed with a haemoximeter (OSM-2, Radiometer). The oxygen content in mmolL−1 was calculated as:
where Hb: haemoglobin; O2sat: oxygen saturation and PO2: partial pressure of oxygen.
From this, oxygen extraction was calculated for the territory of myocardium perfused by the LAD, using a standard formula. Plasma norepinephrine concentrations were analysed with high-performance liquid chromatography with colorimetric electrochemical detection [13,14]. Plasma concentrations of dexmedetomidine were analysed at the Orion Corporation laboratory.
The drugs in the present study were investigated in each dog in the same sequence. Esmolol and dexmedetomidine were compared with their preceding control values, but for the comparison between esmolol and dexmedetomidine, a possible time effect was minimized by an appropriate statistical technique; all esmolol and dexmedetomidine values were first subtracted from their corresponding preceding control value before comparison was made. The non-parametric Wilcoxon signed rank sum test was used and P ≤ 0.05 was considered statistically significant. Linear regression analysis was used to study the relation between the percentage change in haemodynamic indices of myocardial oxygen demand and percentage change in measured myocardial oxygen consumption. Data are presented as mean ± SEM, unless stated otherwise.
Throughout the study period, all dogs maintained a warm body temperature and shivering was not observed. The infusion regimens of esmolol and dexmedetomidine both had sympatholytic effects. Esmolol abolished the tachycardic response to isoprenaline in all dogs. The dose of isoprenaline used to test the beta-adrenergic blockade was 0.45 ± 0.04 μg kg−1. The infusion of dexmedetomidine resulted in plasma concentrations of 1.1 ± 0.3 ng mL−1. Dexmedetomidine decreased plasma norepinephrine concentration by 80 ± 14%: the plasma concentration of norepinephrine at Control 2 was 0.52 ± 0.15 nmol L−1 and after dexmedetomidine 0.06 ± 0.03 nmol L−1 (P < 0.02).
Esmolol and dexmedetomidine decreased haemodynamic indices of myocardial oxygen demand to a similar extent: esmolol decreased the RPP by 16 ± 3% and the PWI by 16 ± 3%, dexmedetomidine decreased the RPP by 26 ± 3% and the PWI by 16 ± 7%. However, these similar decreases resulted from different haemodynamic effects of the two study drugs (Figs 1 and 2). First, dexmedetomidine had a more pronounced bradycardic effect than esmolol (P = 0.01). Second, the two drugs had opposite effects on SAP; dexmedetomidine increased SAP by 15 ± 4% while it decreased by 8 ± 2% with esmolol (P < 0.01). The increase in SAP from dexmedetomidine was accompanied by a parallel increase in SVR, whereas esmolol did not change SVR. Finally, indices of myocardial contractility, dP/dtmax and regional myocardial area decrease, were lower after esmolol than after dexmedetomidine (Fig. 1); the apparent increase in area change after dexmedetomidine did not reach statistical significance (P = 0.091, dexmedetomidine vs. Control 2). The decrease in myocardial contractility after esmolol resulted in a marginal decrease in cardiac output compared to Control 1 (−12 ± 4%, P = 0.05) but not compared to dexmedetomidine (P = 0.17).
In contrast to the decrease in haemodynamic indices of myocardial oxygen demand, neither drug decreased measured myocardial oxygen consumption (Fig. 2). No linear relationship was observed when changes in haemodynamic indices of myocardial oxygen demand (RPP and PWI) were plotted against changes in measured myocardial oxygen consumption for each individual animal (Fig. 3). Both esmolol and dexmedetomidine maintained myocardial oxygen delivery, but by different mechanisms. Dexmedetomidine was associated with a rise in blood-haemoglobin concentration, and thus the arterial oxygen content, by 18% (Table 1). It increased myocardial oxygen extraction by 8%, and tended to decrease coronary flow (−17 ± 15%, P = 0.13). Esmolol maintained the arterial oxygen content and coronary flow, and decreased myocardial oxygen extraction by 10 ± 9%. Neither drug affected coronary venous pH. Thus, both esmolol and dexmedetomidine decreased haemodynamic indices of myocardial oxygen demand to a similar extent, but neither drug decreased directly measured myocardial oxygen consumption.
The perioperative administration of beta-blockers or alpha 2-agonists decreases myocardial ischaemia in certain groups of patients. Theoretically, this beneficial effect is, at least partly, related to their effects on myocardial oxygen demand. To our knowledge, this is the first study comparing the effect of a mainly peripherally acting beta-blocker and a mainly centrally acting alpha 2-agonist on directly measured myocardial oxygen demand.
The main results of this study in chloralose anaesthetized dogs is that both drugs decrease myocardial oxygen demand, as calculated from predictive haemodynamic indices, to a similar extent. However, neither drug decreases directly measured myocardial oxygen consumption. This lack of correlation between haemodynamic indices of myocardial oxygen demand and directly measured myocardial oxygen consumption is in accordance with a previous study in human beings . A possible explanation for this finding is that myocardial oxygen consumption measurements may not have been completely accurate. In previous pilot experiments, we observed that measurements of blood flow per 100 g of myocardial tissue, using a flow probe and methylene blue to delineate the perfusion area, underestimate myocardial blood flow, and thus consumption, compared with measurements using microspheres. However, the percentage error was small, systematic and stable. We therefore concluded that myocardial blood flow measurements using a flow probe can accurately detect a change in oxygen delivery. A more likely explanation for the discrepancy between indirect indices of myocardial oxygen demand and directly measured oxygen consumption may be the inaccuracy of the haemodynamic indices. These indices are often used to estimate the effects of drugs on myocardial oxygen consumption because of methodological limitations concerning the direct measurement of myocardial oxygen consumption. In the current study, RPP and PWI were used because these two indices can be easily calculated from HR, systolic pressure and cardiac output. They have been shown to correlate with myocardial oxygen consumption in chloralose anaesthetized dogs  and in human beings , and they are not subject to inotropic oxygen wasting . However, it has been argued that the conclusions from these studies may have resulted from methodological pitfalls such as pooling of all data instead of using only single data points for each subject [15,17]. Furthermore, these two indices do not include all parameters determining myocardial oxygen demand, but were primarily developed to be clinically useful indices of myocardial oxygen consumption . In the present study, neither dexmedetomidine nor esmolol decreased myocardial oxygen consumption. Myocardial oxygen consumption reflects oxygen demand, because coronary flow was unlimited. In accordance with this finding, our previous studies showed that dexmedetomidine does not affect MVO2 in anaesthetized dogs and goats [18-20]. Other studies have shown that esmolol does not affect MVO2 in anaesthetized dogs [21,22].
In this study, in chloralose anaesthetized dogs, esmolol and dexmedetomidine decreased haemodynamic indices of myocardial oxygen demand to a similar extent. However, this decrease in demand resulted from different mechanisms. Esmolol decreased both HR and aortic pressure. Dexmedetomidine decreased HR to a greater extent than esmolol, but it increased aortic pressure. In the current study, the decrease in aortic pressure in the presence of esmolol seems to result from its cardio-depressive effects, because esmolol suppresses indices of myocardial contractility without affecting the SVR. Hypotension is a known adverse effect of esmolol [23-25] and is not fully explained by its beta-receptor blocking effect . The decrease in myocardial contractility from esmolol in the present study is in accordance with previous studies in which doses of more than 300 μg kg−1 min−1 were used [21,27-29]. Regarding the effect of esmolol on the peripheral vascular resistance, previous studies have not shown consistent results; an increase  as well as no effect  has been observed.
Dexmedetomidine increased aortic pressure and SVR. It has been well described that the cardiovascular effects of dexmedetomidine consist initially of a short-lasting pressor phase, usually lasting less than 20 min, caused by stimulation of alpha 2-adrenergic receptors in peripheral vessel walls; this peripheral vasoconstrictive phase is followed by a depressor phase, due to the central sympatholytic properties of dexmedetomidine [8,31]. In the present study, blood pressure (BP) was still significantly increased approximately 1 h after starting the infusion of dexmedetomidine, despite a significant decrease in norepinephrine concentration. This implies a much longer duration of the vasoconstrictive phase of dexmedetomidine in our study, which could be explained by species differences and the anaesthetic technique used in our studies. It has been shown that the peripheral vasoconstrictive effect of dexmedetomidine is more pronounced in dogs and less pronounced in human beings [32,33]. In a previous work, we emphasized the importance of the anaesthetic technique used when studying the effects of dexmedetomidine . In the present study, we used alpha-chloralose anaesthesia because it has no major effect on central neuroregulation and oxygen metabolism [34,35]. However, it has been shown that alpha-chloralose potentiates the pressor effects of alpha 2-agonists .
Esmolol decreases HR through peripheral beta 1-blockade, but is not always successful in obtaining the target HR [4,37]. In accordance with the more pronounced HR reducing effect of dexmedetomidine compared to esmolol, a case of tachycardia in a cardiac surgical patient has been reported, which was unresponsive to esmolol but resolved after dexmedetomidine . It is likely that a parasympathomimetic effect of dexmedetomidine may be involved in producing bradycardia, in addition to the sympatholytic effect. In our study, HR reduction resulting from sympatholysis was maximal during the esmolol infusion. The further decrease in HR during the dexmedetomidine infusion could therefore be attributed to a parasympathomimetic effect.
It could be argued that the dose of isoprenaline used in our study was too low to test the beta-blockade. However, we strongly believe that the cardiac beta-adrenergic receptors were substantially blocked during the esmolol infusion. First, baseline sympathetic tone, and thus beta-adrenergic activity, was low in these chloralose anaesthetized dogs: norepinephrine concentrations were 0.1-1 nmol L−1, as compared to 3 nmol L−1 in dogs 1 day after a thoracotomy . Second, the dose of isoprenaline used to test the beta-adrenergic blockade, 0.45 ± 0.04 μg kg−1, is in the higher range of the doses currently reported in similar studies (0.125-0.5 μg kg−1) [28,40,41]. Third, it has been shown that the infusion of one-third of the dose used in the current study results in a 70% block of the beta-receptors .
Esmolol and dexmedetomidine had different effects on coronary vascular resistance and on the relative contribution of the individual parameters of myocardial oxygen delivery. The decrease in myocardial oxygen extraction and coronary vascular resistance suggests that esmolol has coronary vasodilating properties. In contrast, dexmedetomidine increased fractional oxygen extraction and calculated coronary vascular resistance [18-20]. It has been suggested that the alpha-adrenergic peripheral vasoconstrictive effects of dexmedetomidine result in a relative shortage of oxygen delivery . However, our findings indicate a possible alternative explanation. Dexmedetomidine increased myocardial oxygen extraction secondary to an increase in haemoglobin and arterial oxygen content, and not secondary to a decrease in coronary venous oxygen content. Indications that the increase in myocardial oxygen extraction was not associated with a critical shortage of myocardial oxygen delivery when giving dexmedetomidine are:
(a) oxygen extraction was still far below maximal ;
(b) coronary venous pH did not decrease;
(c) dexmedetomidine suppressed haemodynamic indices of myocardial oxygen demand.
On the other hand, the observed increase in myocardial oxygen extraction associated with the administration of dexmedetomidine did not increase myocardial oxygen delivery because coronary blood flow tended to decrease.
The increase in haemoglobin after the administration of dexmedetomidine is an interesting feature of this study. The most likely explanation for this finding is that dexmedetomidine causes recruitment of red blood cells from splenic stores. The effects of alpha-adrenoreceptor activation on the splenic capsule and splanchnic capacitance vasculature have already been described . There is evidence that these effects are alpha 2-receptor rather than alpha 1-receptor mediated . Blood volume shifts from abdominal organs, including the spleen, have also been described in pigs  and in male [45,46]. Another possible explanation for the increase in haemoglobin concentration is a transcapillary fluid shift from the intravascular space in organs where venous vasoconstriction exceeds arterial vasoconstriction. This mechanism has been demonstrated in rats with epinephrine . We believe that this explanation is less likely, because the expected decrease in left ventricular end-diastolic pressure associated with such a fluid shift was not observed in our experiments. The increase in haemoglobin concentration associated with the administration of dexmedetomidine, can also, at least in part, explain the observed increase in coronary vascular resistance, as viscosity, of which haematocrit is a major determinant, contributes to vascular resistance .
A limitation of the study is that the results obtained are restricted to dogs; there may be relevant species differences in the effects of sympatholytic drugs on myocardial oxygen consumption. However, in the current study myocardial oxygen consumption was similar to that reported in awake and anaesthetized human beings .
A methodological limitation of the current study is that a crossover design with these two drugs was not feasible. Due to its long plasma half-life, it is impossible to study the effects of any other drug in the same animal after the administration of dexmedetomidine. Therefore, the drugs were always investigated in the same sequence in each experiment; first, the short-acting esmolol and then the long-acting dexmedetomidine. However, we applied well-established statistical methods to minimize a possible time-related effect in the present study.
Finally, we studied only one dose of each drug and perhaps higher doses are needed to decrease myocardial oxygen consumption. However, the doses used resulted in adequate sympatholysis for each drug.
In conclusion, peripheral and central sympatholysis with a beta 1-blocker and an alpha 2-agonist, respectively, decrease haemodynamic indices of myocardial oxygen demand to a similar extent, but do not decrease myocardial oxygen consumption in chloralose anaesthetized dogs.
The authors thank A. Kester for statistical advice and Orion Corporation, Farmos Research, Turku, Finland, for financial support and plasma concentration measurements of dexmedetomidine.
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