The coronary arteries consist of the large epicardial coronary arteries and intramyocardial small coronary arteries and arterioles. The large coronary arteries are conductance vessels and offer little resistance to blood flow, while the small arteries and arterioles are the major source of coronary vascular resistance and regulate distribution of blood flow within the myocardium [1-3]. The large and small coronary arteries are regulated by different mechanisms [1,4,5]. The drugs that dilate the large coronary arteries are beneficial for patients with ischemic heart disease , whereas coronary arteriolar dilators may produce coronary steal phenomenon .
Isoflurane has been reported to dilate the peripheral and coronary resistant vessels [8,9]. Sill et al.  have reported that isoflurane dilates coronary arterioles but not large coronary arteries in a canine model. Isoflurane is associated with regional myocardial blood flow maldistribution and/or ischemia in the presence of coronary stenosis when systemic perfusion pressure is reduced [11,12]. As for sevoflurane, there are some studies concerning the coronary circulation; however, the effects on the large and small coronary arteries remain controversial [13,14].
The purpose of this study was to assess the effects of sevoflurane, as compared to isoflurane, on the large and small coronary arteries by measuring the large coronary artery diameter and coronary blood flow in relation to myocardial oxygen consumption in anesthetized dogs.
The experiments were approved under the Guidelines for Animal Experimentation at Nagasaki University and performed at Laboratory Animal Center for Biomedical Research, Nagasaki University School of Medicine. Twenty mongrel dogs of either sex weighing 11-15 kg were anesthetized with 25 mg/kg pentobarbital intravenously. After tracheal intubation, the lungs of each animal were mechanically ventilated with a volume ventilator (Harvard) supplying 60% N2-40% O2. End-tidal CO2 and anesthetic concentrations were monitored continuously with a gas analyzer (Capnomac Ultima; Datex, Helsinki, Finland). End-tidal CO2 was maintained at a level of 35-40 mm Hg. A heating lamp was used to maintain the esophageal temperature between 36.5 and 38.0 degrees C. Anesthesia was maintained with a continuous infusion of fentanyl at a rate of 20-40 micro gram centered dot kg-1 centered dot h-1 throughout the experiment. In addition, 1% isoflurane was administered during surgical treatments prior to the experiment to avoid a hyperdynamic state. A 7-Fr polyethylene catheter was inserted via the left femoral artery into the abdominal aorta for pressure monitoring and blood sampling. The same type of catheter was inserted into the left femoral vein, through which lactated Ringer's solution was administered at a rate of 10 mL centered dot kg-1 centered dot h-1. A left-sided thoracotomy was performed in the fifth intercostal space. After dissection of the aortic root and left circumflex coronary artery (CX), appropriate-sized electromagnetic flowprobes were placed 5 mm distal from its origin of CX, and both aortic blood flow and CX blood flow were measured by the electromagnetic flowmeter (MFX-2100; Nihon Koden Co., Tokyo, Japan). A pair of miniature piezoelectric crystals (1.5 times 1.5 mm, 12-15 mg) (piezotite; Murata Mfg. Co., Tokyo, Japan) was attached with jelly-type rapid bonding adhesive (Alon Alpha; Konishi Co., Osaka, Japan) on the CX wall 1.5 mm distal from electromagnetic flowprobe. The CX diameter was measured continuously with an ultrasonic dimension unit (NEC-Sanei Co., Tokyo, Japan). The instrument generates a voltage linearly proportional to the transit time of acoustic impulses traveling at the sonic velocity of 1.57 times 106 mm/s between the 5-MHz piezoelectric crystals . Two platinum electrodes (120 micro meter diameter) were implanted into the myocardium in the territory supplied by the CX 2-3 mm and 8-10 mm in depth to measure the inner and outer myocardial blood flow by the electrolytic hydrogen clearance method (UH-meter; Unique Medical Co., Tokyo, Japan). This method measures local blood flow by continuous recording of the tissue concentration of inspired hydrogen with a platinum electrode inserted into the tissue . The simultaneous recording with two or more electrodes in different parts of an organ provides the information about the magnitude and distribution of blood flow within the organ. An 18-gauge catheter (Vennula; Top Co., Tokyo, Japan) was placed into the coronary sinus via the left external jugular vein for blood sampling. Correct position of this catheter was verified from time to time during the experiment by digital palpation. A catheter-tip transducer (PT-157; Goodman Co., Nagoya, Japan) was inserted into the left ventricle through the left atrium to measure the left ventricular pressure continuously, and the peak rate of increase in left ventricular (LV) pressure (LV dP/dtmax) was calculated. Electrocardiogram, arterial pressure, left ventricular pressure, aortic blood flow, CX blood flow, LV dP/dtmax, and CX diameter was recorded by an eight-channel polygraph (361-type; NEC-Sanei Co., Tokyo, Japan). Blood gas was analyzed with ABL 2000 (Radiometer, Copenhagen, Denmark). The hemoglobin concentration and the hemoglobin oxygen saturation in arterial and coronary sinus blood were measured with CO-oxymeter 282 (Instrumentation Laboratories, Lexington, MA).
Thirty minutes were allowed to attain stable circulation and to wash out isoflurane after set-up of the equipment. The first measurements were made to obtain the control value: mean arterial pressure (MAP), heart rate (HR), cardiac output, left ventricular end-diastolic pressure, LV dP/dtmax, CX blood flow, CX diameter, inner and outer myocardial blood flow, arterial and coronary sinus blood gas, hemoglobin concentration, and hemoglobin oxygen saturation. Then the dogs were randomly divided into two groups, sevoflurane group (n = 10) and isoflurane group (n = 10). In both groups the second measurements were performed after a 30-min period of inhalation of each anesthetic at an end-tidal concentration of 0.75 MAC. The final measurements were made after a further 30-min period of inhalation of each anesthetic at 1.5 MAC.
CX vascular resistance (unit) was calculated as CX blood flow/(diastolic aortic pressure--left ventricular end-diastolic pressure). The regional myocardial oxygen consumption (MVO2, mL/min) in the territory supplied by the CX was calculated using the Fick principle (CX blood flow times arteriocoronary sinus oxygen content difference/100). Myocardial oxygen extraction ratio (MO2 exr) was calculated as arteriocoronary sinus oxygen content difference times 100/arterial oxygen content. Inner and outer myocardial blood flow ratio (I/O ratio) was calculated as inner myocardial blood flow/outer myocardial blood flow.
The data were expressed as mean +/- SD or mean +/- SEM. The results of repeated measures were analyzed by one-way analysis of variance. Pairwise comparisons between control and anesthetic values were assessed by Student's paired t-test. The comparisons between groups were assessed by Student's unpaired t-test. P values of less than 0.05 were considered significant.
The effects of sevoflurane and isoflurane on systemic and coronary hemodynamics are presented in Table 1. MAP, HR, and LV dP/dtmax decreased in both groups. Cardiac index decreased in the sevoflurane group, but did not change in the isoflurane group. The large coronary artery diameter decreased significantly during 1.5 MAC sevoflurane and 0.75 MAC and 1.5 MAC isoflurane Figure 1. The change in CX blood flow was remarkably different between the groups. In the sevoflurane group, the CX blood flow decreased in parallel with the decrease in MVO2, and the coronary vascular resistance did not change. On the other hand, in the isoflurane group, the CX blood flow did not change despite the decrease in MVO2, and the coronary vascular resistance decreased significantly during 1.5 MAC isoflurane Figure 2. MO2 exr was decreased with 1.5 MAC sevoflurane and 0.75 and 1.5 MAC isoflurane. The decrease in MO2 exr was significantly greater during isoflurane than during sevoflurane. I/O ratio was unchanged with either anesthetic Figure 3.
Our results show that sevoflurane as well as isoflurane decreased the large coronary artery diameter in parallel with the decrease in MAP. With the change in perfusion pressure, the large coronary artery diameter shows only passive change [1,3]. Thus, the reduction in the diameter of the large coronary artery during either anesthetic would be caused by the decrease in blood pressure. Sill et al.  measured canine epicardial artery diameter using angiograms at the varying coronary perfusion pressure, and reported that isoflurane had no effect on epicardial artery dimensions at a constant hemodynamic state. On the basis of these findings, sevoflurane as well as isoflurane should have no direct effect on the large coronary artery.
Although it is well known that isoflurane dilates the coronary resistant vessel, it is still in dispute whether isoflurane causes "coronary steal" in patients with coronary artery disease [17-19]. It was reported that sevoflurane had an effect similar to isoflurane on the coronary resistant vessels [14,20]. In our present study, there were some different effects on the coronary hemodynamics between isoflurane and sevoflurane. The CX blood flow decreased in parallel with the decrease in MVO2 during sevoflurane, whereas the CX blood flow did not change in spite of the decrease in MVO2 during isoflurane. The CX vascular resistance decreased significantly during isoflurane but not during sevoflurane. Moreover, the MO2 exr, which reveals the myocardial oxygen demand-supply relationship, decreased at 0.75 and 1.5 MAC isoflurane and at 1.5 MAC sevoflurane, and the decrease in MO (2) exr was significantly greater during isoflurane than during sevoflurane. These results clearly demonstrate that sevoflurane is a less potent coronary arteriolar dilator than isoflurane. However, the data on MO2 exr indicate that, although the effect is weaker than that of isoflurane, sevoflurane might also impair the coronary autoregulation. This is because when the coronary autoregulation is maintained, the MO2 exr must be constant and independent of the metabolic needs of myocardium. The decrease in MO2 exr means that there is a luxury perfusion in spite of a decrease in the metabolic needs. The possibility of coronary steal during sevoflurane should be further examined under various physiologic conditions, such as stress and coronary stenosis.
To obtain accurate information about myocardial oxygen demand and supply, it is better to measure the oxygen content of the venous blood from the territory supplied by the CX than that from coronary sinus. However, our animals were fairly small, and deep cannulation into the coronary vein might have interfered with circulation of the blood. Thus we used coronary sinus blood as a substitute. Since the present model had no coronary stenosis, there would not be much difference in coronary venous oxygen between coronary sinus and the territory supplied by the CX.
Bernard et al.  studied chronically instrumented dogs, and indicated that sevoflurane appeared to be a potent coronary vasodilator, and that the effects on coronary blood flow are almost identical to that of isoflurane. However, their model did not allow for the measurement of coronary venous oxygen, so that a disparity between myocardial oxygen supply and demand could not be determined. As they commented, regulation of coronary circulation is known to be dependent on myocardial oxygen demand. Indeed, in their model, sevoflurane produced a greater increase in HR than isoflurane. Thus it seems possible that the increase in coronary blood flow during sevoflurane might be caused from an increase in myocardial oxygen demand due to tachycardia.
Conzen et al.  studied the effects of sevoflurane and isoflurane on systemic hemodynamics and regional blood flow distribution in rats. Inhaled anesthetics were applied to reduce MAP to 70 mm Hg (1.66% sevoflurane and 0.96% isoflurane) and 50 mm Hg (3.95% sevoflurane and 2.43% isoflurane). Myocardial blood flow was reduced at all concentrations of both anesthetics; however, the decrease was less with isoflurane. They indicated that isoflurane caused a more pronounced coronary vasodilation as the rate-pressure product decreased by comparable degrees with both anesthetics. Although sevoflurane caused a significant decrease in coronary vascular resistance at MAP 50 mm Hg, this coronary vasodilation would result from autoregulation to maintain blood flow under critical hypotension. Their model also did not determine a disparity between myocardial oxygen supply and demand.
Larach and Schuler  examined the direct actions of volatile anesthetics on the coronary resistance vessels of isolated rat heart. They reported that, at a higher concentration, the coronary flow reserve was abolished by halothane and isoflurane, but was maintained by sevoflurane. Coronary flow reserve is the increment in flow that can be induced by a maximum vasodilator stimulus such as intracoronary adenosine. Maintained coronary flow reserve reflects the maintained ability of myocardium to increase its blood supply in response to increased nutrient demand.
In the present study we also examined I/O ratio. There was no change in the I/O ratio during either anesthetic, indicating that there is no disadvantageous influence on the regional blood flow distribution. Further studies using the ischemic model would be needed to determine the possibility of producing "coronary steal" by sevoflurane. Concerning the methodology, we used the electrolytic hydrogen clearance method  to measure the inner and outer myocardial blood flow. Use of radioactive microspheres or colored microspheres would be standard technique for this purpose . However, the former is restricted to specially licensed laboratories, and it is costly to inject colored microspheres into the systemic circulation in our experimental model.
In the present study, each anesthetic reduced HR in a dose-dependent manner. The decrease in HR during either anesthetic seems to be explained by the fact that the basal condition was hyperdynamic due to pentobarbital induction and to the open-chest condition, in spite of continuous administration of fentanyl. Both anesthetics reduced MAP in a dose-dependent manner, whereas cardiac index was reduced by sevoflurane but not changed by isoflurane. The different effects on cardiac index would be explained by marked peripheral vasodilation during isoflurane [21,24]. It seems unlikely that sevoflurane might reduce myocardial contractility more than isoflurane, because there was no difference in LV dP/dtmax or MVO2 between two groups.
In conclusion, neither sevoflurane nor isoflurane has any direct effect on the large coronary artery diameter. The vascular resistance of the small coronary artery was reduced by isoflurane but unchanged by sevoflurane. Sevoflurane is a less potent coronary arteriolar dilator than isoflurane.
The authors wish to thank Mr. Hiroyuki Ureshino for his technical assistance.
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© 1995 International Anesthesia Research Society
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