Ann Thorac Surg 1996;62:1737-1742
© 1996 The Society of Thoracic Surgeons
Original Articles: Cardiovascular
Impact of Systemic Depulsation on Tissue Perfusion and Sympathetic Nerve Activity
Koichi Toda, MD,
Eisuke Tatsumi, MD, PhD,
Yoshiyuki Taenaka, MD, PhD,
Toru Masuzawa, PhD,
Hisateru Takano, MD, PhD
Department of Artificial Organs, National Cardiovascular Center Research Institute, Osaka, Japan
Accepted for publication June 18, 1996.
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Abstract
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Background. We postulated that pathophysiologic processes under nonpulsatile circulation are related to the behavior of the sympathetic nerve activity that regulates tissue perfusion.
Methods. Pulsatile and nonpulsatile pumps were installed in parallel in the left heart bypass circuit of anesthetized goats (n = 9) so that pulsatile circulation could be converted to nonpulsatile circulation instantly. At 5 minutes before and after systemic depulsation, we measured hemodynamic indices, renal nerve activity, and regional blood flow of the brain, heart, and renal cortex.
Results. Renal nerve activity was significantly elevated after systemic depulsation (15.6 ± 9.3 versus 19.4 ± 9.8 µV), when mean aortic pressure remained almost constant. The renal cortical flow was significantly reduced after depulsation (3.61 ± 1.23 versus 2.93 ± 1.19 mL•min-1•g-1), whereas no significant difference was found in the regional blood flow of the brain or the heart.
Conclusions. The significant reduction of renal cortical blood flow after systemic depulsation is associated with a significant increase in renal nerve activity. Our results suggest that increased renal nerve activity plays an important role in the reduction of renal function after systemic depulsation.
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Introduction
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Recently, nonpulsatile circulation (NC) has been applied to left heart bypass as well as cardiopulmonary bypass [1], and the physiologic consequences of NC have been studied with interest [2–4]. Previous studies revealed that depulsation of the systemic circulation brought about changes in hemodynamic indices and hormonal factors, which suggested increased sympathetic tone after systemic depulsation [4]. It is generally believed that there is a close relation between tissue perfusion and sympathetic nerve activity (SNA). We therefore focused our interest on the simultaneous changes in SNA and regional blood flow of vital organs induced by systemic depulsation. In this study, we constructed a left heart bypass model by which artificial systemic pulsatile circulation (PC) could be converted instantly to NC, and analyzed directly the renal SNA and the regional blood flow of the brain, heart, and renal cortex simultaneously at 5 minutes before and after systemic depulsation.
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Material and Methods
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Preparation of Animals
Nine adult goats (59 ± 7 kg, mean ± 1 standard deviation) premedicated with ketamine (5 mg/kg intramuscularly) were intubated with an endotracheal tube for mechanical ventilation (Servo Ventilator 900C; Siemens-Elema, Stockholm, Sweden). Each goat was anesthetized by inhalation of isoflurane (1% to 2.5%) and nitrous oxide (30% to 70%) and was immobilized with pancuronium bromide (0.08 mg/kg intravenously) during surgical preparation. All goats received humane care in compliance with the "Guide for the Care and Use of Laboratory Animals" published by the National Institutes of Health (NIH publication 85-23, revised 1985). During the experiment, no transfusion was carried out, and lactated Ringer's solution containing low molecular weight dextran was infused continuously to maintain right atrial pressure within the normal range. The arterial blood gas tensions, pH, and hemoglobin concentration were kept within normal ranges, and body temperature was maintained by warming throughout the experiments.
A pneumatic diaphragm-type pulsatile pump developed in our laboratory [5] and a centrifugal nonpulsatile pump (Bio-Pump; Bio-Medicus, Eden Prairie, MN) were incorporated in parallel to an extracorporeal circuit for total left heart bypass so that conversion between PC and NC could be performed instantly (Fig 1
). The extracorporeal circuit was connected to the anesthetized goat by making a left thoracotomy at the fifth rib and suturing a return cannula of 0.5-inch inner diameter with a graft onto the descending aorta. After administration of heparin (3 mg/kg), an uptake cannula (0.5-inch inner diameter) was inserted into the left atrium, and a vent cannula (0.25-inch inner diameter) was placed in the left ventricular apex. These three cannulas were connected to the extracorporeal circuit (see Fig 1). During PC, most of the blood was vented from the left atrium and returned to the aorta by the pulsatile pump. Blood escaping to the left ventricle was captured by the nonpulsatile pump and joined with blood at the return cannula so that the left ventricular pressure (LVP) was always lower than the aortic pressure (AoP). The pumping rate was fixed at 90 cycles/min regardless of the native heart rate. During NC, all the blood was vented from both the left atrium and the LV and returned to the aorta by the nonpulsatile pump. The circulatory mode was converted from PC to NC instantly by changing the blood path, with the centrifugal pump working at all times.
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Fig 1. . Extracorporeal circuit for pulsatile circulation (PC) and nonpulsatile circulation (NC). Two uptake cannulas and a return cannula of the circuit were placed in the left atrium (LA), the left ventricle (LV), and the descending aorta (Ao), respectively. The blood path in the extracorporeal circuit is indicated by diagonal lines.
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Preparation for Physiologic Monitoring
The left kidney was exposed retroperitoneally through a left flank skin incision, and the renal nerve signals were recorded at the central end of the cut nerve with a pair of platinum wire electrodes. The original renal nerve signals were amplified by a biophysical preamplifier (MEG-125; Nihon Kohden, Tokyo, Japan) with a high-cutoff frequency of 3,000 Hz and a low-cutoff frequency of 50 Hz. The amplified signals, defined as the original renal nerve activity (RNA), were displayed on the oscilloscope for visual evaluation. The original RNA was rectified by a full-wave rectifier circuit and integrated by an R-C integrator with a time constant of 20 milliseconds. This integrated signal, after the bioelectrical noise was subtracted, was defined as the RNA. The bioelectrical noise level was defined as the remaining nerve signals after the RNA was extremely inhibited by administration of hexamethonium bromide (2 mg/kg). The electrocardiogram was recorded by electrodes attached to the extremities. The AoP, LVP, and right atrial pressure were measured with a heparin-filled catheter placed in each of the respective sites. Bypass flow, which was virtually equivalent to systemic blood flow under total left heart bypass, was also measured in the return cannula of the circuit by an electromagnetic flowmeter (MF-200; Nihon Kohden).
Regional Blood Flow Determination
For each measurement of regional blood flow during PC and NC, 2 mL of colored microsphere suspension, containing approximately 6 x 106 microspheres (15 ± 0.2 µm in diameter; Dye-Trak; Triton Technology, Inc, San Diego, CA), was injected slowly through the return cannula. These microspheres were distributed to the tissues and were also collected in the reference blood samples, which were drawn through the aortic catheter starting 10 seconds before injection of the microspheres and continuing for 80 seconds at a constant rate of 25 mL/min by a withdrawal pump (Truth A-2; Eikou, Tokyo, Japan).
After the goats were euthanized, the brain, heart, and right kidney were removed. The brain was divided into the cerebral cortex, cerebellar cortex, mid-brain, and medulla oblongata, which weighed 2 to 3 g. The anterior wall of the left ventricle was carefully dissected free from epicardial fat and divided into two halves, designated as the inner and outer layers, each weighing 2 to 3 g. After the capsule was stripped away, the kidney was cut longitudinally with a brain macrotome, and 5-mm–thick sagittal sections were divided into the renal cortex and medulla along with the arcuate artery. The cortex was then divided into four equal cortical layers, which were designated as C1, C2, C3, and C4 from the outermost to the innermost layers, each weighing 1 to 1.5 g. After each tissue sample and reference blood sample was assayed, as described by Kowallik and associates [6], the regional blood flow of the tissue was calculated with a computer program (Matrix Inversion for Spectrum Seperatio; Triton Technology, Inc).
Experimental Protocol
After operative preparation was completed, inhalation of isoflurane was discontinued and sodium pentobarbital (5 mg•kg-1•h-1) was infused intravenously as an anesthetic. Left heart bypass was initiated gradually with pulsatile flow. After 5 minutes of PC, sequential data of hemodynamic indices and RNA were sampled for 30 seconds, averaged, and designated as the mean values of each variable in PC, and the regional blood flow was determined as mentioned earlier. At 5 minutes after sampling of the data in PC, the circulatory mode was converted from PC to NC with the mean AoP almost constant. After 5 minutes of NC, the mean values of each index and the regional blood flow in NC were determined as in PC.
Values are expressed as mean ± 1 standard deviation, and comparisons between mean values were performed using a paired Student's t test. The level of significance was defined as p less than 0.05.
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Results
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Experiments were carried out under normothermic conditions, and the hemoglobin concentration and arterial blood gas tensions were kept within normal ranges (partial pressure of oxygen in arterial blood, 275 ± 73 mm Hg; partial pressure of carbon dioxide in arterial blood, 31 ± 5 mm Hg; pH, 7.44 ± 0.08; hemoglobin, 9.5 ± 1.4 g/dL). Representative recordings of electrocardiogram, original RNA, AoP, and LVP during PC and NC are shown in Figures 2A and 2B, respectively. The LVP was always maintained lower than the AoP in both PC and NC. This indicated that the bypass circuit fully captured the cardiac return to the left atrium and the left ventricle, and the native ejection from the left ventricle completely disappeared.
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Fig 2. . Electrocardiogram (ECG), original neurogram of renal nerve activity (RNA), aortic pressure (AoP), and left ventricular pressure (LVP) obtained during pulsatile (A) and nonpulsatile (B) circulation. The periodic grouped discharge in renal nerve activity during pulsatile circulation was transformed into sporadic, small grouped discharges after systemic depulsation.
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During PC, the original RNA exhibited periodic grouped discharge (see Fig 2A
). After conversion of the circulatory mode from PC to NC, this periodic discharge transformed into sporadic, small grouped discharges (see Fig 2B). At the end of the experiments, the original RNA was reduced to the noise level after the administration of hexamethonium bromide, which is a known ganglionic blocker. We therefore identified these grouped discharges as the nerve signals of postganglionic renal sympathetic nerve fibers. The quantitative difference between the mean RNA in PC and that in NC is presented in Fig 3A. The mean RNA, which was 15.6 ± 9.3 µV during PC, increased significantly to 19.4 ± 9.8 µV after systemic depulsation.
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Fig 3. . (A) Mean renal nerve activity (RNA) during pulsatile circulation (PC) and nonpulsatile circulation (NC). The mean renal nerve activity was significantly increased after systemic depulsation (*p < 0.05). (B) Averaged regional blood flow in the brain, heart, and renal cortex during pulsatile circulation and nonpulsatile circulation. A significant difference between pulsatile circulation and nonpulsatile circulation was found only in the renal cortex (*p < 0.05). All data are expressed as mean ± 1 standard deviation (n = 9).
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Table 1 summarizes the hemodynamic indices at 5 minutes before and after systemic depulsation. Although no significant difference between PC and NC was found in the mean AoP, mean right atrial pressure, mean LVP, or mean bypass flow, the mean pulse pressure was significantly reduced after systemic depulsation. Slight pulsatility in the aortic pulse wave during NC was considered to be due to changes in preload for the nonpulsatile pump corresponding to the native heart beating.
Figure 3B illustrates the averaged regional blood flow of the brain, heart, and renal cortex, which were measured by the colored microsphere method during PC and NC. Regional blood flows during PC and NC were 0.49 ± 0.12 and 0.48 ± 0.14 mL•min-1•g-1, respectively, in the brain, and 0.62 ± 0.16 and 0.64 ± 0.26 mL•min-1•g-1, respectively, in the heart; no significant difference between PC and NC was detected in regional blood flow of the brain or the heart. On the other hand, the regional blood flow of the renal cortex was 3.61 ± 1.23 mL• min-1•g-1 during PC and was significantly reduced to 2.93 ± 1.19 mL•min-1•g-1 after systemic depulsation. The distribution of regional blood flow within the organs is presented in Table 2. In the brain, systemic depulsation slightly increased the regional blood flow of the cerebral cortex and medulla oblongata and slightly decreased that of the cerebellar cortex and the mid-brain; there was no significant difference between PC and NC in the regional blood flow at any sites. In the heart, the regional blood flow was lower in the outer layer of the anterior wall of the left ventricle in NC as well as PC, and depulsation nonsignificantly increased the regional blood flow of both layers. In the renal cortex, the outermost layer, represented as C1, received the most blood of the four cortical layers. Regional blood flow decreased progressively from the outer to the inner cortex during NC as well as PC. Depulsation uniformly reduced the regional blood flow within the renal cortex, and a significant difference was found between PC and NC in all four layers of the renal cortex.
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Table 2. . Regional Blood Flowa in the Brain, Heart, and Renal Cortex During Pulsatile Circulation and Nonpulsatile Circulation
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Comment
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Despite the large number of studies regarding pathophysiologic processes under NC [2–4], there are few points of agreement among those studies, and the role of pulse pressure in the systemic circulation remains unclear. We consider that the source of variance in the previous studies under cardiopulmonary bypass is the influence of factors other than flow condition. Blood trauma [7], hemodilution [8], hypothermia [9], and reduced native pulmonary circulation, modulating humoral factors [10], are inherent to cardiopulmonary bypass and are supposed to affect the results. To make pulsation of the systemic circulation the sole variable, we constructed a left heart bypass model in which artificial systemic PC could be converted instantaneously to NC. The volume of our extracorporeal circuit was as small as 300 mL, and hemoglobin and body temperature were maintained in the experiment. Furthermore, pulmonary circulation was maintained by the native heart and was considered to be under physiologic pulsatile conditions in this model.
Previous studies demonstrated the increase in the plasma concentration of catecholamines, which reflects the SNA of the whole circulatory bed and adrenal medulla, and proposed an increased sympathetic tone during NC [4]. This study was designed to analyze the change in SNA directly upon depulsation of the systemic circulation. We recorded the RNA in goats, the heart rate and size of which are similar to those in humans, and simultaneously evaluated the difference in the RNA and the regional blood flow of vital organs between PC and NC. In this study, we focused on the change in RNA and regional blood flow during a short period of time because it was demonstrated that the time course of the change in RNA was influenced by anesthetic agents [11].
For the measurement of regional blood flow, many studies have used radioactive microspheres. However, this method has problems of cost and storage and disposal of radioactive materials, which are environmentally hazardous. To avoid these problems, we used newly developed nonradioactive microspheres, which are dyed with different colors (Dye-Trak; Triton Technology, Inc). This method, however, also has limitations. Because 15-µm microspheres are trapped almost exclusively within the glomeruli [12], we could not determine the regional blood flow in the renal medulla by this method. Another problem inherent to this microsphere method is the alteration of regional blood flow induced by the presence of a large number of microspheres. We chose to inject 6 x 106 microspheres because of the report by Baer and associates [13] that repeated injections of 2 to 3 x 106 15-µm microspheres resulted in no significant change in hemodynamic indices or in the regional blood flow in dogs.
We found that systemic depulsation significantly increased the RNA and simultaneously decreased the renal cortical blood flow in all four cortical layers. Because adrenergic nerve terminals are located on afferent arterioles [14] and increased renal nerve stimulation reduces the renal cortical blood flow [15], our results suggest that systemic depulsation reduced renal cortical blood flow by raising the RNA. Because reduced renal cortical blood flow decreases the glomerular filtration rate and, moreover, increased RNA augments renal renin secretion and renal tubular sodium and water reabsorption [16], our results strongly suggest that reduced renal function caused by increased RNA should be taken into account during the acute phase of NC. Previously, Goodman and colleagues [17] investigated the renal cortical blood flow during nonpulsatile left heart bypass in the dog. They demonstrated a decrease in blood flow in the outer renal cortex after 2 hours of nonpulsatile left heart bypass. This suggests that the decreased blood flow in the outer renal cortex that we demonstrated after 5 minutes of NC may last for at least 2 hours. On the other hand, in their study, the inner cortical blood flow was increased after 2 hours of nonpulsatile left heart bypass, and they proposed that the renal cortical blood flow was redistributed from the outer to the inner cortex during nonpulsatile left heart bypass. This redistribution could not be found in our study. In their experiments, only NC was maintained by the extracorporeal circuit and PC was maintained by the native heart, whereas in our study, both PC and NC were maintained by the extracorporeal circuit. It is possible that the discrepancy in the redistribution of renal cortical blood flow may be related to the difference in the experimental model, as well as the species difference.
Because of the demonstrated inhibitory effect of anesthesia on SNA [11], the difference between PC and NC in RNA and renal cortical blood flow is supposed to be more pronounced in awake animals. Counter to this speculation, renal function did not deteriorate during NC in experiments in chronic animal models [18]. This difference implies that the renal hypoperfusion observed in this experiment may be a transitory phenomenon and that in the awake animal, the NC can be accommodated despite the renal hypoperfusion in the acute phase of NC. Further experimental analysis of renal cortical blood flow and RNA in chronic NC may supply more information as to the mechanism of accommodation after systemic depulsation.
In the brain and heart, there was no significant change in regional blood flow after systemic depulsation. This implies that the responses of regional blood flow to NC differ among the renal cortex, the brain, and the heart. We postulate two possible mechanisms to explain this organ-specific response to NC. Ninomiya and co-workers [19] demonstrated that the changes in SNA in response to a change in mean AoP were not identical among the cardiac, splenic, and renal circulatory beds and noted that the effects of baroreflex on SNA to different organs were quantitatively nonuniform. We hypothesize that the effects of systemic depulsation on the sympathetic outflow are not identical among these organs. The other possible mechanism is the influence of factors other than SNA, such as humoral factors and vagal efferent and autoregulation mechanisms. Recently, Tominaga and associates [20] demonstrated that NC had no harmful effects on the autoregulation of cerebral blood flow. We consider that the autoregulation mechanism may attenuate the change in cerebral blood flow after systemic depulsation. The heart is innervated not only by sympathetic nerves, but also by the vagal efferent nerves. Therefore, it is possible that efferent vagal nerve activity may modulate the regional blood flow of the heart.
In conclusion, systemic depulsation increases the mean RNA and reduces the renal cortical blood flow, without significant alteration in cerebral blood flow and myocardial perfusion, when mean AoP is maintained constant. These results suggest that increased RNA plays an important role in the reduction of renal function during the acute phase after systemic depulsation.
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Acknowledgments
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This work was supported in part by a grant from the Japan Cardiovascular Research Foundation, a grant-in-aid for scientific research from the Ministry of Education, Japan (no. 06671368), and special coordination funds for promoting science and technology from the Science and Technology Agency, Japan.
We thank Dr Ishio Ninomiya (Department of Physiology, Institute of Health Sciences, School of Medicine, Hiroshima University, Japan) and Dr Kanji Matsukawa (Department of Cardiac Physiology, National Cardiovascular Center Research Institute, Japan) for their valuable professional suggestions and technical advice throughout the study.
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Footnotes
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Address reprint requests to Dr Taenaka, Department of Artificial Organs, National Cardiovascular Center Research Institute, 5-7-1 Fujishiro-dai, Suita, Osaka 565, Japan.
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Abstract
Introduction
