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Ann Thorac Surg 2001;72:156-162
© 2001 The Society of Thoracic Surgeons

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Original article: cardiovascular

Impacts of pulsatile systemic circulation on endothelium-derived nitric oxide release in anesthetized dogs

Accepted for publication March 15, 2001.

Address reprint requests to Dr Tominaga, Division of Cardiovascular Surgery, Faculty of Medicine, Kyushu University 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582 Japan
e-mail: tomina{at}heart.med.kyushu-u.ac.jp

	Abstract

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Background. The effects of pulsatile flow on endothelium-derived nitric oxide-mediated vasodilation are not fully elucidated in an in vivo model.

Methods. A left ventricular assist device was established in 10 anesthetized dogs with a centrifugal pump and an air-driven pneumatic pump. The systemic circulation was subjected to step changes in the frequency of pulse (0, 30, 60, and 120 bpm with a fixed pulse pressure of 50 mm Hg), and in the amplitude of pulse (0, 20, and 50 mm Hg with a fixed pulse rate of 120 bpm). Hemodynamic variables and calculated total systemic vascular resistance were compared before and after the administration of N^G-Nitro-L-arginine Methyl Ester (L-NAME) (20 mg/kg). Plasma NO^2-/NO^3- concentration levels were also measured.

Results. Total systemic vascular resistance significantly decreased while plasma NO^2-/NO^3- concentration increased in response to the rise in both pulse rate and pulse pressure. However, L-NAME significantly diminished these effects of pulsatile flow.

Conclusions. Both the frequency and the amplitude of pulse wave in the systemic circulation are significant independent stimuli for endothelium-derived nitric oxide-mediated vasodilation in vivo.

	Introduction

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The necessity of pulsatility in the systemic circulation has been a subject of interest and also a major concern in designing total artificial heart and left ventricular assist device. Some earlier studies have reported the beneficial effects of pulsatile systemic perfusion on microcirculation, metabolism, and organ functions [1–4], however, others did not observe any superiority in the pulsatile perfusion over nonpulsatile perfusion [5, 6]. Still other studies also demonstrated that animals could live for a long time with nonpulsatile circulation without hemodynamic deterioration [7–9]. One of the factors that make it difficult to compare these studies is the differences in the pulsatile pump devices and the variety in the pulse waveforms used.

Some contributions have revealed the effects of pulsatile flow on systemic circulation from the physiologic aspects. Fukae and coworkers [10] demonstrated the pulsatile systemic flow to inhibit the efferent sympathetic nerve activity that is significantly correlated with the decrease in peripheral vascular resistance. Toda and coworkers [11] also indicated a significant increase in the renal sympathetic nerve activity after systemic depulsation and implied the arterial baroreflex mechanism was possibly involved. However, it has also been suggested that the presence of factors other than the sympathetic nerve system which might play a role in the elevated vascular resistance in nonpulsatile perfusion [12].

Traditionally, endothelial cells have been reported to play an important role in modulating local circulation by producing and releasing various vasoactive substances. Nitric oxide is one of the endothelium-derived relaxing factors and its production is regulated by flow-induced mechanical stimuli, or fluid shear stress [13–15]. Recent in vitro studies have shown that pulsatile stimulation enhances endothelium-derived nitrous oxide (EDNO) release in cultured endothelial cells and isolated vessels [14, 16], however, such an effect of pulsatility has not yet been adequately investigated in the in vivo studies.

Therefore, to understand the essential role of pulsatility in systemic circulation, this study was designed to demonstrate one of the physiologic mechanisms of pulsatile flow-induced systemic vasodilation through EDNO, and to investigate what factors in pulse wave contribute to the effects in an in vivo model.

To exclude the potentially confounding effect of the sympathetic nerve system, the efferent sympathetic nerve activity was blocked by the administration of hexamethonium. We also used indomethacin to block endothelium-derived prostacyclin, which production has shown to be enhanced by fluid pulsatility [17, 18], to focus on the effect of pulsatility on the EDNO release.

	Material and methods

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Surgical preparation
Ten adult mongrel dogs weighing 15.7 to 24.3 kg (19.5 ± 2.8 kg) were used in this study. Anesthesia was induced with an intravenous thiamyral sodium (25 mg/kg) injection. After endothoracheal intubation, mechanical ventilation was started by using an artificial respirator with a mixture of room air and 100% oxygen. Then 10 µg/kg of fentanyl was slowly injected. The arterial blood gases and blood pH were maintained within the physiologic ranges by adjusting the respiratory rate and tidal volume and also by administering sodium bicarbonate. The arterial pH, PCO₂, and PO₂ were kept at the range of 7.35 to 7.45, 35 to 45 mm Hg, and 90 to 150 mm Hg, respectively. Next, the dogs were placed in the right lateral decubitus position and catheters were inserted into the descending aorta and inferior vena cava through the left femoral artery and vein for pressure monitoring, blood sampling, and drug administration. Anesthesia was then maintained with a continuous intravenous infusion of fentanyl (10 µg/kg/hour), midazolam (0.5 mg/kg/hour), and vecuronium bromide (0.2 mg/kg/hour). The proximal site of the right femoral artery was carefully dissected and an ultrasonic flow probe was placed around the artery. The pressure values and heart rate were monitored continuously on a multichannel oscillograph (Polygraph 360 system, NEC San-ei, Kogyo Tokyo, Japan), and all hemodynamic variables were recorded on an analog-to-digital converter (MacLab System, ADInstruments, Ltd, Dunedin North, New Zealand) simultaneously. A left thoracotomy was then performed through the 5th intercostal space. After 300 U/kg of heparin was given, two cannulas (No. 28F; Polystan A/S, Varlose, Denmark) were inserted into the left atrium through the appendage and into the left ventricle through the apex. An infusion cannula (5.2-mm Sarns; Sarns, 3M Health Care, Ann Arbor, MI) was inserted into the thoracic descending aorta. Left heart bypass was established with a centrifugal pump (Biopump; Bio-Medicus, Inc, Eden Prairie, MN) and a pulsatile wave was produced by an air-driven, diaphragm-type blood pump (TCT 20; Toyobo Co, Ltd, Osaka, Japan). These pumps were serially connected. The centrifugal pump flow rate was increased and the circulatory blood volume, if necessary, was modulated to introduce all blood from the left-side heart into the extracorporeal circuit. A clamp-on type ultrasonic flow probe was placed on the line. The right femoral artery flow rate and pump flow rate were measured continuously (two channel ultrasonic blood flowmeter T-208; Transonic Systems Inc, Ithaca, NY). A blood reservoir was placed within the circuit to control the circulatory blood volume to maintain a constant systemic circulatory blood flow and keep the same hematocrit level. No drug was used to control systemic pressure. A heat exchanger was also placed within the circuit to control the blood temperature. The esophageal temperature and blood temperature were carefully kept at the range of 37° to 38 °C, respectively. The hematocrit and electrolytes were maintained at the same values throughout the experiment within each case, and the average hematocrit value was 30.9%. Indomethacin (3 mg/kg) and hexamethonium bromide (5 mg/kg) were administered 30 minutes before the initiation of the extracorporeal circulation. Hexamethonium bromide (5 mg/kg/hour) was also continuously infused throughout the experiment.

Humane animal care
All animals received humane care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" prepared by the National Academy of Sciences and published by the National Institutes of Health (NIH Publication No. 86-23, revised 1985). This experiment was reviewed by the Committee of the Ethics on Animal Experiments in the Faculty of Medicine, Kyushu University and the Law (No.105) and Notification (No. 6) of the Japanese government.

Study protocol
Effects of pulse rate on the basal hemodynamics
Thirty minutes after the initiation of the extracorporeal systemic perfusion, pulse rate was changed in 4 steps: 0, 30, 60, and 120 bpm. Pulse pressure was set at 50 mm Hg by adjusting the driving pressure of the pneumatic pump. The mean systemic blood pressure, central venous pressure, femoral artery flow rate, and systemic flow rate were measured. Total systemic vascular resistance (TSVR) was calculated by the following formula: . The ratio of the femoral artery flow rate to the systemic flow rate, the maximal rate of pressure velocity (dp/dt max), and the maximal rate of flow velocity in the femoral artery (df/dt max) were also calculated. Each step took 10 minutes and the record of the hemodynamic variables and blood sampling were done in the last 2 minutes. The pump flow rate was kept constant throughout the experiment and the direction of the pulse rate change (step up or step down) was randomly decided.

Effects of pulse pressure on the basal hemodynamics
After the experiment of pulse rate changing, pulse pressure was changed in 3 steps: 0, 20, and 50 mm Hg with a fixed pulse rate of 120 bpm. Blood pressure, central venous pressure, femoral artery flow rate, and systemic flow rate were all measured. TSVR, the ratio of femoral flow rate to systemic flow rate, dp/dt max and df/dt max in the femoral artery were also compared. The pump flow rate was kept constant throughout the measurements. Each step took 10 minutes and the record of the hemodynamic variables and blood sampling were done in the last 2 minutes. The direction of the pulse pressure change (step up or step down) was randomly decided.

Effects of pulse rate and pulse pressure on the plasma NO^2-/NO^3- concentration
Blood samples were taken from the central venous catheter and then centrifuged by 3000 rpm for 40 minutes, and the plasma was immediately frozen at -80 degrees until the measurements were performed. Nitrite (NO^2-) and Nitrate (NO^3-), the stable metabolites of nitric oxide, were measured by a chemiluminescence NO analyzer (Sievers, Inc, Boulder, CO). Briefly, the plasma was incubated with Aspergillus nitrate reductase to reduce nitrate into nitrite and then convert nitrite into NO by the addition of hydrochloric acid. In the analyzer, the amount of NO was determined by measuring the luminescence generated in the presence of ozone [19].

Effects of L-NAME on the hemodynamics
Fifteen minutes after the end of the administration of N^G-Nitro-L-arginine Methyl Ester (L-NAME) (20 mg/kg) (Sigma Chemical Co, St. Louis, MO), an L-arginine analogue that has been shown to specifically inhibit the formation of nitric oxide from the L-arginine, the hemodynamic variables were repeatedly measured in the two study protocol. The percent changes of TSVR were calculated and compared before and after L-NAME to investigate the effects of the frequency and amplitude of pulse wave on EDNO release.

Statistics
All values are expressed as the mean ± standard error of the mean. The changes in the hemodynamic variables in step changes regarding pulse rate and pulse pressure were compared by one-way repeated measures of analysis of variance. A comparison of the variables before and after L-NAME was performed with the paired t test. Differences in the percent change curve of TSVR in step changes in pulse rate and pulse pressure before and after L-NAME were compared by two-way repeated measures of analysis of variance. Differences were considered to be significant when the p value was less than 0.05.

	Results

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Effects of pulse rate on the basal hemodynamics and plasma NO^2-/NO^3- concentration
In this section, pulse pressure was set at 49.2 ± 2.1 mm Hg respectively and a summary of the hemodynamic variables in response to the step changes in pulse rate is shown in Table 1. Blood pressure and TSVR decreased significantly in response to the rise in pulse rate (p = 0.002 and < 0.001). The ratio of the femoral artery flow rate to the systemic flow rate, although not significant (p = 0.076), tended to increase with pulse rate (Table 1). Neither dp/dt max nor df/dt max changed at these three different pulse rates (Fig 1). There was a small but significant increase in plasma NO^2-/NO^3- concentration in response to the rise in pulse rate (p = 0.003), which suggests, although indirectly, that EDNO release is stimulated by frequency of pulse wave (Fig 2A).

View larger version (21K): [in this window] [in a new window]   Fig 1. The bar graphs show pulse rate-related changes in (A) dp/dt max (the maximum rate of pressure velocity) and (B) df/dt max (the maximum rate of flow velocity) before and after L-NAME at a fixed pulse pressure of 50 mm Hg. No differences were observed in the two variables at 30, 60, and 120 bpm, and they were not changed by L-NAME. Values are the mean ± standard error of the mean. (L-NAME = NG-Nitro-L-arginine Meythl Ester; PR= pulse rate.)

View larger version (14K): [in this window] [in a new window]   Fig 2. The bar graph shows changes in plasma NO2-/NO3- concentration (A). The line graph shows percent changes in total systemic vascular resistance before () and after (•) L-NAME (B). Note that plasma NO2-/NO3- concentration showed small but significant increase in response to the rise in pulse rate (p = 0.003) and that the changes in total systemic vascular resistance associated with pulse rate disappeared after L-NAME. Values are the mean ± standard error of the mean. (PR = pulse rate.) *p < 0.001 compared by two-way repeated measures of analysis of variance.

View larger version (17K): [in this window] [in a new window]   Fig 3. The bar graphs show pulse pressure-related changes in (A) dp/dt max (the maximum rate of pressure velocity) and (B) df/dt max (the maximum rate of flow velocity) before and after L-NAME at a fixed pulse rate of 120 bpm. Both dp/dt max and df/dt max significantly increased in response to the rise in pulse pressure. These variables were not changed by L-NAME. Values are the mean ± standard error of the mean. (PR = pulse rate.)

View larger version (13K): [in this window] [in a new window]   Fig 4. The bar graph shows changes in plasma NO2-/NO3- concentration (A). The line graph shows percent changes in total systemic vascular resistance before () and after (•) L-NAME (B). Note that plasma NO2-/NO3- concentration showed a small but significant increase in response to the rise in pulse pressure (p < 0.001) and that the changes in total systemic vascular resistance associated with pulse pressure disappeared after L-NAME. Values are the mean ± standard error of the mean. (PP = pulse pressure.) *p < 0.001 compared by two-way repeated measures of analysis of variance.

	Comment

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
The most important finding in this study is that both the frequency and amplitude of pulse wave in systemic perfusion independently modulates EDNO release and thus regulates the systemic hemodynamics in an in vivo condition. This finding is supported by the observation that TSVR decreased in a pulse rate- and pulse pressure-dependent manner and that these responses were completely abolished by L-NAME, a potent inhibitor of NO synthase. The fact that plasma NO^2-/NO^3- concentration increased in response to the rise in both pulse rate and pulse pressure also support this finding.

It is generally accepted that endothelial cells act as a "biosensor," which detects the changes in the blood flow and regulates the vascular tone by releasing various vasoactive substances continuously to maintain local circulation [13, 14, 18, 20]. Nitric oxide is one of the endothelium-derived relaxing factors, and it also has various other functions such as antiplatelet aggregation [21] and antileukocyte activation [22], and its production is regulated by mechanical stress produced by the blood flow, or fluid shear stress [13–15]. A number of in vitro studies have demonstrated the pulsatile flow, which is exposed on endothelial cells "per se" as a stimulating factor for nitric oxide production [14, 16]. In the in vivo studies, some authors demonstrated the coronary artery in dogs to show pulse pressure- and pulse frequency-related vasodilation that is, at least partially, associated with EDNO release [23, 24], however, these effects of blood pulsatility on the systemic hemodynamics through EDNO have not yet been adequately investigated.

Under a constant systemic flow rate, step increase in pulse rate at a fixed pulse pressure caused a significant decline in TSVR. This change disappeared after L-NAME, suggesting that EDNO is responsible for pulse rate-dependent systemic vasodilation. Several studies performed either in conduit vessels or coronary arteries have demonstrated EDNO to be released in response to changes in pulsatility. Hutcheson and coworkers [16], using cascade bioassay, indicated that the flow-induced EDNO release was enhanced by an increase in pulse frequency and was maximum at 4 Hz in isolated rat vessels. More recently, Canty and Schwartz [23] demonstrated EDNO production to be primarily responsible for pulse frequency-related coronary vasodilation in conscious dogs. These results are consistent with our finding on the systemic circulation. Based on our results, it is conceivable that the frequency of pulse wave itself is suggested to be an independent stimulating factor for EDNO release because TSVR decreased in response to the rise in pulse rate under a fixed pulse pressure and under the same degrees of dp/dt max and df/dt max at pulse rates of 30, 60, and 120 bpm.

On the other hand, in the pulse pressure changing protocol with the fixed pulse rate, both dp/dt max and df/dt max significantly increased in response to the rise in pulse pressure. Because EDNO production is shown to be influenced by changes in flow rather than changes in intravascular pressure [25], consequently an increase in the maximum rate of flow velocity (df/dt max) rather than that in the maximum rate of pressure velocity (dp/dt max) may be involved in pulse pressure-related, EDNO-mediated systemic vasodilation. Some studies indicated the presence of pulse pressure- related, endothelium-independent vasodilation in both the coronary artery and isolated conduit vessels [16, 26], however, in this study, pulse pressure-related systemic vasodilation is shown to be endothelium-dependent because pulse pressure-related vasodilation completely disappeared after the blockade of EDNO production.

It is necessary to note that the degree of the systemic flow rate could influence the experimental results. The advantageous effects of a pulsatile cardiopulmonary bypass on the plasma lactate level and oxygen consumption were evident at a systemic flow rate of below 80 mL/kg/minute; however, at a higher flow rate of 100 mL/kg/minute or more, no such differences were detected [27]. In addition, Tominaga and coworkers [9] reported that in unanesthetized chronic animals, the cardiovascular system can adjust to a nonpulsatile blood flow and can maintain oxidative metabolism with a systemic flow rate of more than 90 mL/kg/minute. Therefore, it is possible that the lower systemic flow rate in this study (65.2 ± 8.7 mL/kg/minute) may induce a beneficial effect of pulsatile flow.

It is also important to recognize that the response of endothelial cells to mechanical stimuli varies with time [28]. In the early phase after the initiation of flow stimuli, EDNO production is thought to be primarily regulated by Ca²⁺-dependent activation and also Ca²⁺-independent phosphorylation of constitutive NO synthase in endothelial cell. In the late phase, the amount of NO synthase expression changes according to the level of shear stress that is exposed on endothelial cells [29]. In this study, with a short duration of each flow pattern, the amount of NO synthase expression seems to be unchanged, therefore, the amount of EDNO is thought to directly correlate with the NO synthase activity enhanced by pulsatile stimulation through the Ca²⁺-dependent and the Ca²⁺-independent pathway, or both.

According to the findings in this study, it could be conceivable that a pulsatile circulatory assist device may thus be more beneficial for patients with acute cardiac failure or cardiogenic shock because pulse-related vasodilation could be expected to counteract the sympathogenic vasoconstriction more strongly and thus maintain the peripheral circulation more effectively because of its stimulus effect for EDNO release.

Study limitation
Because it is extremely difficult to exclude neurogenic influence on vascular tone when blood pressure changes, we used Hexamethonium bromide that is not common in clinical situations. We also used Indomethacin to exclude the effects of prostacyclin, one of the endothelium-derived relaxing factors, in order to focus on EDNO. These drugs may make this study model irrelevant to patients undergoing cardiovascular procedure. However, our findings clearly indicate that pulsatile flow enhances EDNO release and thus, at least partially, contributes to decreased systemic vascular resistance.

In conclusion, we herein demonstrated that both the frequency and the amplitude of pulse wave in the systemic circulation are independent stimulant factors for EDNO release in an in vivo condition. However, this study showed only an acute response to pulsatile flow, therefore, further studies are required to investigate the adaptation and compensation to chronic nonpulsatile flow in order to fully comprehend the essential physiologic role of pulsatility in circulation.

	Acknowledgments

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This study was partly supported by a grant-in-aid for Scientific Research (No. 07457296) from the Ministry of Education, Science and Culture of Japan. The authors would like to thank Noriko Nakahara for her valuable technical assistance. We are also grateful to Kikuko Iwaki for her help in performing the biochemical analysis.

	References

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Shigeki Morita Munetaka Masuda Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nakano, T. Articles by Yasui, H. Search for Related Content PubMed PubMed Citation Articles by Nakano, T. Articles by Yasui, H. Related Collections Cardiac - physiology