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CARDIOVASCULAR ANESTHESIA

Increased Plasma Concentrations of the Mature Form of Adrenomedullin During Cardiac Surgery and Hepatosplanchnic Hypoperfusion

Daisuke Yoshikawa, MD^*, Fuminori Kawahara, MD^*, Nobuhiro Okano, MD, Haruhiko Hiraoka, MD^*, Yuji Kadoi, MD^*, Nao Fujita, MD, Toshihiro Morita, MD, and Fumio Goto, MD^*

*Department of Anesthesiology and Reanimatology, Gunma University School of Medicine, Maebashi, Japan; Department of Anesthesiology, Saitama Cardiovascular and Pulmonary Center, Saitama, Japan; and Department of Anesthesiology, Keiyu Orthopedic Hospital, Gunma, Japan

Address correspondence and reprint requests to Daisuke Yoshikawa, MD, Department of Anesthesiology and Reanimatology, Gunma University School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan. Address e-mail to dyossyjp{at}ybb.ne.jp

	Abstract

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Adrenomedullin is a potent vasodilatory peptide. Plasma adrenomedullin (AM) concentrations increase during and after cardiopulmonary bypass (CPB). However, the cause of this increase and its site of production have not been identified. We investigated the role of the hepatosplanchnic and cerebral circulations in the increase of plasma AM and investigated whether tissue hypoxygenation is a cause of the AM increase seen during CPB. We measured plasma total AM (AM-T) and the biologically active form of AM, mature AM (AM-m), in seven patients undergoing CPB. Both plasma AM-T and AM-m concentrations increased significantly 60 min after weaning from CPB. At this time point, arterial AM-T and AM-m concentrations were 18-fold and 10-fold larger, respectively, than baseline values measured after the induction of anesthesia. The plasma AM-m concentration and the ratio of AM-m/AM-T in blood from the hepatic vein were significantly larger than those from the radial artery or jugular bulb. The AM-m/AM-T ratio decreased during CPB, suggesting that production of the intermediate form of AM, AM-glycine, is more than that of AM-m. The oxygen tension of the hepatic venous blood (PhvO2) was significantly less during CPB. Plasma AM-m concentrations sampled from the hepatic vein showed a significant negative correlation with PhvO2 at 10 min (r = 0.824; P < 0.02) and 60 min (r = 0.828; P < 0.02) after the onset of CPB. These data suggest that the hepatosplanchnic circulation is an important source of AM-m during CPB. Furthermore, hypoxygenation of the hepatosplanchnic region may be an important cause of this AM-m increase.

IMPLICATIONS: Plasma adrenomedullin has been reported to increase during and after cardiac surgery. We found that the concentration of the biologically active mature form of adrenomedullin in the hepatic vein is significantly larger than in the radial artery or jugular bulb and that it shows a significant negative correlation with oxygen tension and saturation of hepatic venous blood.

	Introduction

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Human adrenomedullin (AM) is a potent vasodilator peptide consisting of 52 amino acid residues with an amidated C-terminal tyrosine and a ring structure formed by an intramolecular disulfide bond (1). AM has various physiologic actions in the cardiovascular system, including promoting diuresis and natriuresis, inhibiting aldosterone secretion, and increasing cardiac output (2,3). Plasma concentrations of AM increase in patients with abnormal cardiovascular function, such as hypertension, congestive heart failure, myocardial infarction, pulmonary hypertension, preeclampsia, and chronic renal failure (2,3). Despite the wide tissue distribution of AM and its broad biological activity, a clear physiological role for AM in the control of organ function has not been identified.

Sequence analysis of cloned human AM complementary DNA shows that the human AM precursor consists of 185 amino acids with a putative signal peptide (4). AM is produced from its precursor by a two-step enzymatic reaction. First, the AM precursor is converted to glycine-extended AM (AM-gly), a 53-amino acid inactive intermediate. Subsequently, AM-gly is converted to active, mature AM (AM-m), a 52-amino acid peptide with a C-terminal amide structure, by enzymatic amidation (5). Kitamura et al. (5) have reported that two molecular forms of AM—AM-m and AM-gly—circulate in human blood and that AM-gly is the major circulating molecular form in human plasma. Several studies have investigated the secretion and clearance site of AM-m and AM-gly in humans. Hirayama et al. (6) reported that the vasculature of the lower extremities and heart produce and secrete AM-m and that the lung is the clearance site of circulating AM-m. Nishikimi et al. (7) reported that plasma AM-m concentrations are significantly smaller after they pass through the pulmonary circulation than at venous sites. In contrast, there are no significant differences in arterial and venous AM-gly concentrations. These results suggest that AM-m is produced in many organs and released into veins. Furthermore, the main clearance site of AM-m appears to be the lungs.

Increased plasma concentrations of AM during and after cardiac surgery have been reported (8–10). Several investigators have attempted to determine the sites of AM production and the role of AM increase during and after cardiac surgery; however, the mechanism regulating AM synthesis during cardiopulmonary bypass (CPB) is obscure. These studies used a radioimmunoassay (RIA) that recognizes all forms of the AM molecule (total AM, or AM-T). Biologically active AM-m levels have not been analyzed. It has been reported that hypoxia increases AM messenger RNA (mRNA) levels in a human colorectal carcinoma cell line (11) and also in primary cultures of rat ventricular myocytes (12), suggesting that AM gene transcription can be regulated by tissue oxygen tension. Both hypoxia and functional anemia upregulate AM and AM-receptor mRNAs in a variety of organs in vivo (13). CPB may cause tissue hypoxia during cardiac surgery. Neurological injury after CPB is well described, and cerebral ischemia, presumably due to embolism or hypoperfusion, is a possible cause (14). Inoue et al. (9) reported that AM production in the cerebral vasculature is significantly enhanced after CPB and correlates with aortic cross-clamping time. Fujioka et al. (15) reported that plasma concentrations of AM-m from the radial artery and jugular bulb are significantly increased after clamping and CPB compared with baseline values. Furthermore, the jugular venous oxygen saturation (SjvO₂) correlates with plasma AM-m concentrations in the jugular bulb before clamping, after clamping, and after CPB. These data suggest a relationship between AM production and cerebral oxygen balance during cardiac surgery.

We have previously reported that oxygen consumption exceeds oxygen delivery in the hepatosplanchnic circulation during normothermic CPB (16). Specifically, the hepatic venous oxygen saturation (ShvO₂) decreases from the baseline value 10 and 60 min after the onset of CPB. We hypothesized that, in addition to the cerebral circulation, the hepatosplanchnic circulation is also a site of AM production and that tissue hypoxygenation can activate the AM system during and after CPB. Therefore, we determined the changes in plasma AM-T, AM-gly, and AM-m concentrations simultaneously sampled from the hepatic vein, jugular bulb, and radial artery. We determined whether the cerebral and hepatosplanchnic circulation are sources of plasma AM. Furthermore, we analyzed the relationship between an increase in the AM concentration and the oxygen tension from each site to elucidate the relationship between tissue hypoxygenation and AM production during and after cardiac surgery.

	Methods

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This study was approved by our institutional human investigation committee, and written, informed consent was obtained from all participants. We studied five patients undergoing elective coronary artery bypass grafting for ischemic heart disease and two patients undergoing mitral valve or aortic valve replacement for valve dysfunction.

After premedication with 10 mg of oral diazepam, anesthesia was induced with 0.2 mg/kg of midazolam and 5 µg/kg of fentanyl. Tracheal intubation was facilitated with 0.1 mg/kg of vecuronium. Anesthesia was maintained with 15 µg/kg of fentanyl, vecuronium, 4 mg · kg^-1 · h^-1 of propofol, and 50% oxygen in air. In addition to radial and pulmonary artery catheters for routine monitoring, a hepatic venous catheter (Harmac Medical Products, Buffalo, NY) was inserted into the right hepatic vein via the right femoral vein under fluoroscopic guidance. Internal SjvO₂ was monitored with a 4F fiberoptic oximetry oxygen saturation catheter (dual-lumen oximetry catheter; Baxter) inserted retrogradely into the right jugular bulb.

Our nonpulsatile CPB system uses a membrane oxygenator primed with crystalloid solution and a pump flow of 2.3–2.5 L · min^-1 · m^-2. A mean arterial blood pressure of 50–90 mm Hg was maintained by phenylephrine infusion, and hematocrit was maintained more than 20% by transfusion of packed red blood cells. Nasopharyngeal temperature was maintained >35°C. After CPB, the cardiac index was maintained >3.0 L · min^-1 · m^-2 by administration of dopamine, dobutamine, or both.

Blood samples were obtained from the radial artery, the hepatic vein, and the jugular bulb simultaneously at the following times: 1) after the induction of anesthesia (T1); 2) immediately before CPB (T2); 3) 10 min (T3) and 4) 60 min (T4) after the onset of CPB; 5) immediately after aortic declamp (T5); 6) 60 min after weaning from CPB (T6); and 7) 24 h after the end of the operation (T7). Arterial or venous pH, partial pressure of oxygen, base excess, and hematocrit were measured with a commercial blood gas analyzer (ABL-625; Radiometer, Copenhagen, Denmark). To perform plasma assays, blood samples were collected in chilled tubes containing disodium EDTA (1 mg/mL) and aprotinin (500 kallikrein-inhibiting units/mL) and were centrifuged immediately at 4°C. Plasma samples were frozen and stored at -80°C until assayed.

Both AM-m and AM-T were measured by RIA by using commercially available kits (AM-m RIA Shionogi and AM RIA Shionogi; Shionogi Co., Osaka, Japan). The details of this RIA are described elsewhere (17,18). These assay systems use two monoclonal antibodies against human AM, one recognizing a ring structure of human AM (both kits) and the other recognizing either the C-terminal sequence (AM-m kit) or AM (25–36) (AM-T kit). This sandwich immunoassay allows measurement of human AM-m or AM-T without the extraction of plasma. The minimum quantity of human AM-m or AM-T detectable with these assays is 0.5 pmol/L in both kits. The coefficients of variation for the intraassay and interassay values based on several blood samples were 4.4%–8.2% and 5.5%–8.3% for the AM-m assay and 3.4%–7.3% and 5.8%–7.6% for the AM-T assay, respectively. The recovery rate for 5–100 pmol/L of human AM added to plasma samples was 91%–118% for the AM-m assay and 89%–118% for the AM-T assay, respectively. The plasma AM-gly concentration was calculated with the following formula: AM-gly = AM-T - AM-m.

Data are expressed as the mean ± SD. Plasma concentrations of AM-T, AM-gly, and AM-m and the AM-m/AM-T ratio were analyzed by two-way analysis of variance for repeated measures followed by a post hoc Scheffé test. Correlations between the concentrations of plasma AM-m or AM-T and oxygen tension at each time point were analyzed by calculating Pearson’s correlation coefficients. A P value <0.05 was considered statistically significant.

Results
The plasma concentrations of AM-T and AM-m and the AM-m/AM-T ratio in the healthy individuals (n = 20) were 12.0 ± 2.3 pmol/L, 1.14 ± 0.22 pmol/L, and 0.10 ± 0.033, respectively. Patients’ characteristics are shown in Table 1. Hemodynamic variables and oxygen tension are presented in Table 2. The hepatic venous oxygen tension (PhvO₂) decreased significantly during CPB. In contrast, there was no significant change in the jugular bulb oxygen tension during CPB. Patients whose PhvO₂ was lower at T1 tended to show even smaller values at T2, T3, and T4 (data not shown). There were significant correlations between the PhvO₂ at T1 and T2 (r = 0.771; P < 0.04), T1 and T3 (r = 0.796; P < 0.03), and T1 and T4 (r = 0.877; P < 0.01). Plasma AM-T, AM-gly, and AM-m concentrations increased during cardiac surgery (Fig. 1). Compared with these values after the induction of anesthesia (T1), concentrations of all three types of AM were significantly increased and reached peak levels 60 min after weaning from CPB (T6). The AM-m concentration was also significantly increased 60 min after the onset of CPB (T4) and immediately after aortic declamp (T5). AM-m concentrations sampled from the hepatic vein were significantly larger than those from the radial artery (P = 0.0002) or jugular bulb (P = 0.0004). There were no significant differences in AM-T or AM-gly concentrations among the three sampling sites.

View larger version (12K): [in this window] [in a new window]   Figure 1. Changes in plasma adrenomedullin concentration during and after cardiac surgery. T1 = after the induction of anesthesia; T2 = immediately before cardiopulmonary bypass; T3 = 10 min after the onset of cardiopulmonary bypass; T4 = 60 min after the onset of cardiopulmonary bypass; T5 = immediately after aortic unclamping; T6 = 60 min after weaning from cardiopulmonary bypass; T7 = 24 h after the end of the operation. Values are expressed as mean ± SD. **P < 0.01 compared with T1; *P < 0.05 compared with T1.

View larger version (19K): [in this window] [in a new window]   Figure 2. Changes in the adrenomedullin-mature/adrenomedullin-total ratio during and after cardiac surgery. T1 = after the induction of anesthesia; T2 = immediately before cardiopulmonary bypass; T3 = 10 min after the onset of cardiopulmonary bypass; T4 = 60 min after the onset of cardiopulmonary bypass; T5 = immediately after aortic unclamping; T6 = 60 min after weaning from cardiopulmonary bypass; T7 = 24 h after the end of the operation. Values are expressed as mean ± SD. #P < 0.01 compared with T2; $P < 0.01 compared with T3.

View larger version (22K): [in this window] [in a new window]   Figure 3. Relationship between adrenomedullin-total (AM-T) or adrenomedullin-mature (AM-m) concentrations and oxygen tension in the hepatic vein. PhvO2 = partial oxygen tension of the hepatic vein; CPB = cardiopulmonary bypass. Values are expressed as mean ± SD.

	Discussion

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Previous studies have shown that the plasma AM-T concentration significantly increases during or after CPB (8–10). Our data are consistent with these reports. However, the peak level of AM-T seen in our study was substantially larger than that described in previous reports. This is because our AM-T assay directly measures AM-T in human plasma without a prior extraction step. Using the same assay system, Ohta et al. (18) reported that the AM-T concentrations detected by this method were approximately three times larger than those measured by RIA, the methodology used in previous studies. They also reported that the presence of bilirubin, total lipid, and hemoglobin in human plasma had no influence on the assay. Furthermore, the plasma AM-m concentration also increased during cardiac surgery. The AM-m concentrations measured from the radial artery and jugular bulb were consistent with those previously reported by Fujioka et al. (15). However, in their study, the AM-m concentration in both the radial artery and jugular bulb decreased at 20 minutes after weaning from CPB. In our study, the AM-m concentrations sampled from both sites increased and peaked 60 minutes after weaning from CPB. In the report of Nishikimi et al. (10), the plasma AM-T concentrations continued to increase after CPB and peaked six hours after surgery. Inoue et al. (9) reported that the plasma AM-T concentrations were four times larger after CPB than those measured during CPB. In contrast, Nagata et al. (8) reported that the plasma AM-T concentrations were slightly smaller 20 minutes after weaning from CPB than those measured during CPB. Generally, the AM-m changes parallel those seen for AM-T and AM-gly (7). In this study, the plasma AM-T concentration was three times larger 60 minutes after weaning from CPB than those measured during CPB. Although the AM-m/AM-T ratio decreased during CPB, it is difficult to determine whether AM-m selectively decreased when the AM-T and AM-gly increased. Discrepancies between our findings and those of Fujioka et al. (15) may be due, in part, to differences in patients, protocols, and surgeries.

In this study, the plasma AM-m concentrations measured in the hepatic vein were significantly larger than those from the radial artery or jugular bulb. Hirayama et al. (6) and Nishikimi et al. (7) have reported that the pulmonary circulation is the predominant site of AM-m clearance. This may explain the observed difference in plasma AM-m concentrations between the hepatic vein and radial artery. However, the hepatic vein AM-m concentration was also significantly larger than the jugular bulb AM-m concentration. Furthermore, the AM-m/AM-T ratio for blood from the hepatic vein was significantly larger than that from the radial artery or jugular bulb. Because there were no differences in the AM-gly concentrations among the three sampling sites, AM-m production appears to be selectively increased in the hepatosplanchnic circulation. These data suggest that the hepatosplanchnic circulation is an important source of AM-m during cardiac surgery. In this study, there were significant differences in the AM-m concentrations among sampling sites, whereas there were no differences in the concentrations of AM-T and AM-gly. This may be explained by the fact that significant differences in AM-m concentrations are masked when the differences in AM-T concentrations are measured between sampling sites, because the AM-T concentration is approximately 10 times larger than the AM-m concentration.

Although the major circulating form of AM is AM-gly, the biologically active form of AM is AM-m. AM is produced in two steps: AM-gly, an intermediate 53-amino acid form, is produced from an AM precursor, and then its C terminus is enzymatically amidated, which converts it into AM-m. The AM-m/AM-T ratio in the hepatic vein decreased continuously during CPB. The AM-m/AM-T ratio in the jugular bulb and radial artery increased when CPB was initiated. Thereafter, these values gradually decreased during CPB. Production of AM-T and AM-m was significantly increased and peaked 60 minutes after weaning from CPB. At this time point, plasma concentrations of AM-T and AM-m were largest, whereas the AM-m/AM-T ratio was at its minimum. This suggests that the enzyme activity of the first step is more activated than that of the second step during and immediately after CPB. The reestablishment of pulmonary circulation may also be responsible for a further decrease in the AM-m/AM-T ratio for the radial artery sample 60 minutes after weaning from CPB. At 10 and 60 minutes after the onset of CPB, the AM-m/AM-T ratio in the radial artery increased significantly when compared with the value immediately before CPB. Because the pulmonary circulation is the predominant site of AM-m clearance, these increases in the AM-m/AM-T ratio in the radial artery after the initiation of CPB may reflect a reduction in AM-m clearance in the pulmonary circulation during CPB. However, the increase in the ratio may reflect increased cerebral production of AM-m after the initiation of CPB, because the ratio for the jugular bulb increased and the ratio for the hepatic vein decreased. Inoue et al. (9) reported that AM-T production in the cerebral vasculature was significantly enhanced after CPB. However, they did not analyze cerebral AM-T production before and during CPB. In this study, there were no differences in AM-m concentration or the AM-m/AM-T ratio between the radial artery and jugular bulb. These data do not clarify whether the cerebral circulation is a site of production of AM during CPB. Further studies are needed to elucidate the significance of the cerebral circulation as a site of AM-m production during CPB.

Minamino et al. (19) have examined more than 30 types of cultured cells and found that all of the examined cells secreted significant amounts of AM into the media. In particular, fibroblasts and vascular smooth muscle cells synthesize and secrete AM at relatively fast rates. AM gene expression and release are mainly regulated by inflammation-related substances, such as tumor necrosis factor (TNF)-, interleukin-1ß, lipopolysaccharide, and glucocorticoids. These substances stimulate AM gene expression and secretion in fibroblasts, vascular smooth muscle cells, and endothelial cells, whereas transforming growth factor-ß and interferon- generally suppress AM gene expression. Because most cells do not contain secretory granules, it has been suggested that AM is designed to exert its function as a mediator of local communication for cells, in addition to acting as an endocrine or circulatory factor.

Previous reports have shown that AM production in the vessel wall is regulated at the level of gene expression. It has been demonstrated that AM is secreted via constitutive pathways without intermediate storage in secretory granules (20). Furthermore, the mode of gene expression and the secretion of AM in nonendocrine cell types suggests that AM elicits its effects not in an immediate-early phase, but rather in a delayed phase, of the physiologic reaction, because it usually takes one to two hours to observe a significant increase in AM secretion after stimulation. This may explain the significant increase and peak concentrations of AM-m that were observed 60 minutes after CPB.

In this study, the hepatic venous concentration of AM-m correlated negatively with PhvO₂ at 10 and 60 minutes after the initiation of CPB. It was reported that hypoxia or tissue hypoxygenation increases AM mRNA expression in a human colorectal carcinoma cell line; in primary cultures of rat ventricular myocytes (11,12); and in the brain, liver, lung, kidney, and heart (13). We have reported that oxygen consumption exceeds oxygen delivery specifically in the hepatosplanchnic region during normothermic CPB, resulting in a marked reduction in ShvO₂ (16). In this study, the oxygen tension in the hepatic vein selectively decreased during CPB. Hypoxygenation of the hepatosplanchnic region may stimulate AM-m production during CPB. However, it took several hours for AM gene expression to increase under hypoxic conditions (11,12). There may be a lag time between stimuli for AM production and the increase in the plasma AM concentration. As mentioned in the Results section, there were significant correlations in PhvO₂ between T1 and T2, between T1 and T3, and between T1 and T4. Patients whose PhvO₂ was less after the induction of anesthesia tended to have smaller values immediately before and during CPB. This may explain the negative correlation between AM-m concentrations and PhvO₂ at 10 and 60 minutes after the initiation of CPB, even if there is a lag time between stimuli for AM production and the increase in the plasma AM concentration. Furthermore, there was a negative correlation between the peak AM-m concentration and the lowest PhvO₂ during CPB. These data suggest that hepatosplanchnic hypoxygenation may be an important cause of increased AM expression after CPB.

Cytokines, shear stress, and hypoxia stimulate AM production (21,22). Among these factors, TNF- is the most potent stimulator of AM synthesis. CPB often induces systemic inflammatory responses and augments blood levels of chemotactic factors and proinflammatory cytokines (23). The presence of endotoxemia is relatively common in cardiac surgery (23,24). The gut has been proposed as the source of endotoxemia in cardiac surgery, and one possible mechanism by which this occurs is injury to the gut mucosal barrier because of hypoperfusion or insufficient oxygen delivery (23). Cytokines and endotoxin additively stimulate the production of AM in vascular smooth muscle cells (22). Furthermore, hypoxia increases TNF- production in human monocytes (25). These data suggest that cytokines and tissue hypoxia may additively stimulate AM production during CPB. On the basis of recent studies in AM transgenic mice, AM overexpression elicits resistance to lipopolysaccharide-induced hepatic injury, and this reduces mortality (26). AM may play a protective role in the CPB-induced systemic inflammatory responses.

Both the hyperkalemia and the hypothermia that are used with cardioplegia administration are associated with endothelial-independent vasoconstriction. In addition, endothelin (ET)-1, a potent vasoconstrictor, is released during CPB (27). This combination of vasoconstricting stimuli could create areas of relative underperfusion during CPB. AM inhibits platelet-derived growth factor-induced and thrombin-induced ET-1 production in vascular smooth muscle cells (28). Furthermore, AM has a potent and relatively long-lasting vasodilatory effect. AM appears to play an important physiologic role in counteracting the vasoconstrictive effects of ET-1 (29). AM may reduce tissue hypoperfusion by counteracting vasoconstricting substances such as ET-1 thorough autocrine or paracrine mechanisms. Hiramatsu et al. (30) have reported that imbalances between increased ET-1 and the relatively decreased AM concentrations after CPB used for the Fontan procedure could contribute to increased pulmonary vascular resistance. Further studies will be needed to elucidate the role and mechanisms underlying enhanced production of AM during cardiac surgery.

The major limitation of this study is the small sample size, resulting from the fact that the methods used were invasive and the measurements complex. In addition, this study investigated only the association between AM and PhvO₂ because the observational nature of this study did not permit a causal relationship to be established. An animal model will be needed to test whether tissue hypoxygenation of the hepatosplanchnic area activates the AM system during CPB.

In conclusion, plasma AM-T and AM-m levels increase during and after CPB. Biologically active AM-m concentrations in hepatic venous blood are larger than those from the radial artery and jugular bulb. The hepatosplanchnic circulation is an important source of AM-m during cardiac surgery, and hypoxygenation of the hepatosplanchnic region may be one of the causes of AM-m increases during cardiac surgery.

	Acknowledgments

 
Supported by a Grant-in-Aid (11671478) for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Tokyo, Japan.

	Footnotes

 
Presented in part at the annual meeting of the Japanese Society of Anesthesiologists, Fukuoka, Japan, April 17–21, 2002.

	References

Top Abstract Introduction Methods Discussion References

 

1. Kitamura K, Kangawa K, Kawamoto M, et al. Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma. Biochem Biophys Res Commun 1993; 192: 553–60.[Web of Science][Medline]
2. Jougasaki M, Burnett JC. Adrenomedullin potential in physiology and pathophysiology. Life Sci 2000; 66: 855–72.[Web of Science][Medline]
3. Hinson JP, Kapas S, Smith DM. Adrenomedullin, a multifunctional regulatory peptide. Endocr Rev 2000; 21: 138–67.[Abstract/Free Full Text]
4. Kitamura K, Sakata J, Kangawa K, et al. Cloning and characterization of cDNA encoding a precursor for human adrenomedullin. Biochem Biophys Res Commun 1993; 194: 720–5.[Web of Science][Medline]
5. Kitamura K, Kato J, Kawamoto M, et al. The intermediate form of glycine-extended adrenomedullin is the major circulating molecular form in human plasma. Biochem Biophys Res Commun 1998; 244: 551–5.[Web of Science][Medline]
6. Hirayama N, Kitamura K, Imamura T, et al. Secretion and clearance of the mature form of adrenomedullin. Life Sci 1999; 64: 2505–9.[Web of Science][Medline]
7. Nishikimi T, Matsuoka H, Shimada K, et al. Production and clearance sites of two molecular forms of adrenomedullin in human plasma. Am J Hypertens 2000; 13: 1032–4.[Web of Science][Medline]
8. Nagata N, Kitamura K, Kato J, et al. The effect of hypothermic cardiopulmonary bypass on plasma adrenomedullin in adult cardiac surgical patients. Anesth Analg 1997; 84: 1193–7.[Abstract]
9. Inoue S, Hayashi Y, Ohnishi Y, et al. Cerebral production of adrenomedullin after hypothermic cardiopulmonary bypass in adult cardiac surgical patients. Anesth Analg 1999; 88: 1030–5.[Abstract/Free Full Text]
10. Nishikimi T, Hayashi Y, Iribu G, et al. Increased plasma adrenomedullin concentrations during cardiac surgery. Clin Sci 1998; 94: 585–90.[Medline]
11. Nakayama M, Takahashi K, Murakami O, et al. Induction of adrenomedullin by hypoxia and cobalt chloride in human colorectal carcinoma cells. Biochem Biophys Res Commun 1998; 243: 514–7.[Web of Science][Medline]
12. Cormier-Regard S, Nguyen SV, Claycomb WC. Adrenomedullin gene expression is developmentally regulated and induced by hypoxia in rat ventricular cardiac myocytes. J Biol Chem 1998; 273: 17787–92.[Abstract/Free Full Text]
13. Hofbauer KH, Jensen BL, Kurtz A, Sadner P. Tissue hypoxygenation activates the adrenomedullin system in vivo. Am J Physiol 2000; 278: R513–9.
14. McLean RF, Wong BI, Naylor CD, et al. Cardiopulmonary bypass, temperature, and central nervous system dysfunction. Circulation 1994; 90(5 Pt 2): II250–5.
15. Fujioka S, Sasaki T, Hirata K, et al. The relationship between plasma concentration of mature adrenomedullin and jugular venous oxygen saturation during and after cardiopulmonary bypass. Anesth Analg 2001; 92: 837–41.[Abstract/Free Full Text]
16. Okano N, Hiraoka H, Owada R, et al. Hepatosplanchnic oxygenation is better preserved during mild hypothermic than during normothermic cardiopulmonary bypass. Can J Anaesth 2001; 48: 1011–4.[Web of Science][Medline]
17. Ohta H, Tsuji T, Asai S, et al. One-step direct assay for mature-type adrenomedullin with monoclonal antibodies. Clin Chem 1999; 45: 244–51.[Abstract/Free Full Text]
18. Ohta H, Tsuji T, Asai S, et al. A simple immunoradiometric assay for measuring the entire molecules of adrenomedullin in human plasma. Clin Chim Acta 1999; 287: 131–43.[Web of Science][Medline]
19. Minamino N, Kikumoto K, Isumi Y. Regulation of adrenomedullin expression and release. Microsc Res Tech 2002; 57: 28–39.[Web of Science][Medline]
20. Sugo S, Minamino N, Kangawa K, et al. Endothelial cells actively synthesize and secrete adrenomedullin. Biochem Biophys Res Commun 1994; 201: 1160–6.[Web of Science][Medline]
21. Sugo S, Minamino N, Shoji H, et al. Production and secretion of adrenomedullin from vascular smooth muscle cells: augmented production by tumor necrosis factor-alpha. Biochem Biophys Res Commun 1994; 203: 719–26.[Web of Science][Medline]
22. Sugo S, Minamino N, Shoji H, et al. Interleukin-1, tumor necrosis factor and lipopolysaccharide additively stimulate production of adrenomedullin in vascular smooth muscle cells. Biochem Biophys Res Commun 1995; 207: 25–32.[Web of Science][Medline]
23. Hall RI, Smith MS, Rocker G. The systemic inflammatory response to cardiopulmonary bypass: pathophysiological, therapeutic, and pharmacological considerations. Anesth Analg 1997; 85: 766–82.[Web of Science][Medline]
24. Andersen LW, Landow L, Baek L, et al. Association between gastric intramucosal pH and splanchnic endotoxin, antibody to endotoxin, and tumor necrosis factor-alpha concentrations in patients undergoing cardiopulmonary bypass. Crit Care Med 1993; 21: 210–7.[Web of Science][Medline]
25. Ghezzi P, Dinarello CA, Bianch M, et al. Hypoxia increases production of interleukin-1 and tumor necrosis factor by human mononuclear cells. Cytokine 1991; 3: 189–94.[Web of Science][Medline]
26. Shindo T, Kurihara H, Maemura K, et al. Hypotension and resistance to lipopolysaccharide-induced shock in transgenic mice overexpressing adrenomedullin in their vasculature. Circulation 2000; 101: 2309–16.[Abstract/Free Full Text]
27. Bando K, Vijayaraghavan P, Turrentine M, et al. Dynamic changes of endothelin-1, nitric oxide and cyclic GMP in patients with congenital heart disease. Circulation 1997; 96 (Suppl 2): II346–51.
28. Kohno M, Kano H, Horio T, et al. Inhibition of endothelin production by adrenomedullin in vascular smooth muscle cells. Hypertension 1995; 25: 1185–90.[Abstract/Free Full Text]
29. Ishiyama Y, Kitamura K, Ichiki Y, et al. Hemodynamic effects of novel hypotensive peptide, human adrenomedullin, in rats. Eur J Pharmacol 1993; 241: 271–3.[Web of Science][Medline]
30. Hiramatsu T, Imai Y, Takanashi Y, et al. Time course of endothelin-1 and adrenomedullin after the Fontan procedure. Ann Thorac Surg 1999; 68: 169–72.[Abstract/Free Full Text]

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