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Does atrial appendectomy aggravate secretory function of atrial natriuretic polypeptide?
J
THORAC CARDIOVASC SURG
1991;101:502-8
Does atrial appendectomy aggravate secretory function of atrial natriuretic polypeptide? The present study was designed to clarify how atrial appendectomy affects hemodynamics and secretory function of atrial natriuretic polypeptide in the failing heart. Eleven mongrel dogs were prepared for the experimental model of high-output heart failure by creation of arteriovenous fistulas between femoral arteries and veins. Two months after the first operation, effects of bilateral atrial appeadectomies on basal and pacing-induced seeretions of atrial natriuretic polypeptide were investigated in five dogs with simultaneous measurement of various hemohynamic indices. In the remaining six dogs, used as a control group, pacing-induced secretion of atrial natriuretic polypeptide was examined in the same way as in the appendectomy group. After excision of the atrial appendages, neither systolic blood . pressure nor either atrial pressure changed, but plasma atrial natriuretic polypeptide level was decreased (292 ± 54 to 188 ± 47 pgjmI, P < 0.01) and cardiac output feU (3.7 ± 0.9 to 3.0 ± 0.8 Ljmin, P < 0.01~ During pacing-induced tachycardia, the peak level of plasma atrial natriuretic polypeptide was lower in the appendectomy group than in the control groups (593 ± 213 versus 1170 ± 324 pgjmI, P < 0.05), despite similar left atrial pressures in the two groups. The excised appendages contained approximately 30 % of the total amount of atrial natriuretic polypeptide. These results demonstrate that atrial appendectomy decreases secretory function of atrial natriuretic polypeptide and reduces cardiac output in dogs with experimental high-output heart failure.
Kazunobu Nishimura, MD,a Yoshihiko Saito, MD,b Toshinori Hidaka, Pharmlz," Takafumi Ishihara, Pharmlr,? Kazuwa Nakao, MD, PhD,b Hiroo Imura, MD, PhD,b Yoshifumi Okamoto, MD, PhD,a and Toshihiko Ban, MD, PhD,a Kyoto. Japan
Much recent evidence indicates that the atrium has specific granules, called atrial natriuretic polypeptides (ANPs),1-3 and that ANP is secreted through the coronary sinus from the heart and circulates in the body as a hormone.v" ANP has potent natriuretic, diuretic, and vasorelaxant properties.t-?'? and its administration is effective in patients with congestive heart failure because of reduction in both preload and afterload.'" Stimulating factors for ANP release appear to be atrial distention and tachycardia.I':" Because it is widely known that the plasma ANP level is elevated in patients From the Department of Cardiovascular Surgery, Kyoto University School of Medicine,' the Second Division, Department of Medicine, Kyoto University School of Medicine," and the Suntory Institute for Biomedical Research," Kyoto 606, Japan. Received for publication March 8, 1989. Accepted for publication Feb. 13, 1990. Address for reprints: Kazunobu Nishimura, MD, c/o Professor Yacoub's office, Thoracic and Cardiac Surgical Unit, Harefie1d Hospital, Harefie1d Uxbridge, Middlesex UB9 6JH, United Kingdom.
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with heart failure, ANP is probably one of the important hormones in regulating circulating volume in such cases. To date, several investigators have reported the changes in plasma ANP level during and after various cardiac operations.P?' According to their reports, plasma ANP levels decreased during cardiopulmonary bypass 17 and increased immediately after bypass was discontinued.'! The plasma ANP level remained fairly high in patients with elevated atrial pressure." Thus ANP may be related to electrolyte fluid balance during postoperative heart failure. The atrial appendage contains more ANP than other atrial tissue. Excision or ligation of the atrial appendages is frequently performed during insertion of withdrawal cannulas and is sometimes applied during mitral valve repair for prevention of thrombus formation. As yet, the effects of surgical intervention to the atrium on release of ANP and cardiac function are unknown. In the present study, we investigated the changes in plasma ANP before and after atrial appendectomy and examined the responses of ANP secretion to pacing-induced tachycardia with simultaneous measurement of various hemodynam-
Volume 101 Number 3 March 1991
Atrial natriuretic polypeptide
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Fig. 1. Outline ofthe study protocol. Atrial pacing was performed at a rate of 150 beats/min before and after atrial appendectomy. Arrows denote the blood sampling points for measurement of plasma ANP. In the control group, blood was withdrawn in the same points as in the appendectomy group.
ic parameters in dogs with experimental high-output heart failure. We chose the heart failure model to study the effects of atrial appendectomy, because management of electrolyte fluid balance in patients with heart failure is more significant clinically than in those with a normal heart.
Methods Animal preparation. Eleven mongrel dogs weighing an average of 12.1 ± 1.6 kg were used in this study. After they were anesthetized with pentobarbital (25 rug/kg, intravenously), the femoral arteries and veins were exposed bilaterally. Arteriovenous (AV) fistulas were produced through a side-toside anastomosis 10 to 15 mm in length by a continuous 6-0 monofilament suture. The preliminary experiment performed on another day demonstrated a shunt in these fistulas to be about 35% to 40%. All dogs were treated with antibiotics for 2 days after the operation. Study protocol: Dogs with high-output heart failure were anesthetized with thiopental (10 mg/kg, intravenously) and chloralose (80 mg/kg, intravenously). Anesthesia was maintained with an intravenous infusion of chloralose (40 ttig] kg/hr), The dogs were intubated and then supported by positive-pressure ventilation. After a thoracotomy was performed in the left fourth intercostal space, catheters (Argyle Intramedicut catheter, 1.5 mm in diameter, Japan Sherwood Corp., Tokyo, Japan) were inserted into the aorta via the internal mammary artery, into the right atrium via the external jugular vein, and into the left atrium directly. An electromagnetic flow probe was placed around the ascending aorta and connected to a flowmeter (MF27, Nihon Kohden Corp., Tokyo, Japan) to measure the cardiac output. One stainless steel electrode (TAK-1, Matsuda Ika Corp., Tokyo, Japan) was sewn to the left atrial wall for atrial pacing, and another was sewn to the subcutaneous tissue as an indifferent electrode. Pressures in the aorta and both atria, heart rate, and cardiac output were monitored by a polygraph (RMP6008, Nihon Kohden Corp.) and
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weeks after operation Fig. 2. Time course of plasma ANP level after production of AV fistulas. The plasma ANP level was increased to 200 to 560 pg/rnl between 8 and 10 weeks after the AV fistula operation. recorded continuously by a recorder (WT683G, Nihon Kohden Corp.). Heart rate, systolic blood pressure, left atrial pressure, right atrial pressure, and cardiac output were measured to assess cardiac function in this study. Fig. 1 shows the outline of the study protocol. After completion of the preexperimental preparation, atrial pacing was performed at a fixed rate of 150 beats/min in all dogs to exclude
The Journal of Thoracic and Cardiovascular Surgery
5 0 4 Nishimura et al.
LAP
mmHg
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Fig. 3. Influence of atrial appendectomy on hemodynamics and plasma ANP level. Cardiac output fell and plasma ANP level decreased at 30 minutes after the completion of atrial appendectomy. In the control group, parameters did not change over the same time course. LAP, Left atrial pressure; RAP, right atrial pressure; CO,cardiac output; B, before appendectomy; A, after appendectomy (in the control group, it merely means after 30 minutes passed without the operative procedure); NS, not significant.
Table I. Comparison on basal data between two groups Control (n = 5)
Body weight (kg) Heart weight (gm/kg) SBP(mm Hg) HR (beats/min) LAP (mm Hg) RAP (mm Hg) CO (L/min) ANP (pg/rnl)
12.7 ± 10.3 ± 157 ± 149 ±
Appendectomy (n = 6)
11.5 ± 0.8
0.5 0.6 24 3
11.1 ± 0.2 141 ± 7 150 ± I
10.1 ± 0.9
8.6 ± 0.8
5.7 ± l.l 3.1 ± 0.7 318 ± 42
4.8 ± 0.3 3.7 ± 0.4 292 ± 54
Values are mean ± standard error of the mean. SBP, Systolic blood pressure; HR. heart rate; LAP. left atrial pressure; RAP, right atrial pressure; CO. cardiac output; ANP, atrial natriuretic polypeptide.
the influence of heart rate by surgical intervention. After stabilization of hemodynamics, blood samples for measurement of plasma ANP level were obtained twice at an interval of 10 minutes for the first baseline data. Thereafter, dogs were divided into two groups. Five dogs underwent surgical excision of both the left and right atrial appendages, and the incision was closed by a simple running suture (appendectomy group). This operation took about 10 minutes. After an equilibration period of at least 30 minutes blood samples were obtained again. In the remaining six dogs (control group), blood sampling was performed without any operative procedure in the same time course as the appendectomy group. After a further 30 minutes, the second baseline data were obtained twice at an interval of 10 minutes in both groups. Then the heart rate was increased to 225 beats/ min for 10 minutes and was returned to 150 beats/min to
examine the response of ANP secretion to pacing-induced tachycardia. Blood samples were withdrawn every 10 minutes during and after tachycardia. All dogs used in this experiment were killed, and then the heart was excised to measure weight and ANP content in various parts. Blood sampling: Blood samples for measurement of ANP were obtained from the arterial monitor line. The blood samples were transferred to chilled disposable tubes containing aprotinin (1000 kallikrein inactivator units per milliliter) and ethylenediaminetetraacetic acid (1 mg/rnl) and then immediately centrifuged at 4 0 C. Aliquots of plasma were stored at - 200 C until the assay. Atrial tissues and extraction: Excised atria were immediately frozen in liquid nitrogen and stored at -70 C until extraction. Specimens were boiled for 5 minutes in 10 volumes of acetic acid, 1 mol/L, containing hydrogen chloride, 20 mmol/L, to abolish intrinsic proteolytic activity and then homogenized, as previously described.P 23 The homogenate was centrifuged for 30 minutes at 4 0 C, and the supernatant was stored until the assay. Radioimmunoassay: The plasma and tissue concentration of ANP was measured by radioimmunoassay as previously described.vV This radioimmunoassay recognizes a carboxyterminal fragment of ANP, a_ANP,17-28 and the minimal detectable quantity of ANP is 1 pg/tu be.Intraassay and interassay variances were 8.3% and 11.5%, respectively. Data analysis: All values are presented as means ± standard error. Paired and unpaired Student's t tests were used to determine statistical significance of differences. 0
Results Evaluation of heart failure. Fig. 2 shows the postoperative time course of the plasma ANP level. Plasma
Volume 101
Atrial natriuretic polypeptide
Number 3 March 1991
HR
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Fig. 4. Time course of changes in plasma ANP level and hemodynamic parameters during pacing-induced tachycardia in the appendectomy group. HR, Heart rate; S BP, systolicblood pressure; LAP, left atrial pressure; RAP, right atrial pressure; CO, cardiac output.
Fig. 5. Time course of changes in plasma ANP level and hemodynamic parameters durign pacing-induced tachycardia in the control group. Abbreviations are the same as those in Fig. 4.
ANP levels in dogs with an AV fistulaincreased progressively and reached about fivefold to tenfold compared with the preoperative level. Mean heart weight in these dogswas 10.6 ± 0.9 gm/kg, whichwas heavier than that in nine normal dogs (7.3 ± 1.1 gm/kg). The AV shunt causedan increasein cardiac output (3.4 ± 0.7 L/min in dogs with an AV fistula versus 0.8 ± 0.3 L/min in normal dogs) and elevation of both left atrial pressure (9.0 ± 1.1 versus 3.3 ± 1.6 mm Hg) and right atrial pressure (5.4 ± 1.0 versus 1.2 ± 1.4 mm Hg). Thus the AV fistula caused high-output heart failure in the dogs about 8 to 10 weeks after the operation. Baseline body weight, heart weight, hemodynamic parameters, and
plasma ANP levels were similar in the control and the appendectomy group (Table I). Influence of appendectomy in hemodynamics and plasma ANP level. After excision of both atrial appendages,systolicbloodpressure,left atrial pressure, and right atrial pressure did not change, but cardiac output decreased significantly from 3.7 ± 0.9 to 3.0 ± 0.8 L/ min (p < 0.01), as illustrated in Fig. 3. Becauseheart rate wasconstant withthe fixed rate of l50beats/min byatrial pacing, decrease in cardiac output implied decrease in stroke volume.Although neither atrial pressure nor heart rate changed, plasma ANP leveldecreased after appendectomy from 292 ± 54 to 188 ± 47 pg/rnl (p < 0.01).
The Journal of
5 0 6 Nishimura et al.
Thoracic and Cardiovascular Surgery
~
LAP
ANP
mmHg
pg/ml
1000
20
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......... appendectomy group
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HR 225
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HR 150
Fig. 6. Comparison between the two groups in peak levelsof left atrial pressure and plasma ANP in response to the increase in heart rate. LAP, Left atrial pressure; HR, heart rate.
Table II. ANP content in excised right and left atrial appendages
Weight (gm) ANP content (ug)
. RAA
LAA
1.03 ± 0.50 4.3 ± 1.2
2.02 ± 0.44 24.3 ± 10.9
NA 16.28 ± 4.14 82.0 ± 34.4
Percentage of excised appendages 16.1 ± 5.4 26.3 ± 4.7
RAA. Right atrial appendage: LA A, left atrial appendage: NA, nonauriele atrium (remaining atrium).
In the control group, none of the parameters, including plasma ANP level,changed over the same time course, as shown in Fig. 3. Response to pacing-induced tachycardia. Fig. 4 shows the time course of changes in hemodynamics and plasma ANP in the appendectomy group, and Fig. 5 shows the same data from the control group. Increase in the heart rate from 150 to 225 beats/min significantly elevated left and right atrial pressure, with a trivial fall in systolic blood pressure, and it decreased cardiac output in both the appendectomy and the control group. In the control group, plasma ANP increased from 318 ± 42 to 1170 ± 324 pg/rnl (p < 0.01) during tachycardia and returned to the baseline 20 minutes after the end of the stimulation. In the appendectomy group, the same stimulation after appendectomy increased the plasma ANP level from 188 ± 47 to 593 ± 213 pg/ml (p < 0.01). Although there was no significant difference in left atrial pressure during rapid pacing between the two groups, the peak level of ANP in the appendectomy group was lower
than that in the control group (p < 0.05). Fig. 6 showsthe changes in left atrial pressure and plasma ANP level in response to the increase in heart rate in both groups. ANP content in excised atrial appendages. Table II shows the weight of excised right and left atrial appendages and their ANP content. The left atrial appendage was heavier and had more ANP than the right atrial appendage. The average percentage of weight of excised appendages was 16.1% ± 5.4% and their ANP content corresponded to 26.3% ± 4.7% of the whole amount of ANP contained in the atria. Discussion The results of this study prove that atrial appendectomy decreases secretory function of ANP in failing hearts early postoperatively. It has been demonstrated previously that elevation of atrial pressure and increase in heart rate are the major factors in stimulating ANP secretion. 11-16 Although both the atrial pressure and the heart rate were unchanged in this study, plasma ANP
Volume 101 Number 3 March 1991
level was stillsignificantly decreased by atrial appendec"tomy. This implies that ANP secretion was directly reduced by removing atrial tissue that contained a high concentration of ANP. Analysis of ANP content in excised atrial appendages showed that they contained about 30%of the wholeamount of ANP. This outcome is consistent with the observation that the plasma ANP level was reduced to approximately 60% to 70% of the baseline after atrial appendectomy, supposing that the plasma ANP level is in proportion to ANP content in atrial tissue. Thus atrial appendectomydecreased ANP secretion withoutinfluencing atrial pressureor heart rate. In addition, although the plasma ANP level increased during pacing-induced tachycardia in both the control and the appendectomy groups,the absolutevalueof plasma ANP concentration was significantly lower in the appendectomy groupthan inthe controlgroupdespitethe almostequal left atrial pressure. This suggests that atrial appendectomy decreasedthe secretory function of ANP inresponse to the risein atrial pressureor increasein heart rate. This result, moreover, supports the previous view reported by Veress and Sonnenberg" that right atrial appendectomy reduced the renal response to acute hypervolemia inthe rat. It isconceivable that sucha reduced response to secretionof ANP after atrial appendectomy may affectthe fluid-electrolyte balanceduring the immediate postoperative period.17 Thisstudy did not showwhether excision of the left or the right atrial appendage might contribute more to the decrease in ANP. Although we23 havereported previouslythat ANP contentin the human right atrial appendage wasmuch higher in severe than in mild congestive heart failure, comparisons of the ANP content in human atrial tissues havenot beenmade betweenthe right and the left atrial appendage. It is probably true that the more volume-loaded or pressure-loaded atrium may tend to produce more ANP. We have observed that the right atrium in patients with an atrial septal defect contains more messenger ribonucleic acid (which is thought to reflect the ability to produce ANP) than does the left atrium (unpublished observation). This observation suggests that the right atrial appendage should be treated withcaution,in particular in right heart failureor disease associated with high right atrial pressure. The reason that cardiac output was decreased after excision of the atrial appendages is not clear. Atrial appendectomy wasperformedwithlittle bleeding, and the condition of the animalswas stabilizedbeforebloodsamplesweretaken.The decreasein atrial volumeby excision ofatrialtissues may havereducedthe so-called atrial kick, which isimportantto fillventricularend-diastolic volume. It is unlikely that a drop in stroke volume was provoked
Atrial natriuretic polypeptide
507
by reduction of ventricular contractility because atrial pressurewasunchanged.Therefore wespeculatethat the drop in stroke volume was caused by reduction of atrial kick. Becauseatrial appendectomyaggravates both cardiac functionand secretoryfunctionof ANP, surgicaltrauma to the atria should be avoided, if possible. However, the questionof whether these effectspersist after atrial healing connot be answeredin this study. We23 have reported that atrial tissuecontainsabundant ANP in variousparts of the failing heart, and even ventricles sometimes produce ANP in dilated cardiomyopathy and left ventricular aneurysm.P Therefore the remaining atria and ventricles may compensate for secretory function of ANP. Even if this is true, it is more meaningful clinically that the decrease in ANP release and the reduction in cardiac output occurduring the early postoperative stage, which is the critical period in the postoperative management. The experimental model used in this study was prepared by creation of AV fistulas, as severalinvestigators have already reported.26-29 However, we created the fistulas betweenthe femoral arteries and veins rather than betweenthe abdominal aorta and the inferior vena cava, to minimizesurgical trauma. High-output heart failure resulted8 to 10weeksafter the fistulas had been created. We found this modelto behighlyusefulfor investigating the changes of plasma ANP level and hemodynamics in the failing heart. Would the same findings beobserved if the effect of atrial appendectomy wasexaminedin normal hearts? We havehad similarresultsfrom dogshavinga normal heart, but these results were not as distinct as those from this study. Excision of both atrial appendages in four dogs witha normalheart had a tendencyto decreaseANP level and cardiac output (unpublisheddata). However, these changes had no statistical significance because of relativelysmall changesof ANP within a lowlevel. Thus the influence of atrial appendectomywas more evidentin the failingheart, in whichthe basal ANP levelwas high and the control of body fluid balance was important. In summary, the present study demonstrates that atrial appendectomy decreases secretory function of ANP and reducesstrokevolumein dogswith high-output heart failure. Secretion of ANP during tachycardia was also diminished by atrial appendectomy. A decrease of stroke volumemay be explainedby reduction of the atrial kick. Thus the importance of the atrial appendage in the failing heart should be considered. We thank physicians in the Second Division, Department of Medicine, Kyoto University School of Medicine, for their
5 0 8 Nishimura et al.
encouragement and advice. The excellent assistance of Miss Y. Yasui in handling of instruments and Miss C. Nakai in measurement of radioimmunoassay are also gratefully acknowledged. REFERENCES I. DeBold AJ, Borensein HB, Veress AT, Sonnenberg H. A
2.
3. 4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
rapid and potent natriuretic response to intravenous injection of atrial myocardial extract in rats. Life Sci 1981;28:89-94. Kangawa K, Matsuo H. Purification and complete amino acid sequence of a-human atrial natriuretic polypeptide. Biochem Biophys Res Commun 1984;118:131-9. Needleman P, Adams SP, Cole BR, et al. Atrio-peptins as cardiac hormones. Hypertension 1985;7:469-82. Sugawara A, Nakao K, Moril N, et al. a-Human atrial natriuretic polypeptide is released from the heart and circulates in the body. Biochem Biophys Res Commun 1985;129:439-46. Nakao K, Sugawara A, Shiono S, et al. Secretory form of atrial natriuretic polypeptide as cardiac hormone in humans and rats. Can J Physiol PharmacoI1987;65:175661. Sugawara A, Nakao K, Morii N, et al. Significance of ahuman atrial natriuretic polypetide as a hormone in man. Hypertension 1986;8(suppl 1):151-5. Yukimura T, Hoh K, Tanenaga T, Yamamoto K, Kangawa K, Matsuo H. Renal effects of synthetic a-human atrial natriuretic polypeptide (a-hANP) in anesthetized dogs. Eur J Pharmacol 1984;103:363-6. Maack T, Marison DN, Camargo MJE, et al. Effects of auriculin (atrial natriuretic factor) on blood pressure, renal function, and the renin-aldosterone system in dogs. Am J Med 1984;77:1069-75. Burnet JC Jr, Granger JP, Opgenoth TS. Effects of synthetic atrial natriuretic factor on renal function and renin release. Am J Physiol 1984;247:F863-6. Saito Y, Nakao K, Nishimura K, et al. Clinical application of atrial natriuretic polypeptide in patients with congestive heart failure: beneficial effects on left ventricular function. Circulation 1987;76:115-24. Ledsome JR, Wilson N, Courneya CA, Rankin AJ. Release of atrial natriuretic peptide by atrial distension. Can J Physiol Pharmacol 1985;63:739-42. Lang RE, ThOlken H, Ganten D, Luft FC, Ruskoaho H, Unger TH. Atrial natriuretic factor--a circulating hormone stimulated by volume loading. Nature 1985;314: 264-6. Goetz KL, Wang Be, Geer PG, Sundet WG, Needleman P. Effects of atriopeptin infusion versus effects of left atrial stretch in awake dogs. Am J Physiol I986;250:R221-6. Rankin AJ, Courneya CA, Wilson N, Ledsome JR. Tachycardia releases atrial natriuretic peptide in the anesthetized rabbit. Life Sci 1986;38:1951-7.
The Journal of Thoracic and Cardiovascular Surgery
15. Schiebinger RJ, Linden J. Effects of atrial contraction frequency on atrial natriuretic peptide secretion. Am J PhysioI1986;251:HI095-9. 16. Nishimura K, Nakao K, Saito Y, Imura H, Ban T. Atrial natriuretic polypeptide is stimulated by atrial pacing without elevation of atrial pressure in consciousdogs with complete atrioventricular block. In: Advances in atrial peptide research, ASH symposium series, Vol II, New York: Raven Press, 1988:448-51. 17. Nishimura K, Fujiwara Y, Matsumoto M, et al. Plasma levelof atrial natriuretic polypeptide during and after cardiopulmonary bypass. J Jpn Assoc Thorac Surg 1988; 36:2213-20. 18. Stewart JM, Seligman KP, Zeballos G, et al. Elevated atrial natriuretic peptide after the Fontanprocedure. Circulation 1987;76:(Pt 2):III 77-82. 19. Hedner J, Towle A, Saltzman L, et al. Changes in plasma atrial natriuretic peptide: immunoreactivity in patients undergoing coronary artery bypass graft placements. Regul Pept 1987;17:151-7. 20. Schwab TR, Edwards BS, DeVries WG, Zimmerman RS, Burnet JC Jr. Atrial endocrine function in humans with artificial hearts. N Engl J Med 1986;315:1398-401. 21. Nishimura K, Fukurnasu H, Ban T, et al. Atrial natriuretic polypeptide in sheep with total artificial heart. In: Artificial Heart 2: proceedings of the second international symposium on artificial heart and assist device. Tokyo: Springer-Verlag, 1988:313-8. 22. Nakao K, Sugawara A, Morii N, et al. Radioimmunoassay for a-human and rat atrial natriuretic polypeptide. Biochern Biophys Res Commun 1984;124:815-21. 23. Sugawara A, Nakao K, Morii N, et al. Synthesis of atrial natriuretic polypeptide in human failing hearts. J Clin Invest 1988;81:1962-70. 24. Veress AT, Sonnenberg H. Right atrial appendectomy reduces the renal response to acute hypervolemia in the rat. Am J Physiol 1984;247:R61O-3. 25. Saito Y, Nakao K, Nishimura K, et al. Augmented expression of atrial natriuretic polypeptide gene in ventricle of human failing heart. J Clin Invest 1989;83:298-305. 26. Ferguson TB, Gregg DE, Shadle OW. Effects of bloodand saline infusion on cardiac performance in normal dogs and dogs with arteriovenous fistulas. Circ Res 1954;2:565-72. 27. Davis JO, Urquhart J, Higgins JT Jr, Rubin EC, Hartroft PM. Hypersecretion of aldosterone in dogs with a chronic aortic-caval fistula and high output heart failure. Circ Res 1964;14:471-85. 28. Newman WH, Webb JG, Privitera PJ. Persistence of myocardial failure following removal of chronic volume overload. Am J Physiol 1982;243:H876-83. 29. Villarreal D, Freeman RH, Davis JO, Verburg KM, Vari RC. Atrial natriuretic factor secretion in dogs with experimental high-output heart failure. Am J Physiol 1987; 252:H692-6.
THORAC CARDIOVASC SURG
1991;101:502-8
Does atrial appendectomy aggravate secretory function of atrial natriuretic polypeptide? The present study was designed to clarify how atrial appendectomy affects hemodynamics and secretory function of atrial natriuretic polypeptide in the failing heart. Eleven mongrel dogs were prepared for the experimental model of high-output heart failure by creation of arteriovenous fistulas between femoral arteries and veins. Two months after the first operation, effects of bilateral atrial appeadectomies on basal and pacing-induced seeretions of atrial natriuretic polypeptide were investigated in five dogs with simultaneous measurement of various hemohynamic indices. In the remaining six dogs, used as a control group, pacing-induced secretion of atrial natriuretic polypeptide was examined in the same way as in the appendectomy group. After excision of the atrial appendages, neither systolic blood . pressure nor either atrial pressure changed, but plasma atrial natriuretic polypeptide level was decreased (292 ± 54 to 188 ± 47 pgjmI, P < 0.01) and cardiac output feU (3.7 ± 0.9 to 3.0 ± 0.8 Ljmin, P < 0.01~ During pacing-induced tachycardia, the peak level of plasma atrial natriuretic polypeptide was lower in the appendectomy group than in the control groups (593 ± 213 versus 1170 ± 324 pgjmI, P < 0.05), despite similar left atrial pressures in the two groups. The excised appendages contained approximately 30 % of the total amount of atrial natriuretic polypeptide. These results demonstrate that atrial appendectomy decreases secretory function of atrial natriuretic polypeptide and reduces cardiac output in dogs with experimental high-output heart failure.
Kazunobu Nishimura, MD,a Yoshihiko Saito, MD,b Toshinori Hidaka, Pharmlz," Takafumi Ishihara, Pharmlr,? Kazuwa Nakao, MD, PhD,b Hiroo Imura, MD, PhD,b Yoshifumi Okamoto, MD, PhD,a and Toshihiko Ban, MD, PhD,a Kyoto. Japan
Much recent evidence indicates that the atrium has specific granules, called atrial natriuretic polypeptides (ANPs),1-3 and that ANP is secreted through the coronary sinus from the heart and circulates in the body as a hormone.v" ANP has potent natriuretic, diuretic, and vasorelaxant properties.t-?'? and its administration is effective in patients with congestive heart failure because of reduction in both preload and afterload.'" Stimulating factors for ANP release appear to be atrial distention and tachycardia.I':" Because it is widely known that the plasma ANP level is elevated in patients From the Department of Cardiovascular Surgery, Kyoto University School of Medicine,' the Second Division, Department of Medicine, Kyoto University School of Medicine," and the Suntory Institute for Biomedical Research," Kyoto 606, Japan. Received for publication March 8, 1989. Accepted for publication Feb. 13, 1990. Address for reprints: Kazunobu Nishimura, MD, c/o Professor Yacoub's office, Thoracic and Cardiac Surgical Unit, Harefie1d Hospital, Harefie1d Uxbridge, Middlesex UB9 6JH, United Kingdom.
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with heart failure, ANP is probably one of the important hormones in regulating circulating volume in such cases. To date, several investigators have reported the changes in plasma ANP level during and after various cardiac operations.P?' According to their reports, plasma ANP levels decreased during cardiopulmonary bypass 17 and increased immediately after bypass was discontinued.'! The plasma ANP level remained fairly high in patients with elevated atrial pressure." Thus ANP may be related to electrolyte fluid balance during postoperative heart failure. The atrial appendage contains more ANP than other atrial tissue. Excision or ligation of the atrial appendages is frequently performed during insertion of withdrawal cannulas and is sometimes applied during mitral valve repair for prevention of thrombus formation. As yet, the effects of surgical intervention to the atrium on release of ANP and cardiac function are unknown. In the present study, we investigated the changes in plasma ANP before and after atrial appendectomy and examined the responses of ANP secretion to pacing-induced tachycardia with simultaneous measurement of various hemodynam-
Volume 101 Number 3 March 1991
Atrial natriuretic polypeptide
50 3
Heart rate (atrial pacing)
~Hif~~§9ma appendectomy
ai
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CD
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(1)
-10
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10 i
20 i
30 i
40 r
1 1 1 1 1 1 1 1 Sampling point
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(1): second base line
Fig. 1. Outline ofthe study protocol. Atrial pacing was performed at a rate of 150 beats/min before and after atrial appendectomy. Arrows denote the blood sampling points for measurement of plasma ANP. In the control group, blood was withdrawn in the same points as in the appendectomy group.
ic parameters in dogs with experimental high-output heart failure. We chose the heart failure model to study the effects of atrial appendectomy, because management of electrolyte fluid balance in patients with heart failure is more significant clinically than in those with a normal heart.
Methods Animal preparation. Eleven mongrel dogs weighing an average of 12.1 ± 1.6 kg were used in this study. After they were anesthetized with pentobarbital (25 rug/kg, intravenously), the femoral arteries and veins were exposed bilaterally. Arteriovenous (AV) fistulas were produced through a side-toside anastomosis 10 to 15 mm in length by a continuous 6-0 monofilament suture. The preliminary experiment performed on another day demonstrated a shunt in these fistulas to be about 35% to 40%. All dogs were treated with antibiotics for 2 days after the operation. Study protocol: Dogs with high-output heart failure were anesthetized with thiopental (10 mg/kg, intravenously) and chloralose (80 mg/kg, intravenously). Anesthesia was maintained with an intravenous infusion of chloralose (40 ttig] kg/hr), The dogs were intubated and then supported by positive-pressure ventilation. After a thoracotomy was performed in the left fourth intercostal space, catheters (Argyle Intramedicut catheter, 1.5 mm in diameter, Japan Sherwood Corp., Tokyo, Japan) were inserted into the aorta via the internal mammary artery, into the right atrium via the external jugular vein, and into the left atrium directly. An electromagnetic flow probe was placed around the ascending aorta and connected to a flowmeter (MF27, Nihon Kohden Corp., Tokyo, Japan) to measure the cardiac output. One stainless steel electrode (TAK-1, Matsuda Ika Corp., Tokyo, Japan) was sewn to the left atrial wall for atrial pacing, and another was sewn to the subcutaneous tissue as an indifferent electrode. Pressures in the aorta and both atria, heart rate, and cardiac output were monitored by a polygraph (RMP6008, Nihon Kohden Corp.) and
pg/ml
600
•
500
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•
400
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•
•
•
300
• • • • • • • • • 100 •• • • • • • a •. 2 a 4 6
•
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200
•
•
8
10
weeks after operation Fig. 2. Time course of plasma ANP level after production of AV fistulas. The plasma ANP level was increased to 200 to 560 pg/rnl between 8 and 10 weeks after the AV fistula operation. recorded continuously by a recorder (WT683G, Nihon Kohden Corp.). Heart rate, systolic blood pressure, left atrial pressure, right atrial pressure, and cardiac output were measured to assess cardiac function in this study. Fig. 1 shows the outline of the study protocol. After completion of the preexperimental preparation, atrial pacing was performed at a fixed rate of 150 beats/min in all dogs to exclude
The Journal of Thoracic and Cardiovascular Surgery
5 0 4 Nishimura et al.
LAP
mmHg
I/min
,.....,
NS
10
•. 0
5
2.0
_ NS ,.....,
P
,.....,
NS ,.....,
co
appende ct omy group
llcontro, group
3·0 1·0
0
0
RAP
pg/ml
B A
ANP P
,.----,
NS ,.---,
mmHg
10
NS ,.....,
300
NS
,.----,
200
5
100 B
A
B
B
A
A
B
A
Fig. 3. Influence of atrial appendectomy on hemodynamics and plasma ANP level. Cardiac output fell and plasma ANP level decreased at 30 minutes after the completion of atrial appendectomy. In the control group, parameters did not change over the same time course. LAP, Left atrial pressure; RAP, right atrial pressure; CO,cardiac output; B, before appendectomy; A, after appendectomy (in the control group, it merely means after 30 minutes passed without the operative procedure); NS, not significant.
Table I. Comparison on basal data between two groups Control (n = 5)
Body weight (kg) Heart weight (gm/kg) SBP(mm Hg) HR (beats/min) LAP (mm Hg) RAP (mm Hg) CO (L/min) ANP (pg/rnl)
12.7 ± 10.3 ± 157 ± 149 ±
Appendectomy (n = 6)
11.5 ± 0.8
0.5 0.6 24 3
11.1 ± 0.2 141 ± 7 150 ± I
10.1 ± 0.9
8.6 ± 0.8
5.7 ± l.l 3.1 ± 0.7 318 ± 42
4.8 ± 0.3 3.7 ± 0.4 292 ± 54
Values are mean ± standard error of the mean. SBP, Systolic blood pressure; HR. heart rate; LAP. left atrial pressure; RAP, right atrial pressure; CO. cardiac output; ANP, atrial natriuretic polypeptide.
the influence of heart rate by surgical intervention. After stabilization of hemodynamics, blood samples for measurement of plasma ANP level were obtained twice at an interval of 10 minutes for the first baseline data. Thereafter, dogs were divided into two groups. Five dogs underwent surgical excision of both the left and right atrial appendages, and the incision was closed by a simple running suture (appendectomy group). This operation took about 10 minutes. After an equilibration period of at least 30 minutes blood samples were obtained again. In the remaining six dogs (control group), blood sampling was performed without any operative procedure in the same time course as the appendectomy group. After a further 30 minutes, the second baseline data were obtained twice at an interval of 10 minutes in both groups. Then the heart rate was increased to 225 beats/ min for 10 minutes and was returned to 150 beats/min to
examine the response of ANP secretion to pacing-induced tachycardia. Blood samples were withdrawn every 10 minutes during and after tachycardia. All dogs used in this experiment were killed, and then the heart was excised to measure weight and ANP content in various parts. Blood sampling: Blood samples for measurement of ANP were obtained from the arterial monitor line. The blood samples were transferred to chilled disposable tubes containing aprotinin (1000 kallikrein inactivator units per milliliter) and ethylenediaminetetraacetic acid (1 mg/rnl) and then immediately centrifuged at 4 0 C. Aliquots of plasma were stored at - 200 C until the assay. Atrial tissues and extraction: Excised atria were immediately frozen in liquid nitrogen and stored at -70 C until extraction. Specimens were boiled for 5 minutes in 10 volumes of acetic acid, 1 mol/L, containing hydrogen chloride, 20 mmol/L, to abolish intrinsic proteolytic activity and then homogenized, as previously described.P 23 The homogenate was centrifuged for 30 minutes at 4 0 C, and the supernatant was stored until the assay. Radioimmunoassay: The plasma and tissue concentration of ANP was measured by radioimmunoassay as previously described.vV This radioimmunoassay recognizes a carboxyterminal fragment of ANP, a_ANP,17-28 and the minimal detectable quantity of ANP is 1 pg/tu be.Intraassay and interassay variances were 8.3% and 11.5%, respectively. Data analysis: All values are presented as means ± standard error. Paired and unpaired Student's t tests were used to determine statistical significance of differences. 0
Results Evaluation of heart failure. Fig. 2 shows the postoperative time course of the plasma ANP level. Plasma
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HR
@160WA225Vij:0J500%j
(atrial pacing) **p
1000 ANP 500
HR
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40
(min)
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.
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-10
0
;~
10
20
30
40
(min)
Fig. 4. Time course of changes in plasma ANP level and hemodynamic parameters during pacing-induced tachycardia in the appendectomy group. HR, Heart rate; S BP, systolicblood pressure; LAP, left atrial pressure; RAP, right atrial pressure; CO, cardiac output.
Fig. 5. Time course of changes in plasma ANP level and hemodynamic parameters durign pacing-induced tachycardia in the control group. Abbreviations are the same as those in Fig. 4.
ANP levels in dogs with an AV fistulaincreased progressively and reached about fivefold to tenfold compared with the preoperative level. Mean heart weight in these dogswas 10.6 ± 0.9 gm/kg, whichwas heavier than that in nine normal dogs (7.3 ± 1.1 gm/kg). The AV shunt causedan increasein cardiac output (3.4 ± 0.7 L/min in dogs with an AV fistula versus 0.8 ± 0.3 L/min in normal dogs) and elevation of both left atrial pressure (9.0 ± 1.1 versus 3.3 ± 1.6 mm Hg) and right atrial pressure (5.4 ± 1.0 versus 1.2 ± 1.4 mm Hg). Thus the AV fistula caused high-output heart failure in the dogs about 8 to 10 weeks after the operation. Baseline body weight, heart weight, hemodynamic parameters, and
plasma ANP levels were similar in the control and the appendectomy group (Table I). Influence of appendectomy in hemodynamics and plasma ANP level. After excision of both atrial appendages,systolicbloodpressure,left atrial pressure, and right atrial pressure did not change, but cardiac output decreased significantly from 3.7 ± 0.9 to 3.0 ± 0.8 L/ min (p < 0.01), as illustrated in Fig. 3. Becauseheart rate wasconstant withthe fixed rate of l50beats/min byatrial pacing, decrease in cardiac output implied decrease in stroke volume.Although neither atrial pressure nor heart rate changed, plasma ANP leveldecreased after appendectomy from 292 ± 54 to 188 ± 47 pg/rnl (p < 0.01).
The Journal of
5 0 6 Nishimura et al.
Thoracic and Cardiovascular Surgery
~
LAP
ANP
mmHg
pg/ml
1000
20
15
10
control group
......... appendectomy group
NS[
~J"
p
500
r
5
p
0
HR 150
HR 225
0
HR 225
HR 150
Fig. 6. Comparison between the two groups in peak levelsof left atrial pressure and plasma ANP in response to the increase in heart rate. LAP, Left atrial pressure; HR, heart rate.
Table II. ANP content in excised right and left atrial appendages
Weight (gm) ANP content (ug)
. RAA
LAA
1.03 ± 0.50 4.3 ± 1.2
2.02 ± 0.44 24.3 ± 10.9
NA 16.28 ± 4.14 82.0 ± 34.4
Percentage of excised appendages 16.1 ± 5.4 26.3 ± 4.7
RAA. Right atrial appendage: LA A, left atrial appendage: NA, nonauriele atrium (remaining atrium).
In the control group, none of the parameters, including plasma ANP level,changed over the same time course, as shown in Fig. 3. Response to pacing-induced tachycardia. Fig. 4 shows the time course of changes in hemodynamics and plasma ANP in the appendectomy group, and Fig. 5 shows the same data from the control group. Increase in the heart rate from 150 to 225 beats/min significantly elevated left and right atrial pressure, with a trivial fall in systolic blood pressure, and it decreased cardiac output in both the appendectomy and the control group. In the control group, plasma ANP increased from 318 ± 42 to 1170 ± 324 pg/rnl (p < 0.01) during tachycardia and returned to the baseline 20 minutes after the end of the stimulation. In the appendectomy group, the same stimulation after appendectomy increased the plasma ANP level from 188 ± 47 to 593 ± 213 pg/ml (p < 0.01). Although there was no significant difference in left atrial pressure during rapid pacing between the two groups, the peak level of ANP in the appendectomy group was lower
than that in the control group (p < 0.05). Fig. 6 showsthe changes in left atrial pressure and plasma ANP level in response to the increase in heart rate in both groups. ANP content in excised atrial appendages. Table II shows the weight of excised right and left atrial appendages and their ANP content. The left atrial appendage was heavier and had more ANP than the right atrial appendage. The average percentage of weight of excised appendages was 16.1% ± 5.4% and their ANP content corresponded to 26.3% ± 4.7% of the whole amount of ANP contained in the atria. Discussion The results of this study prove that atrial appendectomy decreases secretory function of ANP in failing hearts early postoperatively. It has been demonstrated previously that elevation of atrial pressure and increase in heart rate are the major factors in stimulating ANP secretion. 11-16 Although both the atrial pressure and the heart rate were unchanged in this study, plasma ANP
Volume 101 Number 3 March 1991
level was stillsignificantly decreased by atrial appendec"tomy. This implies that ANP secretion was directly reduced by removing atrial tissue that contained a high concentration of ANP. Analysis of ANP content in excised atrial appendages showed that they contained about 30%of the wholeamount of ANP. This outcome is consistent with the observation that the plasma ANP level was reduced to approximately 60% to 70% of the baseline after atrial appendectomy, supposing that the plasma ANP level is in proportion to ANP content in atrial tissue. Thus atrial appendectomydecreased ANP secretion withoutinfluencing atrial pressureor heart rate. In addition, although the plasma ANP level increased during pacing-induced tachycardia in both the control and the appendectomy groups,the absolutevalueof plasma ANP concentration was significantly lower in the appendectomy groupthan inthe controlgroupdespitethe almostequal left atrial pressure. This suggests that atrial appendectomy decreasedthe secretory function of ANP inresponse to the risein atrial pressureor increasein heart rate. This result, moreover, supports the previous view reported by Veress and Sonnenberg" that right atrial appendectomy reduced the renal response to acute hypervolemia inthe rat. It isconceivable that sucha reduced response to secretionof ANP after atrial appendectomy may affectthe fluid-electrolyte balanceduring the immediate postoperative period.17 Thisstudy did not showwhether excision of the left or the right atrial appendage might contribute more to the decrease in ANP. Although we23 havereported previouslythat ANP contentin the human right atrial appendage wasmuch higher in severe than in mild congestive heart failure, comparisons of the ANP content in human atrial tissues havenot beenmade betweenthe right and the left atrial appendage. It is probably true that the more volume-loaded or pressure-loaded atrium may tend to produce more ANP. We have observed that the right atrium in patients with an atrial septal defect contains more messenger ribonucleic acid (which is thought to reflect the ability to produce ANP) than does the left atrium (unpublished observation). This observation suggests that the right atrial appendage should be treated withcaution,in particular in right heart failureor disease associated with high right atrial pressure. The reason that cardiac output was decreased after excision of the atrial appendages is not clear. Atrial appendectomy wasperformedwithlittle bleeding, and the condition of the animalswas stabilizedbeforebloodsamplesweretaken.The decreasein atrial volumeby excision ofatrialtissues may havereducedthe so-called atrial kick, which isimportantto fillventricularend-diastolic volume. It is unlikely that a drop in stroke volume was provoked
Atrial natriuretic polypeptide
507
by reduction of ventricular contractility because atrial pressurewasunchanged.Therefore wespeculatethat the drop in stroke volume was caused by reduction of atrial kick. Becauseatrial appendectomyaggravates both cardiac functionand secretoryfunctionof ANP, surgicaltrauma to the atria should be avoided, if possible. However, the questionof whether these effectspersist after atrial healing connot be answeredin this study. We23 have reported that atrial tissuecontainsabundant ANP in variousparts of the failing heart, and even ventricles sometimes produce ANP in dilated cardiomyopathy and left ventricular aneurysm.P Therefore the remaining atria and ventricles may compensate for secretory function of ANP. Even if this is true, it is more meaningful clinically that the decrease in ANP release and the reduction in cardiac output occurduring the early postoperative stage, which is the critical period in the postoperative management. The experimental model used in this study was prepared by creation of AV fistulas, as severalinvestigators have already reported.26-29 However, we created the fistulas betweenthe femoral arteries and veins rather than betweenthe abdominal aorta and the inferior vena cava, to minimizesurgical trauma. High-output heart failure resulted8 to 10weeksafter the fistulas had been created. We found this modelto behighlyusefulfor investigating the changes of plasma ANP level and hemodynamics in the failing heart. Would the same findings beobserved if the effect of atrial appendectomy wasexaminedin normal hearts? We havehad similarresultsfrom dogshavinga normal heart, but these results were not as distinct as those from this study. Excision of both atrial appendages in four dogs witha normalheart had a tendencyto decreaseANP level and cardiac output (unpublisheddata). However, these changes had no statistical significance because of relativelysmall changesof ANP within a lowlevel. Thus the influence of atrial appendectomywas more evidentin the failingheart, in whichthe basal ANP levelwas high and the control of body fluid balance was important. In summary, the present study demonstrates that atrial appendectomy decreases secretory function of ANP and reducesstrokevolumein dogswith high-output heart failure. Secretion of ANP during tachycardia was also diminished by atrial appendectomy. A decrease of stroke volumemay be explainedby reduction of the atrial kick. Thus the importance of the atrial appendage in the failing heart should be considered. We thank physicians in the Second Division, Department of Medicine, Kyoto University School of Medicine, for their
5 0 8 Nishimura et al.
encouragement and advice. The excellent assistance of Miss Y. Yasui in handling of instruments and Miss C. Nakai in measurement of radioimmunoassay are also gratefully acknowledged. REFERENCES I. DeBold AJ, Borensein HB, Veress AT, Sonnenberg H. A
2.
3. 4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
rapid and potent natriuretic response to intravenous injection of atrial myocardial extract in rats. Life Sci 1981;28:89-94. Kangawa K, Matsuo H. Purification and complete amino acid sequence of a-human atrial natriuretic polypeptide. Biochem Biophys Res Commun 1984;118:131-9. Needleman P, Adams SP, Cole BR, et al. Atrio-peptins as cardiac hormones. Hypertension 1985;7:469-82. Sugawara A, Nakao K, Moril N, et al. a-Human atrial natriuretic polypeptide is released from the heart and circulates in the body. Biochem Biophys Res Commun 1985;129:439-46. Nakao K, Sugawara A, Shiono S, et al. Secretory form of atrial natriuretic polypeptide as cardiac hormone in humans and rats. Can J Physiol PharmacoI1987;65:175661. Sugawara A, Nakao K, Morii N, et al. Significance of ahuman atrial natriuretic polypetide as a hormone in man. Hypertension 1986;8(suppl 1):151-5. Yukimura T, Hoh K, Tanenaga T, Yamamoto K, Kangawa K, Matsuo H. Renal effects of synthetic a-human atrial natriuretic polypeptide (a-hANP) in anesthetized dogs. Eur J Pharmacol 1984;103:363-6. Maack T, Marison DN, Camargo MJE, et al. Effects of auriculin (atrial natriuretic factor) on blood pressure, renal function, and the renin-aldosterone system in dogs. Am J Med 1984;77:1069-75. Burnet JC Jr, Granger JP, Opgenoth TS. Effects of synthetic atrial natriuretic factor on renal function and renin release. Am J Physiol 1984;247:F863-6. Saito Y, Nakao K, Nishimura K, et al. Clinical application of atrial natriuretic polypeptide in patients with congestive heart failure: beneficial effects on left ventricular function. Circulation 1987;76:115-24. Ledsome JR, Wilson N, Courneya CA, Rankin AJ. Release of atrial natriuretic peptide by atrial distension. Can J Physiol Pharmacol 1985;63:739-42. Lang RE, ThOlken H, Ganten D, Luft FC, Ruskoaho H, Unger TH. Atrial natriuretic factor--a circulating hormone stimulated by volume loading. Nature 1985;314: 264-6. Goetz KL, Wang Be, Geer PG, Sundet WG, Needleman P. Effects of atriopeptin infusion versus effects of left atrial stretch in awake dogs. Am J Physiol I986;250:R221-6. Rankin AJ, Courneya CA, Wilson N, Ledsome JR. Tachycardia releases atrial natriuretic peptide in the anesthetized rabbit. Life Sci 1986;38:1951-7.
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15. Schiebinger RJ, Linden J. Effects of atrial contraction frequency on atrial natriuretic peptide secretion. Am J PhysioI1986;251:HI095-9. 16. Nishimura K, Nakao K, Saito Y, Imura H, Ban T. Atrial natriuretic polypeptide is stimulated by atrial pacing without elevation of atrial pressure in consciousdogs with complete atrioventricular block. In: Advances in atrial peptide research, ASH symposium series, Vol II, New York: Raven Press, 1988:448-51. 17. Nishimura K, Fujiwara Y, Matsumoto M, et al. Plasma levelof atrial natriuretic polypeptide during and after cardiopulmonary bypass. J Jpn Assoc Thorac Surg 1988; 36:2213-20. 18. Stewart JM, Seligman KP, Zeballos G, et al. Elevated atrial natriuretic peptide after the Fontanprocedure. Circulation 1987;76:(Pt 2):III 77-82. 19. Hedner J, Towle A, Saltzman L, et al. Changes in plasma atrial natriuretic peptide: immunoreactivity in patients undergoing coronary artery bypass graft placements. Regul Pept 1987;17:151-7. 20. Schwab TR, Edwards BS, DeVries WG, Zimmerman RS, Burnet JC Jr. Atrial endocrine function in humans with artificial hearts. N Engl J Med 1986;315:1398-401. 21. Nishimura K, Fukurnasu H, Ban T, et al. Atrial natriuretic polypeptide in sheep with total artificial heart. In: Artificial Heart 2: proceedings of the second international symposium on artificial heart and assist device. Tokyo: Springer-Verlag, 1988:313-8. 22. Nakao K, Sugawara A, Morii N, et al. Radioimmunoassay for a-human and rat atrial natriuretic polypeptide. Biochern Biophys Res Commun 1984;124:815-21. 23. Sugawara A, Nakao K, Morii N, et al. Synthesis of atrial natriuretic polypeptide in human failing hearts. J Clin Invest 1988;81:1962-70. 24. Veress AT, Sonnenberg H. Right atrial appendectomy reduces the renal response to acute hypervolemia in the rat. Am J Physiol 1984;247:R61O-3. 25. Saito Y, Nakao K, Nishimura K, et al. Augmented expression of atrial natriuretic polypeptide gene in ventricle of human failing heart. J Clin Invest 1989;83:298-305. 26. Ferguson TB, Gregg DE, Shadle OW. Effects of bloodand saline infusion on cardiac performance in normal dogs and dogs with arteriovenous fistulas. Circ Res 1954;2:565-72. 27. Davis JO, Urquhart J, Higgins JT Jr, Rubin EC, Hartroft PM. Hypersecretion of aldosterone in dogs with a chronic aortic-caval fistula and high output heart failure. Circ Res 1964;14:471-85. 28. Newman WH, Webb JG, Privitera PJ. Persistence of myocardial failure following removal of chronic volume overload. Am J Physiol 1982;243:H876-83. 29. Villarreal D, Freeman RH, Davis JO, Verburg KM, Vari RC. Atrial natriuretic factor secretion in dogs with experimental high-output heart failure. Am J Physiol 1987; 252:H692-6.