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Activity of plasma angiotensin II in experimental coarctation of the aorta
Activity of plasma angiotensin II in experimental coarctation of the aorta Will C. Sealy, M.D., Pasit Paniiayanond, M.D., John Alexander, M.D., and Anthony V. Seaber, Durham, N. C.
Rtients with coarctation of the thoracic aorta may have significant arterial hypertension above the coarctation; however, in addition, many have an abnormal elevation of blood pressure below the coarctation. In spite of the hypertension, patients do not have progresive changes that lead to a malignant phase.v 2 The question of why hypertension occurs in coarctation has most often been answered by calling attention to the similarity of the arterial obstruction in coarctation with that seen in renal hypertension. In individuals with hypertension from coarctation of the aorta, elevations of plasma angiotensin II above normal levels are rarely encountered," although two exceptions have been noted from our hospital.4 In experimental coarctation of the aorta,« 6 an immediate elevation in the level of angiotensin II does occur, but this returns to the precoarctation levels within 3 to 9 days, in spite of a continued increase in blood pressure. This study was undertaken for three purposes: (I) to relate exactly the relationship between changes in plasma angiotensin II and the rise in the distal mean blood pressure after experimental coarctation, (2) to relate the persistence of the elevation of angiotensin II with the continued rise in blood From the Division of Thoracic Surgery, Duke University Medicat Center, Durham, N. C. 27701. Supported by U. S. Public Health Service Grants, S TOI HL 05284 and 5 R-l HL 01782 and by the John Klein Fund. Received for publication Aug. 9, 1972.
pressure both above and below the coarctation, and (3) to determine whether a reduction of the distal mean pressure from its postcoarctation levels, without a change in the stenosis, would again increase the angiotensin II levels. Methods
In this study, coarctation of the aorta was produced by the method described below. Anesthesia was induced with sodium thiamylal given intravenously, 30 mg. per kilogram. Through a left lateral thoracotomy incision, a coarctation of the descending aorta was produced by a wedge resection of the aortic wall. The cross-sectional area was reduced to approximately 80 per cent of normal, and a mean arterial pressure gradient from 50 to 100 mm, Hg was produced. Penicillin and streptomycin were given for 3 days after the operation. Arterial blood pressure above and below the coarctation, was measured directly by indwelling catheters placed through the subclavian artery above and the femoral artery below. An indwelling catheter was placed through the femoral vein into the inferior vena cava at a point just above the renal veins for blood samples to determine angiotensin II. Blood pressure readings above and below the coarctation and samples for determination of angiotensin II were taken simultaneously. The angiotensin II determinations were made by the biometric assay method described by Gunnells.' These re283
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Table I. Angiotensin II and hypertension in coarctation of the aorta: A verage changes in 22 dogs
Time
Control Clamp* Immediatelyt 15 min. 1 hr. Day 1 Day 2 Day 3 Day 4 Day 7 Day 14 Day 21 Day 22-28 Day 29-35 Day 36-56 Day 57-77
Proximal mean pressures (mm, Hg)
Distal mean pressures (mm. Hg)
Mean anglotensin levels (ng.llOO ml.)
113 167 157 141 144 129 144 143 146 138 151 166 175 154 188 180
110 0 53 63 81 70 84 90 93 94 112 121 132 130 155 140
413 937 967 954 811 640 557 506 475 430 416 418 365 414 326 360
No. 0/ dogs
22 22 22 22 22 17 16 14 12 12 12 12 9
7 7 3
'Within 2 minutes after complete aortic occlusion. tWithin 2 minutes after release of the clamps.
suits are reported in nanograms per 100 ml. of plasma. In the first group, 22 adult dogs weighing 15 to 20 kilograms, maintained on unrestricted diets, were employed. In this group the following schedule for determinations was made. At least three control blood pressure and angiotensin II determinations were made at different sittings. Then, simultaneous blood pressure recordings and samples for angiotensin II were obtained just before the aorta was crossclamped, while it was clamped, immediately after, and at 15 and 60 minute intervals after the establishment of the coarctation. Simultaneous determinations were made on the awake animal daily for up to 14 days and then at approximately I week intervals thereafter (Table I). In 2 dogs, the aorta was exposed through a left thoracotomy, cross-clamped for 30 minutes, and then released. The abovedescribed schedule for blood pressure and angiotensin II determinations was used. In another group of 6 dogs, a left thoracotomy was carried out, and an inflatable cuff was placed around the aorta at the level of the. second pair of intercostal ar-
teries. It was then brought out through the chest wound, the chest was closed tightly, and ventilation was maintained. Again, blood pressure above and below the coarctation and samples for angiotensin were obtained immediately and at 15, 30, and 60 minutes after a 60 minute period of partial occlusion. This was then followed by 10 minutes of complete occlusion and measurements immediately and at 15, 30, 60, and 90 minutes (Table II). In a third group of animals, the effect of chronic stimulation of the carotid sinus nerve was observed by means of an implanted system consisting of two electrodes, one to each of the carotid sinus nerves. A receiving set was implanted beneath the skin between the scapulas. The electrodes were placed according to the technique of Neistadt and Schwartz. 8 In all of the animals, coarctation of the thoracic aorta had been constructed approximately 3 weeks before, with hypertension established before the installation of the electrodes. Approximately 10 days to 2 weeks later, the program of stimulation was begun. This allowed the electrodes to become stabilized and prevented stimulation of surrounding
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Table II. Effect of temporary constriction of thoracic aorta on angiotensin II levels: A verage in 6 dogs
Description
Proximal mean pressures (mm, Hg)
Distal mean pressures (mm. Hg)
Mean angiotensin Change in angiotensin II II levels (per cent) (ng'/lOO mi.)
Control 108
107
529
Immediately* 15 min. 30 min. 60 min.
Partial constriction 129 33 151 63 150 93 147 78
1,150 875 800 1,158
+117.3 + 65.3 + 51.2 +117.3
10 min.
Complete constriction 178 0
1,588
+200.0
1,278 1,011 795 627 500
+142.5 +91.1 + 50.2 + 18.5 - 3.5
Immediate releaset 15 min. 30 min. 60 min. 90 min.
Release oj 10 min. constriction 139 137 129 128 123 124 121 121 120 120
• Within 2 minutes after partial constriction. tWithin 2 minutes after release of the clamps.
structures. The stimulus was continuously applied with a radio-frequency apparatus * in 4 dogs; it was done for 6 days in 3 animals and for 12 days in 1 dog. Two additional dogs had continuous stimulation for 1 day and for 8 hours, respectively. A stimulus of 50 cycles per second at 5 v., employed in all of the animals, was found to be adequate to cause bradycardia and a reduction in the blood pressure both above and below the constriction. One normal dog had the stimulus applied in the manner described. The determinations of the blood pressure and the angiotensin II levels in this dog were obtained as described above. Results
Of the 22 dogs used, 12 survived beyond 21 days. The ten early deaths were caused by the following: congestive heart failure in 4, operative failure in 3, pulmonary embolus in 2, and an unexplained cause in 1. Both dogs that had the sham operation survived. *Barastat eNS, Medtronic Inc., Minneapolis, Minn.
The data on the 22 dogs that had coarctation are shown in Table I. One hour after construction of the coarctation, plasma renin activity increased 120 per cent, the distal mean blood pressure decreased an average of 29 mm. Hg, and the proximal blood pressure increased an average of 32 mm.Hg. In 17 dogs at the 48 hour period, the distal mean arterial pressure was still 40 mm. Hg below the control, while the angiotensin II level was 30 per cent above control, and the proximal mean blood pressure was an average of 31 mm. Hg above control values. Distal mean blood pressure and angiotensin II levels then returned toward normal, reaching this point usually by the third to the ninth day. However, distal mean blood pressure and proximal mean blood pressure continued to rise at a time when the angiotensin II levels were returning or had returned to the preoperative values. A late phase of stable hypertension occurred between 10 and 21 days after creation of the coarctation. It was characterized by an elevation of the distal mean pressure to an
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average of +25 mm. Hg, a normal angiotensin II level, and a marked elevation in proximal mean blood pressure to an average of +57 mm. Hg. The data on the 12 dogs that survived for 21 days or more are shown in Figs. 1 and 2.
Fig. 3. The relationship of proximal mean blood pressure, distal mean blood pressure, and plasma renin activity in a representative experiment.
The blood pressure changes above and below the coarctation, as well as the levels of angiotensin II, are shown for a typical experiment in Fig. 3. For each dog the angiotensin II levels and distal mean blood pressure were compared independent of time. A regression line, by the method of least squares, and its correlation coefficient were calculated. A positive test for homogeneity was established via the method of Rao." The data on angiotensin II levels and distal mean blood pressure from all dogs were then grouped, and a composite regression line and correlation coefficient were calculated. A significant inverse relationship of distal mean blood pressure and plasma renin activity was shown (r = -0.58, p < 0.01 ). In both dogs that had sham operations, there was a mild elevation in angiotensin II levels, usually an average of 13 per cent, an average increase in distal mean blood pressure of 13 mm. Hg, and a proximal blood pressure of 6 mm. Hg 1 hour following operation. On the second postoperative day, the blood pressure and angiotensin II levels were both normal.
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Table III. The effect of carotid sinus nerve stimulation on blood pressure and angiotensin II in 6 dogs Description Control 15 min. stimulation 60 min. stimulation 120 min. stimulation 4 hr. stimulation 6-8 hr. stimulation Day 1 stimulation Day 3 stimulation Day 5 stimulation Day 7 stimulation Day 9 stimulation Day 12 stimulation Stimulation off
Proximal pressure (mm. Hg)* 219/148 167/113 170/113 155/104 188/128 177/130 171/116 188/119 193/114 208/129 213/135 190/140 210/143
(182) (140) (139) (125) (156) (152) (142) (151) (142) (167) (173) (164) (174)
Distal pressure (mm. Hg)* 158/130 114/94 107/86 105/84 118/105 127/113 115/95 110/89 113/90 135/110 133/110 150/125 145/120
(145) (102) ( 96) ( 93) (120) (119) (104) ( 98) ( 99) (121) (120) (137) (132)
Angiotensin lJ (ng.!lOO ml.)
No. of dogs
512 973 880 957 896 1,155 809 755 769 500 500 484 540
6 6 6 4 2 1 4 4 4 2 2 1 2
• Figures in parentheses are mean values.
In the second group, the aorta was partially constricted for 60 minutes, which produced an average gradient of about 69 mm. Hg followed by a 117 per cent increase in angiotensin II (Table II). After the aorta had been completely occluded for 10 minutes and then released, the angiotensin II levels increased on an average of 142.5 per cent. Actually, the level of angiotensin II was I,158 nanograms per 100 ml. before the complete occlusion; after the complete occlusion was released, the figure was 1,278 nanograms per 100 ml. Ninety minutes after a full aortic lumen had been established, the level of angiotensin II was back to normal range. The third group received continuous stimulation of the carotid sinus nerve (Table III). Fig. 4 shows values for a representative dog, while Fig. 5 provides data on a noncoarctation dog. In the coarctation dogs, there was a bradycardia that persisted. A drop in the blood pressure both above and below the coarctation was associated with an increase in the angiotensin II levels. As can be seen in the figures, the distal mean pressure gradually crept back to the prestimulus level; as this occurred, the angiotensin II levels diminished toward normal. The stimulus was stopped in 2 dogs, after 4 days in 1 and after 8 days in the other. Within 24 hours, the blood pressures above
and below the coarctation, the angiotensin levels, and the pulse rates had returned to the prestimulation levels. After cessation of stimulation in 1 of these 2 animals, the proximal pressure returned to a level of 190/135 mm. Hg (with a mean of 160) from a prestimulus level of 180/120 mm. Hg (mean 148). In this same animal, the distal pressure was increased to 140/115 mm. Hg (mean 127) from the stimulus level of 95/70 mm. Hg (mean 77). At this time the angiotensin level was 600 nanograms for 100 mI., which was the level recorded before the stimulus was instituted. A similar finding was noted in another dog that was continuously stimulated for 8 hours: The angiotensin level returned the next day to 500 nanograms per 100 ml. from the stimulus level of 1,111. The proximal blood pressure on the day after stimulation was 220/150 mm. Hg (mean 188), an increase from 180/135 mm. Hg, while a mean of 157 mm. Hg was noted when stimulation was in progress. The distal pressure returned to 150/130 mm. Hg (mean 139) from 130/115 mm. Hg (mean 122). The response of stimulation of the control dog is shown in Fig. 5. The same pattern occurred, with the angiotensin II level returning to normal while the mean distal blood pressure escaped to the prestimulation level.
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It was noted that in the experimental and the control dogs, the increase in angiotensin II occurred within 15 minutes after the start of stimulation. Discussion Experimental coarctation of the thoracic aorta, although a simple vascular obstruction, initiates a complex series of events that eventually results in arterial hypertension both above and below the coarctation site. In an attempt to explain the pathogenesis of the hypertension, other observers have noted that the level of plasma angiotensin II becomes elevated above normal for a few days after experimental coarctation of the aorta. Our studies on experimental coarctation have confirmed this; however, they have been further extended to determine more precisely the correlation between the changes in the blood pressure above and below the stenotic area with the appearance and disappearance of the increase in the plasma angiotensin II level. Angiotensin II was found to increase as soon as the aorta was cross-clamped and to remain elevated
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immediately after the coarctation was established. From that point on, there was a gradual diminution in the angiotensin II level as the distal mean blood pressure returned to its precoarctation range. The relationship between the angiotensin II level and the distal mean blood pressure behaved as a negative feedback system, with the distal mean pressure as the afferent loop and the plasma angiotensin II level as the efferent loop. Thus, one must assume that angiotensin II must in some way have altered the blood pressure. However, this effect was more complex than could be explained by pressor action of angiotensin II. During the immediate postcoarctation period, the proximal mean blood pressure, after an immediate rise for an hour or so, dropped back to almost normal at a time when the angiotensin II level was the highest. The proximal pressure remained at this range for the first day or so and then gradually increased to hypertensive levels, although it did not become stable until about 14 to 21 days had passed. Even though the level of angiotensin II had now reverted to normal, the distal mean arterial pressure continued to increase at approximately the same rate as the proximal mean arterial pressure. Both distal and proximal pressures
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Plasma angiotensin II in coarctation oj aorta
usually became stable and definitely hypertensive at about 14 to 21 days. The role of angiotensin II in initiating hypertension is still unclear, even though its changes were followed closely in our studies. When angiotensin II was at its highest level, the proximal mean arterial pressure was neither at its peak postcoarctation level nor even markedly elevated. If angiotensin II was sufficiently concentrated to exert a pressor effect, it would be expected to raise this pressure. Since the increase in the pressure, both above and below the coarctation, was gradual, it is possible that the increase was based on a blood volume change such as might be caused by aldosterone increase, which could result from the effect of angiotensin II on the adrenals. However, when the aorta was crossclamped, angiotensin II increased rather strikingly over a period as short as 15 minutes or less. Thus our studies do not make it clear whether angiotensin II works by exerting its vasopressor quality, or by acting on the aldosterone system, or perhaps by a combination of both. The increase in pressure continued for such a long time after angiotensin II returned to normal that it was not likely that it acted to reset the baroreceptors in the carotid and aortic areas. Since renal artery stenosis produced by Goldblatt's'? method can cause arterial hypertension, it has been assumed that the hypertension seen in coarctation is similar. However, there are differences between experimental renal and coarctation hypertension. The coarctation divides the body into two large vascular compartments serviced by one pump, with large vascular beds other than the renal bed in the compartment below the constriction. The nonrenal vascular beds have to adjust to changes in pressure and flow, and it is not illogical to assume that they do so by reflexes or hormonal action on the cardiovascular system, both locally and systemically. How effective this is in driving the blood pressure up is difficult to assess. Pressure may be maintained by autoregulation, as proposed by Guyton." The
289
dominant role of the kidney in the control of hypertension related to experimental coarctation of the aorta is supported by the work of Scott and his colleagues.w-> These observers, in several different studies on the dog, noted that when the kidney was transplanted into the neck above the site of the aortic constriction, the hypertension disappeared. Of course, others have noted that coarctation below the renal arteries fails to produce hypertension above them. On the other hand, the observations of Habib" as well as studies in our laboratory have thrown some doubt on the premise that the transfer of the kidney above the coarctation always causes the pressure to revert to normal, particularly in long-term experiments. Continued elevation of angiotensin II, even in the face of severe hypertension, does not always occur in experimental renal hypertension in dogs. Thus the reversion of angiotensin II to normal levels in experimental coarctation cannot be used as an argument against a renal factor. 1 0 - 1 9 The other mechanisms that increase and maintain hypertension in the kidney are still the subject of great controversy. The continued rise in blood pressure, both above and below the coarctation, even after plasma angiotensin II returns to normal, does point to other influences, which in coarctation could arise from other organs as well as the kidneys. Another difference between the two types is the fact that a malignant variety of hypertension can be produced in experimental renal hypertension, whereas this has not occurred in experimental coarctation of the aorta. In addition, man does not develop malignant hypertension with coarctation except after removal of the obstructions"; on the other hand, such an occurrence is well known in renal hypertension. The effect of continuous stimulation of the carotid sinus nerve on experimental hypertension was of interest, for temporarily the high pressure was reduced. Again, a negative feedback mechanism was operative in this situation, just as when the coarctation was created. When the distal mean blood pressure was reduced, the angiotensin II
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levels increased, only to revert to normal when the distal mean blood pressure again approached the hypertensive range. Although these experiments were not designed to study the efficacy of continuous carotid sinus nerve stimulation for control of hypertension, it was of interest that, after 3 to 5 days in 4 of the dogs, in spite of maintenance of the bradycardia, the blood pressure returned to its prestimulation levels. Thus the hypertension "escaped" from the control of the buffer nerves. The events recorded in experimental coarctation hypertension are difficult to relate to the hypertension that is associated with the disorder in man. However, there are certain aspects that are worthy of comment. The hypertension in clinical coarctation is benign, since it is not associated with small vessel changes or the clinical state of malignant hypertension. Its principle adverse effects occur locally at the coarctation site and perhaps in the left ventricle. The findings in experimental coarctation are consistent with this. However, it is of great interest that a malignant variety of hypertension related to coarctation does occur in man; paradoxically, it occurs after the removal of the coarctation and restoration of the aortic lumen to normal size. Actually, there are two types of hypertension that develop at this time. The first occurs within 24 hours after operation and is transient. The systolic pressure is the most strikingly elevated, with a high of 280 mm. Hg sometimes recorded. An explanation for this unexpected and sometimes alarming increase in blood pressure is the increase in buffer nerve activity resulting from the release of tension in the carotid and aortic areas that follows the relief of the aortic coarctation. The second variety of hypertension, strikingly diastolic, is more dramatic, and its origin is still more obscure. It occurs about 36 to 48 hours after restoration of the aortic lumen to normal size. This is a true malignant variety of hypertension. There is marked arteriolar degeneration, but it occurs only in those vessels below the coarctation site. Eventually, infarction and necrosis of the bowel
Thoracic and Cardiovascular Surgery
may occur. Studies reported in this laboratory have shown that there is a marked increase in norepinephrine secretion" after resection of coarctation of the aorta in most patients. It is possible that the increase in norepinephrine, acting on the vascular bed below the coarctation, a bed that is different perhaps because of increased arteriolar tone, causes almost complete obstruction. This greatly increases the peripheral resistance and causes the diastolic hypertension. If obstruction were almost complete, gangrene and necrosis would occur. The postulated increased tone in the distal arteriolar bed could be a manifestation of autoregulation. It is interesting to speculate whether the two stages of hypertension that occur before the pressure returns to normal after resection represents stages that, in reverse, might occur when experimental coarctation-related hypertension is induced. This study has confirmed that, immediately after experimental coarctation, there is an increase in the activity in the reninangiotensin system that is related directly to the level of the distal mean arterial blood pressure. This mechanism apparently ceases when the distal pressure reaches approximate precoarctation levels, but it can be started again by dropping the distal pressure with continuous stimulation of the carotid sinue nerve. Since the. proximal mean blood pressure requires 2 to 3 days to reach hypertensive levels and the distal mean pressure requires the same period of time to reach even precoarctation levels, it appears that the action of the increased angiotensin II level involves an aldosterone rather than a pressor mechanism.
Conclusion As with hypertension from other causes, both known and unknown, the type of hypertension found in experimental coarctation is exceedingly complex. First, a simple obstruction is induced. Second, a pressor and aldosterone stimulating substance is elaborated by the kidney and plays a role for a few days. Then the renal hormonal substance returns to normal, but the hyper-
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tension continues to develop, both increased and maintained by unknown factors that may be of both renal and nonrenal origin. REFERENCES Reifenstein, G. H., Levine, S. A., and Gross, R. E.: Coarctation of the Aorta, Am. Heart J. 33: 146, 1947. 2 Sealy, W. C.: Indications for Surgical Treatment of Coarctation of the Aorta, Surg. Gynecol. Obstet. 97: 301, 1953. 3 Amsterdam, E. A., Albers, W. H., Christlieb, A. R., Morgan, C. L., Nadas, A. S., and Hickler, R. B.: Plasma Renin Activity in Children With Coarctation of the Aorta, Am. J. Cardiol. 23: 396, 1969. 4 Sealy, W. C.: Coarctation of the Aorta and Hypertension, Ann. Thorac. Surg, 3: 15, 1967. 5 Yagi, S., Kramsch, D. M., Madoff, I. M., and Hollander, W.: Plasma Renin Activity in Hypertension Associated With Coarctation of the Aorta, Am. J. Physiol. 115: 605, 1968. 6 Van Way, C. W., Anderson, W. J., Michelakis, A. M., Manlove, A., and Oates, J. A.: The Role of Renin in Coarctation of the Aorta. Surg, Forum 20: 207, 1969. 7 Gunnells, J. C., Jr., Grim, C. E., Robinson, R. R., and Wildermann, N. M.: Plasma Renin Activity in Healthy Subjects and Patients With Hypertension, Arch. Intern. Med. 119: 232, 1967. 8 Neistadt, A., and Schwartz, S. I.: Effects of Electrical Stimulation of the Carotid Sinus Nerve in Reversal of Experimentally Induced Hypertension, Surgery 61: 923, 1967. 9 Rao, C. R.: Advanced Statistical Methods in Biometric Research, New York, 1952, John Wiley & Sons, Inc., pp. 230-235. 10 Goldblatt, H., Kahn, J. R., and Hanzel, R. F.: Studies on Experimental Hypertension: The Effect On Blood Pressure of Constriction of the Abdominal Aorta Above and Below the Site of Origin of Both Main Renal Arteries, J. Exp. Med. 69: 649, 1939. II Guyton, A. C., Coleman, T. G., Fourcade, J. C., and Navar, L. G.: Physiologic Control of Arterial Pressure, Bull. N. Y. Acad. Med. 45: 811, 1969.
12 Scott, H. W., Jr., and Bahnson, H. T.: Evidence For a Renal Factor in the Hypertension of Experimental Coarctation of the Aorta, Surgery 30: 206, 1951. 13 Scott, H. W., Jr., Collins, H. A., Langa, A. M., and Olsen, N. S.: Additional Observations Concerning the Physiology of the Hypertension Associated With Experimental Coarctation of the Aorta, Surgery 36: 445, 1954. 14 Scott, H. W., Jr., McGee, L. S., Jr., Youngblood, R. W., Killen, D. A., Harris, A. P., and Lance, E. M.: Further Studies of Renal and Adrenal Factors in the Hypertension of Coarctation of the Aorta, Surg. Forum 9: 343, 1958. 15 Habib, W. K., and Nanson, E. M.: The Causes of Hypertension in Coarctation of the Aorta, Ann. Surg. 168: 771, 1968. 16 Brown, T. C., Davis, J. 0., Olichney, M. J., and Johnston, C. I.: Relation of Plasma Renin to Sodium Balance and Arterial Pressure in Experimental Renal Hypertension, Circ. Res. 18: 475, 1966. 17 Blair-West, 1. R., Coghlan, J. P., Denton, D. A., Orchard, E., Scoggins, B. A., and Wright, R. D.: Renin-Angiotension-Aldosterone System and Sodium Balance in Experimental Renal Hypertension, Endocrinology 83: 1199, 1968. 18 Bianchi, G., Tenconi, L. T., and Lucca, R.: Effect in the Conscious Dog of Constriction of the Renal Artery to a Sole Remaining Kidney on Haemodynamics, Sodium Balance, Body Fluid Volumes, Plasma Renin Concentration and Pressor Responsiveness to Angiotensin, Clin. Sci. 38: 741, 1970. 19 Gross, F.: The Renin-Angiotensin System and Hypertension, Ann. Intern. Med. 75: 777, 1971. 20 Sealy, W. c., Harris, J. S., Young, W. G., Jr., and Callaway, H. A., Jr.: Paradoxical Hypertension Following Resection of Coarctation of the Aorta, Surgery 42: 135, 1957. 21 Goodall, M. C., and Sealy, W. C.: Increased Sympathetic Nerve Activity Following Resection of Coarctation of the Thoracic Aorta, Circulation 39: 345, 1969.
Rtients with coarctation of the thoracic aorta may have significant arterial hypertension above the coarctation; however, in addition, many have an abnormal elevation of blood pressure below the coarctation. In spite of the hypertension, patients do not have progresive changes that lead to a malignant phase.v 2 The question of why hypertension occurs in coarctation has most often been answered by calling attention to the similarity of the arterial obstruction in coarctation with that seen in renal hypertension. In individuals with hypertension from coarctation of the aorta, elevations of plasma angiotensin II above normal levels are rarely encountered," although two exceptions have been noted from our hospital.4 In experimental coarctation of the aorta,« 6 an immediate elevation in the level of angiotensin II does occur, but this returns to the precoarctation levels within 3 to 9 days, in spite of a continued increase in blood pressure. This study was undertaken for three purposes: (I) to relate exactly the relationship between changes in plasma angiotensin II and the rise in the distal mean blood pressure after experimental coarctation, (2) to relate the persistence of the elevation of angiotensin II with the continued rise in blood From the Division of Thoracic Surgery, Duke University Medicat Center, Durham, N. C. 27701. Supported by U. S. Public Health Service Grants, S TOI HL 05284 and 5 R-l HL 01782 and by the John Klein Fund. Received for publication Aug. 9, 1972.
pressure both above and below the coarctation, and (3) to determine whether a reduction of the distal mean pressure from its postcoarctation levels, without a change in the stenosis, would again increase the angiotensin II levels. Methods
In this study, coarctation of the aorta was produced by the method described below. Anesthesia was induced with sodium thiamylal given intravenously, 30 mg. per kilogram. Through a left lateral thoracotomy incision, a coarctation of the descending aorta was produced by a wedge resection of the aortic wall. The cross-sectional area was reduced to approximately 80 per cent of normal, and a mean arterial pressure gradient from 50 to 100 mm, Hg was produced. Penicillin and streptomycin were given for 3 days after the operation. Arterial blood pressure above and below the coarctation, was measured directly by indwelling catheters placed through the subclavian artery above and the femoral artery below. An indwelling catheter was placed through the femoral vein into the inferior vena cava at a point just above the renal veins for blood samples to determine angiotensin II. Blood pressure readings above and below the coarctation and samples for determination of angiotensin II were taken simultaneously. The angiotensin II determinations were made by the biometric assay method described by Gunnells.' These re283
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Table I. Angiotensin II and hypertension in coarctation of the aorta: A verage changes in 22 dogs
Time
Control Clamp* Immediatelyt 15 min. 1 hr. Day 1 Day 2 Day 3 Day 4 Day 7 Day 14 Day 21 Day 22-28 Day 29-35 Day 36-56 Day 57-77
Proximal mean pressures (mm, Hg)
Distal mean pressures (mm. Hg)
Mean anglotensin levels (ng.llOO ml.)
113 167 157 141 144 129 144 143 146 138 151 166 175 154 188 180
110 0 53 63 81 70 84 90 93 94 112 121 132 130 155 140
413 937 967 954 811 640 557 506 475 430 416 418 365 414 326 360
No. 0/ dogs
22 22 22 22 22 17 16 14 12 12 12 12 9
7 7 3
'Within 2 minutes after complete aortic occlusion. tWithin 2 minutes after release of the clamps.
suits are reported in nanograms per 100 ml. of plasma. In the first group, 22 adult dogs weighing 15 to 20 kilograms, maintained on unrestricted diets, were employed. In this group the following schedule for determinations was made. At least three control blood pressure and angiotensin II determinations were made at different sittings. Then, simultaneous blood pressure recordings and samples for angiotensin II were obtained just before the aorta was crossclamped, while it was clamped, immediately after, and at 15 and 60 minute intervals after the establishment of the coarctation. Simultaneous determinations were made on the awake animal daily for up to 14 days and then at approximately I week intervals thereafter (Table I). In 2 dogs, the aorta was exposed through a left thoracotomy, cross-clamped for 30 minutes, and then released. The abovedescribed schedule for blood pressure and angiotensin II determinations was used. In another group of 6 dogs, a left thoracotomy was carried out, and an inflatable cuff was placed around the aorta at the level of the. second pair of intercostal ar-
teries. It was then brought out through the chest wound, the chest was closed tightly, and ventilation was maintained. Again, blood pressure above and below the coarctation and samples for angiotensin were obtained immediately and at 15, 30, and 60 minutes after a 60 minute period of partial occlusion. This was then followed by 10 minutes of complete occlusion and measurements immediately and at 15, 30, 60, and 90 minutes (Table II). In a third group of animals, the effect of chronic stimulation of the carotid sinus nerve was observed by means of an implanted system consisting of two electrodes, one to each of the carotid sinus nerves. A receiving set was implanted beneath the skin between the scapulas. The electrodes were placed according to the technique of Neistadt and Schwartz. 8 In all of the animals, coarctation of the thoracic aorta had been constructed approximately 3 weeks before, with hypertension established before the installation of the electrodes. Approximately 10 days to 2 weeks later, the program of stimulation was begun. This allowed the electrodes to become stabilized and prevented stimulation of surrounding
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Table II. Effect of temporary constriction of thoracic aorta on angiotensin II levels: A verage in 6 dogs
Description
Proximal mean pressures (mm, Hg)
Distal mean pressures (mm. Hg)
Mean angiotensin Change in angiotensin II II levels (per cent) (ng'/lOO mi.)
Control 108
107
529
Immediately* 15 min. 30 min. 60 min.
Partial constriction 129 33 151 63 150 93 147 78
1,150 875 800 1,158
+117.3 + 65.3 + 51.2 +117.3
10 min.
Complete constriction 178 0
1,588
+200.0
1,278 1,011 795 627 500
+142.5 +91.1 + 50.2 + 18.5 - 3.5
Immediate releaset 15 min. 30 min. 60 min. 90 min.
Release oj 10 min. constriction 139 137 129 128 123 124 121 121 120 120
• Within 2 minutes after partial constriction. tWithin 2 minutes after release of the clamps.
structures. The stimulus was continuously applied with a radio-frequency apparatus * in 4 dogs; it was done for 6 days in 3 animals and for 12 days in 1 dog. Two additional dogs had continuous stimulation for 1 day and for 8 hours, respectively. A stimulus of 50 cycles per second at 5 v., employed in all of the animals, was found to be adequate to cause bradycardia and a reduction in the blood pressure both above and below the constriction. One normal dog had the stimulus applied in the manner described. The determinations of the blood pressure and the angiotensin II levels in this dog were obtained as described above. Results
Of the 22 dogs used, 12 survived beyond 21 days. The ten early deaths were caused by the following: congestive heart failure in 4, operative failure in 3, pulmonary embolus in 2, and an unexplained cause in 1. Both dogs that had the sham operation survived. *Barastat eNS, Medtronic Inc., Minneapolis, Minn.
The data on the 22 dogs that had coarctation are shown in Table I. One hour after construction of the coarctation, plasma renin activity increased 120 per cent, the distal mean blood pressure decreased an average of 29 mm. Hg, and the proximal blood pressure increased an average of 32 mm.Hg. In 17 dogs at the 48 hour period, the distal mean arterial pressure was still 40 mm. Hg below the control, while the angiotensin II level was 30 per cent above control, and the proximal mean blood pressure was an average of 31 mm. Hg above control values. Distal mean blood pressure and angiotensin II levels then returned toward normal, reaching this point usually by the third to the ninth day. However, distal mean blood pressure and proximal mean blood pressure continued to rise at a time when the angiotensin II levels were returning or had returned to the preoperative values. A late phase of stable hypertension occurred between 10 and 21 days after creation of the coarctation. It was characterized by an elevation of the distal mean pressure to an
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average of +25 mm. Hg, a normal angiotensin II level, and a marked elevation in proximal mean blood pressure to an average of +57 mm. Hg. The data on the 12 dogs that survived for 21 days or more are shown in Figs. 1 and 2.
Fig. 3. The relationship of proximal mean blood pressure, distal mean blood pressure, and plasma renin activity in a representative experiment.
The blood pressure changes above and below the coarctation, as well as the levels of angiotensin II, are shown for a typical experiment in Fig. 3. For each dog the angiotensin II levels and distal mean blood pressure were compared independent of time. A regression line, by the method of least squares, and its correlation coefficient were calculated. A positive test for homogeneity was established via the method of Rao." The data on angiotensin II levels and distal mean blood pressure from all dogs were then grouped, and a composite regression line and correlation coefficient were calculated. A significant inverse relationship of distal mean blood pressure and plasma renin activity was shown (r = -0.58, p < 0.01 ). In both dogs that had sham operations, there was a mild elevation in angiotensin II levels, usually an average of 13 per cent, an average increase in distal mean blood pressure of 13 mm. Hg, and a proximal blood pressure of 6 mm. Hg 1 hour following operation. On the second postoperative day, the blood pressure and angiotensin II levels were both normal.
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Table III. The effect of carotid sinus nerve stimulation on blood pressure and angiotensin II in 6 dogs Description Control 15 min. stimulation 60 min. stimulation 120 min. stimulation 4 hr. stimulation 6-8 hr. stimulation Day 1 stimulation Day 3 stimulation Day 5 stimulation Day 7 stimulation Day 9 stimulation Day 12 stimulation Stimulation off
Proximal pressure (mm. Hg)* 219/148 167/113 170/113 155/104 188/128 177/130 171/116 188/119 193/114 208/129 213/135 190/140 210/143
(182) (140) (139) (125) (156) (152) (142) (151) (142) (167) (173) (164) (174)
Distal pressure (mm. Hg)* 158/130 114/94 107/86 105/84 118/105 127/113 115/95 110/89 113/90 135/110 133/110 150/125 145/120
(145) (102) ( 96) ( 93) (120) (119) (104) ( 98) ( 99) (121) (120) (137) (132)
Angiotensin lJ (ng.!lOO ml.)
No. of dogs
512 973 880 957 896 1,155 809 755 769 500 500 484 540
6 6 6 4 2 1 4 4 4 2 2 1 2
• Figures in parentheses are mean values.
In the second group, the aorta was partially constricted for 60 minutes, which produced an average gradient of about 69 mm. Hg followed by a 117 per cent increase in angiotensin II (Table II). After the aorta had been completely occluded for 10 minutes and then released, the angiotensin II levels increased on an average of 142.5 per cent. Actually, the level of angiotensin II was I,158 nanograms per 100 ml. before the complete occlusion; after the complete occlusion was released, the figure was 1,278 nanograms per 100 ml. Ninety minutes after a full aortic lumen had been established, the level of angiotensin II was back to normal range. The third group received continuous stimulation of the carotid sinus nerve (Table III). Fig. 4 shows values for a representative dog, while Fig. 5 provides data on a noncoarctation dog. In the coarctation dogs, there was a bradycardia that persisted. A drop in the blood pressure both above and below the coarctation was associated with an increase in the angiotensin II levels. As can be seen in the figures, the distal mean pressure gradually crept back to the prestimulus level; as this occurred, the angiotensin II levels diminished toward normal. The stimulus was stopped in 2 dogs, after 4 days in 1 and after 8 days in the other. Within 24 hours, the blood pressures above
and below the coarctation, the angiotensin levels, and the pulse rates had returned to the prestimulation levels. After cessation of stimulation in 1 of these 2 animals, the proximal pressure returned to a level of 190/135 mm. Hg (with a mean of 160) from a prestimulus level of 180/120 mm. Hg (mean 148). In this same animal, the distal pressure was increased to 140/115 mm. Hg (mean 127) from the stimulus level of 95/70 mm. Hg (mean 77). At this time the angiotensin level was 600 nanograms for 100 mI., which was the level recorded before the stimulus was instituted. A similar finding was noted in another dog that was continuously stimulated for 8 hours: The angiotensin level returned the next day to 500 nanograms per 100 ml. from the stimulus level of 1,111. The proximal blood pressure on the day after stimulation was 220/150 mm. Hg (mean 188), an increase from 180/135 mm. Hg, while a mean of 157 mm. Hg was noted when stimulation was in progress. The distal pressure returned to 150/130 mm. Hg (mean 139) from 130/115 mm. Hg (mean 122). The response of stimulation of the control dog is shown in Fig. 5. The same pattern occurred, with the angiotensin II level returning to normal while the mean distal blood pressure escaped to the prestimulation level.
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It was noted that in the experimental and the control dogs, the increase in angiotensin II occurred within 15 minutes after the start of stimulation. Discussion Experimental coarctation of the thoracic aorta, although a simple vascular obstruction, initiates a complex series of events that eventually results in arterial hypertension both above and below the coarctation site. In an attempt to explain the pathogenesis of the hypertension, other observers have noted that the level of plasma angiotensin II becomes elevated above normal for a few days after experimental coarctation of the aorta. Our studies on experimental coarctation have confirmed this; however, they have been further extended to determine more precisely the correlation between the changes in the blood pressure above and below the stenotic area with the appearance and disappearance of the increase in the plasma angiotensin II level. Angiotensin II was found to increase as soon as the aorta was cross-clamped and to remain elevated
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immediately after the coarctation was established. From that point on, there was a gradual diminution in the angiotensin II level as the distal mean blood pressure returned to its precoarctation range. The relationship between the angiotensin II level and the distal mean blood pressure behaved as a negative feedback system, with the distal mean pressure as the afferent loop and the plasma angiotensin II level as the efferent loop. Thus, one must assume that angiotensin II must in some way have altered the blood pressure. However, this effect was more complex than could be explained by pressor action of angiotensin II. During the immediate postcoarctation period, the proximal mean blood pressure, after an immediate rise for an hour or so, dropped back to almost normal at a time when the angiotensin II level was the highest. The proximal pressure remained at this range for the first day or so and then gradually increased to hypertensive levels, although it did not become stable until about 14 to 21 days had passed. Even though the level of angiotensin II had now reverted to normal, the distal mean arterial pressure continued to increase at approximately the same rate as the proximal mean arterial pressure. Both distal and proximal pressures
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Plasma angiotensin II in coarctation oj aorta
usually became stable and definitely hypertensive at about 14 to 21 days. The role of angiotensin II in initiating hypertension is still unclear, even though its changes were followed closely in our studies. When angiotensin II was at its highest level, the proximal mean arterial pressure was neither at its peak postcoarctation level nor even markedly elevated. If angiotensin II was sufficiently concentrated to exert a pressor effect, it would be expected to raise this pressure. Since the increase in the pressure, both above and below the coarctation, was gradual, it is possible that the increase was based on a blood volume change such as might be caused by aldosterone increase, which could result from the effect of angiotensin II on the adrenals. However, when the aorta was crossclamped, angiotensin II increased rather strikingly over a period as short as 15 minutes or less. Thus our studies do not make it clear whether angiotensin II works by exerting its vasopressor quality, or by acting on the aldosterone system, or perhaps by a combination of both. The increase in pressure continued for such a long time after angiotensin II returned to normal that it was not likely that it acted to reset the baroreceptors in the carotid and aortic areas. Since renal artery stenosis produced by Goldblatt's'? method can cause arterial hypertension, it has been assumed that the hypertension seen in coarctation is similar. However, there are differences between experimental renal and coarctation hypertension. The coarctation divides the body into two large vascular compartments serviced by one pump, with large vascular beds other than the renal bed in the compartment below the constriction. The nonrenal vascular beds have to adjust to changes in pressure and flow, and it is not illogical to assume that they do so by reflexes or hormonal action on the cardiovascular system, both locally and systemically. How effective this is in driving the blood pressure up is difficult to assess. Pressure may be maintained by autoregulation, as proposed by Guyton." The
289
dominant role of the kidney in the control of hypertension related to experimental coarctation of the aorta is supported by the work of Scott and his colleagues.w-> These observers, in several different studies on the dog, noted that when the kidney was transplanted into the neck above the site of the aortic constriction, the hypertension disappeared. Of course, others have noted that coarctation below the renal arteries fails to produce hypertension above them. On the other hand, the observations of Habib" as well as studies in our laboratory have thrown some doubt on the premise that the transfer of the kidney above the coarctation always causes the pressure to revert to normal, particularly in long-term experiments. Continued elevation of angiotensin II, even in the face of severe hypertension, does not always occur in experimental renal hypertension in dogs. Thus the reversion of angiotensin II to normal levels in experimental coarctation cannot be used as an argument against a renal factor. 1 0 - 1 9 The other mechanisms that increase and maintain hypertension in the kidney are still the subject of great controversy. The continued rise in blood pressure, both above and below the coarctation, even after plasma angiotensin II returns to normal, does point to other influences, which in coarctation could arise from other organs as well as the kidneys. Another difference between the two types is the fact that a malignant variety of hypertension can be produced in experimental renal hypertension, whereas this has not occurred in experimental coarctation of the aorta. In addition, man does not develop malignant hypertension with coarctation except after removal of the obstructions"; on the other hand, such an occurrence is well known in renal hypertension. The effect of continuous stimulation of the carotid sinus nerve on experimental hypertension was of interest, for temporarily the high pressure was reduced. Again, a negative feedback mechanism was operative in this situation, just as when the coarctation was created. When the distal mean blood pressure was reduced, the angiotensin II
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levels increased, only to revert to normal when the distal mean blood pressure again approached the hypertensive range. Although these experiments were not designed to study the efficacy of continuous carotid sinus nerve stimulation for control of hypertension, it was of interest that, after 3 to 5 days in 4 of the dogs, in spite of maintenance of the bradycardia, the blood pressure returned to its prestimulation levels. Thus the hypertension "escaped" from the control of the buffer nerves. The events recorded in experimental coarctation hypertension are difficult to relate to the hypertension that is associated with the disorder in man. However, there are certain aspects that are worthy of comment. The hypertension in clinical coarctation is benign, since it is not associated with small vessel changes or the clinical state of malignant hypertension. Its principle adverse effects occur locally at the coarctation site and perhaps in the left ventricle. The findings in experimental coarctation are consistent with this. However, it is of great interest that a malignant variety of hypertension related to coarctation does occur in man; paradoxically, it occurs after the removal of the coarctation and restoration of the aortic lumen to normal size. Actually, there are two types of hypertension that develop at this time. The first occurs within 24 hours after operation and is transient. The systolic pressure is the most strikingly elevated, with a high of 280 mm. Hg sometimes recorded. An explanation for this unexpected and sometimes alarming increase in blood pressure is the increase in buffer nerve activity resulting from the release of tension in the carotid and aortic areas that follows the relief of the aortic coarctation. The second variety of hypertension, strikingly diastolic, is more dramatic, and its origin is still more obscure. It occurs about 36 to 48 hours after restoration of the aortic lumen to normal size. This is a true malignant variety of hypertension. There is marked arteriolar degeneration, but it occurs only in those vessels below the coarctation site. Eventually, infarction and necrosis of the bowel
Thoracic and Cardiovascular Surgery
may occur. Studies reported in this laboratory have shown that there is a marked increase in norepinephrine secretion" after resection of coarctation of the aorta in most patients. It is possible that the increase in norepinephrine, acting on the vascular bed below the coarctation, a bed that is different perhaps because of increased arteriolar tone, causes almost complete obstruction. This greatly increases the peripheral resistance and causes the diastolic hypertension. If obstruction were almost complete, gangrene and necrosis would occur. The postulated increased tone in the distal arteriolar bed could be a manifestation of autoregulation. It is interesting to speculate whether the two stages of hypertension that occur before the pressure returns to normal after resection represents stages that, in reverse, might occur when experimental coarctation-related hypertension is induced. This study has confirmed that, immediately after experimental coarctation, there is an increase in the activity in the reninangiotensin system that is related directly to the level of the distal mean arterial blood pressure. This mechanism apparently ceases when the distal pressure reaches approximate precoarctation levels, but it can be started again by dropping the distal pressure with continuous stimulation of the carotid sinue nerve. Since the. proximal mean blood pressure requires 2 to 3 days to reach hypertensive levels and the distal mean pressure requires the same period of time to reach even precoarctation levels, it appears that the action of the increased angiotensin II level involves an aldosterone rather than a pressor mechanism.
Conclusion As with hypertension from other causes, both known and unknown, the type of hypertension found in experimental coarctation is exceedingly complex. First, a simple obstruction is induced. Second, a pressor and aldosterone stimulating substance is elaborated by the kidney and plays a role for a few days. Then the renal hormonal substance returns to normal, but the hyper-
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tension continues to develop, both increased and maintained by unknown factors that may be of both renal and nonrenal origin. REFERENCES Reifenstein, G. H., Levine, S. A., and Gross, R. E.: Coarctation of the Aorta, Am. Heart J. 33: 146, 1947. 2 Sealy, W. C.: Indications for Surgical Treatment of Coarctation of the Aorta, Surg. Gynecol. Obstet. 97: 301, 1953. 3 Amsterdam, E. A., Albers, W. H., Christlieb, A. R., Morgan, C. L., Nadas, A. S., and Hickler, R. B.: Plasma Renin Activity in Children With Coarctation of the Aorta, Am. J. Cardiol. 23: 396, 1969. 4 Sealy, W. C.: Coarctation of the Aorta and Hypertension, Ann. Thorac. Surg, 3: 15, 1967. 5 Yagi, S., Kramsch, D. M., Madoff, I. M., and Hollander, W.: Plasma Renin Activity in Hypertension Associated With Coarctation of the Aorta, Am. J. Physiol. 115: 605, 1968. 6 Van Way, C. W., Anderson, W. J., Michelakis, A. M., Manlove, A., and Oates, J. A.: The Role of Renin in Coarctation of the Aorta. Surg, Forum 20: 207, 1969. 7 Gunnells, J. C., Jr., Grim, C. E., Robinson, R. R., and Wildermann, N. M.: Plasma Renin Activity in Healthy Subjects and Patients With Hypertension, Arch. Intern. Med. 119: 232, 1967. 8 Neistadt, A., and Schwartz, S. I.: Effects of Electrical Stimulation of the Carotid Sinus Nerve in Reversal of Experimentally Induced Hypertension, Surgery 61: 923, 1967. 9 Rao, C. R.: Advanced Statistical Methods in Biometric Research, New York, 1952, John Wiley & Sons, Inc., pp. 230-235. 10 Goldblatt, H., Kahn, J. R., and Hanzel, R. F.: Studies on Experimental Hypertension: The Effect On Blood Pressure of Constriction of the Abdominal Aorta Above and Below the Site of Origin of Both Main Renal Arteries, J. Exp. Med. 69: 649, 1939. II Guyton, A. C., Coleman, T. G., Fourcade, J. C., and Navar, L. G.: Physiologic Control of Arterial Pressure, Bull. N. Y. Acad. Med. 45: 811, 1969.
12 Scott, H. W., Jr., and Bahnson, H. T.: Evidence For a Renal Factor in the Hypertension of Experimental Coarctation of the Aorta, Surgery 30: 206, 1951. 13 Scott, H. W., Jr., Collins, H. A., Langa, A. M., and Olsen, N. S.: Additional Observations Concerning the Physiology of the Hypertension Associated With Experimental Coarctation of the Aorta, Surgery 36: 445, 1954. 14 Scott, H. W., Jr., McGee, L. S., Jr., Youngblood, R. W., Killen, D. A., Harris, A. P., and Lance, E. M.: Further Studies of Renal and Adrenal Factors in the Hypertension of Coarctation of the Aorta, Surg. Forum 9: 343, 1958. 15 Habib, W. K., and Nanson, E. M.: The Causes of Hypertension in Coarctation of the Aorta, Ann. Surg. 168: 771, 1968. 16 Brown, T. C., Davis, J. 0., Olichney, M. J., and Johnston, C. I.: Relation of Plasma Renin to Sodium Balance and Arterial Pressure in Experimental Renal Hypertension, Circ. Res. 18: 475, 1966. 17 Blair-West, 1. R., Coghlan, J. P., Denton, D. A., Orchard, E., Scoggins, B. A., and Wright, R. D.: Renin-Angiotension-Aldosterone System and Sodium Balance in Experimental Renal Hypertension, Endocrinology 83: 1199, 1968. 18 Bianchi, G., Tenconi, L. T., and Lucca, R.: Effect in the Conscious Dog of Constriction of the Renal Artery to a Sole Remaining Kidney on Haemodynamics, Sodium Balance, Body Fluid Volumes, Plasma Renin Concentration and Pressor Responsiveness to Angiotensin, Clin. Sci. 38: 741, 1970. 19 Gross, F.: The Renin-Angiotensin System and Hypertension, Ann. Intern. Med. 75: 777, 1971. 20 Sealy, W. c., Harris, J. S., Young, W. G., Jr., and Callaway, H. A., Jr.: Paradoxical Hypertension Following Resection of Coarctation of the Aorta, Surgery 42: 135, 1957. 21 Goodall, M. C., and Sealy, W. C.: Increased Sympathetic Nerve Activity Following Resection of Coarctation of the Thoracic Aorta, Circulation 39: 345, 1969.