Studies of Plasma Renin Activity in Coarctation of the Aorta CHARLES W. VAN WAY 111, M.D.,* ANDREW M. MICHELAKIS, M.D., PH.D., WILLIAM J. ANDERSON, M.D.,t ANDREW MANLOVE, JOHN A. OATES, M.D.

Experimental and clinical studies were performed to assess the From the Departments of Surgery, Medicine role of the renin-angiotensin system in producing hypertension and Pharmacology and the S. R. Light Laboratory, in coarctation of the aorta. Basal and stimulated peripheral Vanderbilt University School of Medicine, plasma renin activity were determined in the canine model and Nashville, Tennessee, in four patients with coarctation. The animal studies showed and the Department of Surgery, no significant elevation of peripheral plasma renin activity University of Colorado Medical Center, (PPRA), and no increase in the response of PPRA to stimuli. Denver, Colorado The human studies showed a significant elevation in the response to PPRA to postural change and to exercise in three of four patients with coarctation, as compared to the same patients after correction of the coarctation. It is concluded tion releases renin in a manner analogous to the kidney that hyperactivity of the renin-angiotensin system is not the distal to a renal arterial stenosis.39 The intent of the studies presently reported has been primary cause in coarctation hypertension in dog or man. It is nonetheless probable that the renin-angiotensin system has a role to investigate the response of peripheral plasma renin in coarctadon hypertension, and further studies will be necessary activity to experimental creation and repair of coarctato determine its place. tion, and to repair of coarctation in patients. Both and pharmacologic stimuli have been used to physiologic C OARCTATION of the aorta is readily diagnosed, and

its treatment is straightforward and definitive. But, we have little more idea of the mechanism by which it causes hypertension than did the pioneers of the 1940's who first carried out its surgical correction.7'13 Teleologically, the patient with a coarctation requires a higher head of pressure proximal to the coarctation to obtain normal distal perfusion. This does not explain the mechanism by which the body brings this about. The work of Scott and Bahnson29 first showed that the presence of renal tissue distal to the coarctation was required to produce hypertension. This has been verified by others.21'24'32 The discovery of the renin-angiotensin system offered a possible explanation for the role of the kidney in the production of hypertension in coarctation. Acutely, the kidney distal to an aortic constric-

study the responsiveness of peripheral plasma renin activity. Portions of this work have been briefly reported earlier.40'41 Materials and Methods

Experimental Studies A total of 39 dogs were studied according to one or

both of two separate protocols. In Protocol I, coarctation was created in 21 dogs, and peripheral plasma renin activity (PPRA) studied serially before and after operation. Four controls were subjected to sham operation. In Protocol II, coarctation was created in 17 dogs. Responsiveness of PPRA to the hypotensive agent diazoxide was studied before and after operation. In 5 dogs with long-established coarctation and hypertension, responsiveness of PPRA was studied before and * Assistant Professor of Surgery, University of Colorado School of after correction of the coarctation. Responsiveness of Medicine, Denver, Colorado. PPRA to diazoxide was determined in seven control t USAF Medical Center, Keesler AFB, Mississippi 39534. dogs. Responsiveness of PPRA to treadmill exercise Supported by USPHS grants GM-01742, HE-12683, GM-15431 and before and after correction of long-established coarctaFR-00095. Reprint requests: Charles W. Van Way, III, M.D., Department of tions was studied in two dogs. A standard initial preparation was carried out in all Surgery, University of Colorado Medical Center, 4200 East Ninth Avenue, Box C-313, Denver, Colorado 80220. animals. The spleen was removed to facilitate radio-

229

VAN WAY AND OTHERS

AORTA

LEFT SUBCLAV/APN ARTERY

J7

FIG. 1. Diagram of coarctation preparation.29

isotopic volume studies. One carotid artery was explanted to a subcutaneous location so that blood pressure could be measured proximal to the coarctation. Blood pressure measurements were made on supine, restrained animals, trained to tolerate measurements made while awake. Most dogs can be trained in this way; the few dogs which could not be trained were not entered into these studies. Under these conditions, nearly all dogs showed phasic variation of blood pressure and pulse rate with respiration. In preliminary studies, it was found that dogs receiving Nembutal anesthesia exhibited a drop in the mean blood pressure and a twofold or three-fold increase in PPRA. Because of these findings, all pressure measurements were by simultaneous percutaneous cannulation of the carotid and femoral arteries with #20 needles connected through salinefilled tubing to Statham P23Dc strain gauge transducers. Pressures were recorded on a Grass Model 7 polygraph. Mean pressures were determined using capacitative damping of the polygraph amplifiers. Identical transducers and amplifiers were used for carotid and femoral pressures. The electronic calibration of the amplifiers was verified periodically with mercury column calibration of the entire system. The coarctation preparation is illustrated in Figure 1. It was described by Scott and Bahnson29 and was

Ann. Surg.

o

March 1976

originally suggested by Blalock and Park.3 After exposure of the aorta and subclavian artery through a left thoracotomy incision, the subclavian was divided at its exit from the chest and anastomosed end to side to the distal aorta. The aorta between the subclavian origin and anastomosis was divided and the ends oversewn. In this way the blood supply to the lower half of the body was not interrupted during the procedure. The four control animals in Protocol 1 underwent ligation and division of the subclavian artery. To correct the coarctation, the two oversewn ends and the subclavian artery were resected, and a short length of Dacron graft used to reconstruct the vessel. Blood transfusion was not necessary during creation of the coarctation, but was needed during correction of the coarctation. Plasma renin activity was measured by Boucher's method,4 as modified by Gordon, et al.12 In a few of the later studies, radioimmunoassay was used to measure angiotensin II, after a three-hour incubation similar to that used in Boucher's method. Peripheral arterial blood samples were drawn at the time of blood pressure measurement. In each dog on Protocol I, 3 to 5 pre-coarctation samples were assayed for plasma renin activity, and 10 to 20 post-coarctation samples were obtained over 3 to 12 months. Serial determinations were made of sodium, potassium, choloride, serum urea nitrogen, and hematocrit. Nine dogs died during the first 6 weeks postoperatively, leaving 12 dogs for long-term study. In sub-groups of 4 dogs each, measurements were made of the radio-iodinated serum albumin space and the radiosodium space. The radio-iodinated serum albumin studies were done using commercially-prepared 125R ISA (Squibb). Sampling was carried out at 15, 20 and 30 minutes after intravenous injection. A 1:4000 dilution standard was used to calculate the amount injected. Counting was done on an automated well counter (Auto- Gama, Packard) with a calculated counting error of 0.5% to 1.0%. The syringe was counted before and after injection to correct for residual activity left in the syringe after injection. Counts were plotted on semi-log paper and extrapolated to To, and the C0 thus obtained was used to calculate dilution volume. Radiosodium spaces were found by injecting 2.0 ,uc of 22Na intravenously. Correction was made for urinary excretion. Plasma samples were counted using the automated well counter. Studies with sampling at 24, 28 and 96 hours showed that the C0 obtained by extrapolation did not differ significantly from the count obtained at 48 hours. In the dogs on Protocol II, diazoxide stimulation of PPRA was carried out. It was determined that the maximal elevation of plasma renin activity occurred 10 to 20 minutes after intravenous administration of

Vol. 183 . NO. 3

diazoxide. Samples were drawn before and 15 minutes after administration to the awake, supine, restrained animals. Blood pressure was monitored by intra-arterial needles. The dose was either 2.5 mg/kg or 5.0 mg/kg for the dogs studied before and after creation of coarctation; 2.5 mg/kg was used for dogs studied before and after correction of the coarctation. Exercise tests were done using a standard inclined treadmill modified by the addition of a wooden cage to restrain the animals. Samples were drawn before and just after exercise, and at intervals for an hour thereafter. Renin activity was determined by radioimmunoassay of angiotensin II after a three-hour incubation. Testing was done 4 weeks before, 9 weeks after, and 10 months after correction of the coarctation. Clinical Studies Four patients were studied with determination of PPRA in the supine and standing position, and during and after treadmill exercise. Studies were carried out before and 2 to 4 months after correction of coarctation. Peripheral venous blood was assayed for renin activity by Boucher's method in three patients and by radioimmunoassay in one. All patients were young men, between the ages of 13 and 23, and in otherwise good health. Patients were placed on a 100 mEq (2.2 gm) sodium diet for several days prior to study. Equilibration on this diet was verified by determination of urinary sodium output. Morning blood samples (8 A.M.) were obtained before the patient arose from the supine position. The patient was kept standing for 15 minutes, and a second sample drawn (8:15 A.M.). A third sample was drawn after normal activity for three hours (11 A.M.). A graded treadmill exercise test was carried out in the afternoon in three patients, using mild exercise of 2 miles Blood pressure: 88-N

Carotid 200- A 150100

Control

Femoral O

50-

Post-coarctation 39 days

231

COARCTATION OF THE AORTA

mmHg

TABLE 1. Blood Pressure and Peripheral Plasma Renin Activity

Peripheral plasma renin activity Blood Pressure (Mean Carotid) Dog 855-M 856-M 864-M 944-M 57-N 58-N 59-N 61-N 78-N 86-N 88-N 109-N

Preop

Postop*

Preop

Postopt

130 145 121 121 146 134 127 123 125 119 138 117

156 164 141 154 155 155 150 173 165 188 177 132

410 180 160 315 680 995 110 120 260 770 850 265

610 755 440 240 660 730 275 65 460 390 800 230

* 20-90 days. t 20-90 days inclusive.

hour, zero grade for 10 minutes, and a moderate exercise of 3 miles per hour, 5% grade for 15 minutes. Samples were drawn before exercise, after the 10 minutes of mild exercise, and after the 15 minutes of moderate exercise; then 15, 30, and 60 minutes after the exercise period. Pulse rate and electrocardiogram were monitored continuously during the exercise, and cuff blood pressure was obtained intermittantly. The fourth patient (LK) was studied in a similar manner, using a set of standard Masters steps instead of a treadmill. Mild exercise was 5 minutes of going over and back twice a minute; moderate exercise was 10 minutes of going over and back 4 times a minute. The first three studies were done in the Clinical Research Center at Vanderbilt University Hospital; the last at Nashville General Hospital. per

Results Experimental Studies, Protocol I All of the 12 dogs surviving over 6 weeks developed hypertension. All 12 had systolic blood pressure evaluation of over 30 mm Hg and mean elevations of 20 mm or more, and 10 of 12 had diastolic elevations of over 10 mm Hg. Hypertension developed between 3 and 24 days in the surviving animals, with a mean TABLE 2. Mean Peripheral Plasma Renin Activity: Mean PPRA (ng Ang/JOO ml/3 hr) ± SE

250200150-

Coarctation with Hypertension 12 dogs Sham operation 4 dogs

00-

500-

FIG. 2. Change in

(Mean value: ng. Ang./l00 ml/3 hr)

pulse contour

produced by coarctation.

*

20-90 days

inclusive.

Preop

Postop*

426 ± 90

471 ± 69

405 ± 113

432 ± 153

232

VAN WAY AND OTHERS

190.

MEAN B.P

170

|

140 140. ooo . w

120.w

PPRA ng

Ang

/lOO

rrd

300 200

100

O1020 0

March 1976

term

160.I

130

*

Measurements of PPRA showed no significant longchanges. In most animals an initial rise in PPRA

-M

855-

180.

Ann. Surg.

10 20 3040 5060 70 80

DAYS AFTER CREATION OF C OARCTATION

FIG. 3. Mean blood pressure and PPRA in a typical sive rise is blood pressure evident. While the PPRA sh dog; the progresg of variation, it does not become persistently elevate d.

of 8 days. On followup over 6 to 12 months, one animal failed to stay hypertensive, bu t the rest remained hypertensive, generally becominjg more hypertensive as time passed. In 8 dogs, the mean femoral pressiure eventually rose to 10 to 40 mm Hg higher tha n the control mean femoral pressure. In four dogs it re-mained below the control mean. Changes in pulse contour which occurre d as a result of the coarctation are shown in Fig. 2. The carotid pulse developed a peaked contour similar to th at in the preoperative femoral pulse. The femoral r)ulse wave became flattened. The mean control blood pressure was relatively high in all animals. As shown in Table 1, tU ie mean pressure in most dogs was 110 to 120 mm Hg. seen

and a rapid fall to control levels was seen during the first week postoperatively. Mean control values varied widely, from 110 to 995. For purposes of comparison, all control values for each animal and all postoperative values between 30 and 90 days were averaged (Table 1). Coarctation produced no significant change in the mean levels of PPRA in the group of dogs receiving this procedure, and there was no significant change in PPRA following the sham operation in control animals (Table 2). No late elevations of PPRA were found in those animals followed for as long as 24 months. Fig. 3 shows the blood pressure and PPRA values obtained in one dog followed for 9 months. Changes in serum electrolytes, serum urea nitrogen, and hematocrit before and two months after creation of coarctation are presented in Table 3. No significant changes were seen in sodium, potassium, or SUN. About half the animals had a low hematocrit two months after operation. This anemia did not appear to be related to changes in blood pressure or PPRA. It probably represented failure to recover red cell mass after operation. Six of the 7 anemic dogs were studied 6 to 12 months after operation and had normal hematocrits. Serial PPRA studies in these dogs showed no changes after the hematocrit was normal. No changes were seen in the radioiodinated serum albumin space or in the radiosodium space, measured before and two months after creation of coarctation (Figs. 4 and 5). Experimental Studies, Protocol II Diazoxide lowers blood pressure by peripheral arteriolar dilation. It stimulates release of renin from the kidney. Two dose levels were given in this study, 2.5 mg/kg and 5.0 mg/kg. The lower dose level pro-

TABLE 3. Electrolytes, SUN, Hematocrit

Sodium

Dog 855-M 856-M 864-M 944-M 57-N 58-N 59-N 61-N 78-N 86-N 88-N 108-N

Serum Urea Nitrogen

Potassium

Hematocrit

Preop

Postop

Preop

Postop

Preop

Postop

Preop

Postop

143 150 146 140 142 145 145 147 153 157 156 152

140 156 152 150 144 145 147 138 143 136 142 138

3.6 4.0 3.5 3.9

3.9 4.0 3.8 4.2 4.3 3.7 4.2 3.3 3.8 5.1 4.0 3.9

15 20 14 18 16

19 20 17 15 14 21 33 26 25 16 28 16

36 38 44 38 43 38 35 41 39 33 38 35

38 40 36 39 23 25 18 38 35 19 14 26

3.1 3.9 3.4 3.7 4.0 3.9 4.6 3.9

Postop: mean of values 20-90 days following coarctation.

14

19 19 22 19 17 13

Vol. 183

*

233

COARCTATION OF THE AORTA

No. 3

R

8

'251SA

SPACE

In two of the Protocol II animals, treadmill exercise tests were carried out before correction and two months

and 10 months after correction. There

6±

83!15

in

responsiveness of PPRA

to

were no

changes

exercise (Table 4).

,0 I.-

x 0 w

FIG. 4. Effect of coarctation upon '25R ISA

space.

-11

0 OD

0

5

.-O

POST

CONTROL

COARC TATION

duced hypotension, 50 to 75% of control blood pressure for 10 to 15 minutes with relatively few side effects, and no effect upon PPRA at 15 minutes in control animals. The higher level produced more profound hypotension of the same duration, side effects of agitation and vomiting, and an increase of PPRA of about 100%o at 15 minutes in control animals. A change in responsiveness of the renin release mechanism should manifest itself either as an increase in the amount of reinin released after the larger dose, or as a lowering of the threshold for renin release, producing a change at the lower dose. Blood pressure changes in the Protocol II animals were similar to those seen in the Protocol I animals (Fig. 6). The 5 dogs in which coarctation was corrected with a graft had been hypertensive for 6 to 12 months prior to correction. The corrected dogs all remained mildly hypertensive, with mean pressures 10 to 30 mm Hg higher than control. There was no significant change following creation of coarctation in the response of PPRA to stimulation with diazoxide at 2.5 or 5 mg/kg (Fig. 7). After correction of coarctation there was a slight increase in the response of PPRA to stimulation with 2.5 mg/kg of diazoxide, but this was not statistically significant (Fig. 8).

Clinical Studies Significant increases in the responsiveness of PPRA to exercise and postural change were noted in 3 out of 4 patients with coarctation (Table 5). The results from one of the patients (DG) is shown in Fig. 9. Patients DG, DC, and LK showed a markedly greater rise of PPRA in response to exercise and to standing preoperatively than they did postoperatively. Patient RB showed the same response to standing and to exercise preoperatively and postoperatively. All patients had good clinical results, with return of the blood pressure to normal in each case. Patient DG had an episode of paradoxical hypertension and abdominal pain on the afternoon of the fourth postoperative day. Peripheral plasma renin activity was 1040 ng Ang/100 ml at 12:30 P.M. His pain and hypertension responded promptly to reserpine. The next day he was asymptomatic; his PPRA was 360 ng Ang/100 ml at 2:30 P.M. This evidence suggests that the reninangiotensin system may be active in post-coarctation hypertension. The syndrome- of post-repair hypertension and abdominal pain has been reviewed by Tawes, et al.36 Discussion A renal

cause

for hypertension in coarctation of the

aorta was proposed in the 1930's. Rytand,28 building on

Goldblatt's classic work." demonstrated an increased resistance at the arteriolar level in a patient with coarctation, and went on to show that constriction of

2001

22NA SPACE

180MEAN B. P

(5)

160-

(mm Hg)

FIG. 5. Effect of coarctation upon t2Na space.

0-

30 3

140-

0

o 0

0 0

120-

10

I

PS POST COARCTATION

FIG. 6. Blood pressure

changes

correction of coarctation.

in

dogs

with creation and then with

VAN WAY AND OTHERS

234 J(_ EZ2>

300-

PERCENT 200CHANGE IN PRA

100O 0-

FIG. 7. Effect of diazoxide creation of coarctation.

upon

Ann. Surg.

9

March 1976

tionally small kidney. In short, renal functional abnormalities are seen in coarctation, but their contribution to the hypertension is not clear. Few studies of aldosterone secretion have been done. Timmis and Gordon37 measured urinary aldosterone in three children and did not show a change after correction of the coarctation. The place of mechanical factors in coarctation hyperDIAZOXIDE mg/kg tension has been difficult to assess. The basic assumption of the mechanical hypothesis is that hypertension 5.0 (5 DOGS) exists above the coarctation because cardiac output is normal and peripheral vascular resistance is increased by the coarctation. Habib and Nanson15 producing 2.5 ( 6 DOGS) coarctation with ameroid constrictors in young puppies, found that hypertension was produced only if the aorta

plasma renin actiivity before and after

was

constricted above the renal arteries, and that trans-

plantation of the kidney to the neck caused the blood cardiac pressure to fall, at least until pyelonephritis developed. the aorta above the renal arteries p However, correction of the coarctation caused a further ducedbypcardiac hypertrophy in rats similar to that pro duced by fall. Constriction of the ascending aorta caused death in partial renal artery occlusion. Goldblatt10 produced malignant two of three animals, but the survivor was not hyperhypertension in dogs by contriction of the supra-renal tensive. The results were interpreted as showing evidence aorta. of both mechanical and renal factors. Further evidence for the renal fa ttr Cogent arguments against the mechanical hypothesis coarcta29 tion hypertension was presented by Scoltt and Bahnson, were presented by Harris et al.16 First, if the mechanical and Scott, et al.,30,31 who produced hyp ertension in dogs hypotheses were true, the carotid pressure should be using the preparation shown in Fig. 1,, highest immediately after creation of the coarctation, strated that transplantation of a kidney( reand should gradually fall as collateral vessels enlarge. versed the hypertension. Sealy32 descrit)ed preparation This is exactly opposite to the usual course of events. involving bypass around the coarctatiIon Second, in at least some patients, and in a number of arteries, leaving the kidneys in situ. TIhis animal studies, a progressive rise in the femoral blood the hypertension. pressure has been observed. This implies a progressive Studies of renal function in coarctatioi have lnot shdowdn nse in peripheral vascular resistance distal to the the cause of the hypertension. Gesest eca stutieo coarctation, and is difficult to reconcile with the 12 patients before and after correctiorieof coarctatin na mechanical hypothesis. The renal blood flow increased and th e filtration fracStudies of the renin-angiotensin system in human tion decreased after correction. This w-as coarctation have shown mixed results. In 1964, Morris et sistent with efferent arteriolar constric in coarcta- al.,23 in a study of 138 hypertensive patients, found tion, presumably a compensatory mecha :tion to maintain elevated levels of plasma angiotensin II only in patients ihsm a normal glomerular filtration rate witth lowered renal arterial pressure. Luomanmaki, et al *.20 showed that patients with coarctation had natures;is after sodium loading which was lower than conttrols, pattern similar to that seen in renal hypertensiion, but different from the exaggerated naturesis seen in "(essential" hypertension. Kirkendall, et al.19 showed rielatively normal renal function studies in coarctation paltients. The renal 200blood flow was low to normal, and th e postglomerular PERCENT vascular resistance was somewhat elev rated. Harris, et al.,16 in studying patients before and aLfter coarctation, CHANGE 100DIA ZOX IDE showed low to normal renal plasma flovv and glomerular 2.5mg/kg filtration rates, with immediate postoperaLtive elevations in IN PRA (5 DOGS) both of these. Filtration fraction rema mned unchanged. 0Later postoperative studies showed re version towards FIG. 8. Effect of diazoxide upon plasma renin activity before and after preoperative levels. The findings were felIt to show a func- correction of a long-standing coarctation. iroduced

and to

then demon-

the

neck

a

to

the

also

felt

to

a

renal

reversed

be

con-

Vol. 183 * No. 3

COARCTATION OF THE AORTA

TABLE 4. Exercise Tests in Dogs, Before and After Correction of Long-standing Coarc tation (PRA Expressed as ng Angiotensin IIIIOO m113 hr Incubation) 437-N

Control After exercise 15 min 45 min 60 min

484-N

Preop

Postop

Preop

Postop

400

280 1291 579 426 400

668 4270 1521 1155

634 3780 5210 3030 4250

585 290 695 -

with renal hypertension and coarctation. Pickens26 showed in one patient that the plasma renin activity dropped markedly after correction of the coarctation. Brown, et al.,5 measured peripheral plasma renin activity in 276 hypertensive patients. They found no elevation in 4 patients with coarctation and no change after correction. PPRA was elevated in severely hypertensive patients with renal artery stenosis. Imbs17 found elevation of PPRA in 3 of 6 patients with coarctation. Werning, et al.43 measured PPRA in 10 patients, supine and standing; only one showed elevation. Bilateral renal venous renin activity was normal in 3 patients. Amsterdam, et al.' found no significant differences in PPRA between 16 children with coarctation and 11 controls.

235 Experimentally, Skinner, McCubbin and Page, in 196434 showed release of a pressor substance into renal venous blood following partial inflation of a balloon in the supra-renal aorta. Yagi et al.44 showed elevation of PPRA from one to 24 hours following suture constriction of the descending aorta in dogs. PPRA returned to normal in one or two weeks, but hypertension persisted. Sealy et al.,32,33 using the bioassay for angiotensin II, found similar results in dogs. Svane and Jensen35 studied granulation of cells in the juxtaglomerular apparatus of the kidney. They found elevations in the "juxtaglomerular rating" in kidneys located below coarctations, but not in kidneys transplanted above them. Contrary to Scott et al. ,3 they found that the presence of one kidney below the coarctation was sufficient to maintain hypertension even if the other kidney was transplanted above the coarctation. The relationship of granulation of the juxtaglomerular apparatus to hypertension is not constant. Nolla-Panades and Simpson25 found that hypertension was produced in rats by silver clip constriction of the supra-renal aorta without producing elevation of the juxtaglomerular index. When the clip was placed on the aorta between the two renal arteries, hypertension was produced, and the juxtaglomerular index was elevated in kidneys distal

TABLE 5. Peripheral Plasma Renin Activ ity in Patients Before and 2 to 4 Months After Correctioni of Coarctation (PPRA Erpressed as ng Angiotensin 11/100 ml/3 hr Incubation)

Postural Response

Exercise Test Name LK (13 BM) Preop Postop (2 mos) RB (16 WM) Preop Postop (4 mos) DG (25 WM) Preop

Postop (31/2 mos)

DC (19 WM) Preop Postop (1 wk) (4 mos)

11 AM, (Normal

8:15 AM* (Standing)

Activity)

Control

Mild Exercise

Moderate

8 AM

Exercise

15m

30m

60m

299 389

1628 1540

228 621

228 1000

1560 300

2042 738

519

260

204 183

122 128

450 660 725

1445 2450 2000

420 570

485 695

1450 1215

-535

745

470 470

320 250

1800 1400

400

460

1490

2000

1500

170 140

280

160 200

320

230

320

740 320 600 200 190

840

5200 -

400

280 300 470

4000

5570

220

Standing. Normal activity. Renin activity on RB done using radioimmunoassay techniques; renin activities bioassay technique. 4,12)

350

1000

620

500

180

3500

460

45m

105m

7600

7840

45m

105m

380

240

* '

on

LK. DG AND DC done using modified Boucher's

VAN WAY AND OTHERS

236 GD

GoD~

D.G.

!.

2000-

(n

1800-

600400-

PRA ng Ang

200-

per

1000-

lOOml 800-

600-

C

Dl

a

E

-b

VD0 Post -op

400-

'n

2000-

Pre-op

Post op

Exercise Test

FIG. 9. Responsiveness of plasma renin activity to standing and to exercise before and after correction of a coarctation in a patient (D. G.)

to the clip and low in kidneys proximal to the clip. Itskovitz et al.,18 reported normal granularity of the juxtaglomerular apparatus in one patient with coarctation. Tobin et al.38 showed a good correlation between juxtaglomerular granulation and renal renin content. In studies of renal renin content, Pregoli et al.27 found it to be increased in rat kidneys distal to a clip only when

the contralateral kidney was left in place. Similar results were reported by Masuyama et al.,21 who also found that rats with silver clips on the supra-renal aorta showed no elevation in renal renin activity, but were hypertensive. Apparently, neither hypergranularity of the juxtaglomerular apparatus nor elevation of renal renin content is necessary for hypertension. A problem in the study of the renin-angiotensin system is that a single normal value of plasma renin activity does not exclude elevated values at other times. It is difficult to assess overall, or mean, activity of the system. There is no measurement comparable, for example, to measurement of 24-hour urinary excretion of the adrenal hormones. Juxtaglomerular indices and renal renin content, as noted, do not correlate well with the presence of hypertension, and do not provide a reliable measure of the secretory activity of the system. For this reason, the present study was designed to measure activity of the renin-angiotensin system by its response to pharmacologic and physiologic stimuli. The animal studies confirmed the findings of Yagi44 and Sealy32 that renin activity rises transiently following creation of coarctation, but returns to normal after a few days, while the blood pressure continues to rise. Studies of renin response to diazoxide and to exercise in dogs showed no further evidence of increased activity in the renin-angiotensin system.

Ann. Surg.

o

March 1976

The studies in human coarctation showed that the renin-angiotensin system may be hyper-responsive to stimuli, even in the absence of elevation of the plasma renin activity at rest. But the experimental results suggest strongly that increased activity of the reninangiotensin system is not the primary cause of coarctation hypertension as elevation of PPRA was not found in dogs, and was inconstant in the human subjects. There remains the possibility that the normal level of PPRA observed in coarctation hypertension is inappropriately high for the degree of elevation of blood pressure. Theoretically, elevation of the carotid blood pressure should lower adrenergic output. Since adrenergic stimulation is one of the factors which causes renin secretion, elevation of the carotid pressure should cause a diminution in renin secretion. If, at the same time, intrarenal pressure receptors are stimulated by diminished pressure distal to the coarctation, the level of renin secretion may stay constant at a level high enough to produce hypertension proximal to the coarctation. Miller et al.22 showed that transient lowering of the renal artery pressures to 50 mm Hg produced a rapid release from that kidney, and suggested that this release might be significant in the development of hypertension in experimental renal artery stenosis. Gutmann et al.14 have shown that lowering the renal artery pressure to 75 mm Hg is sufficient to produce an elevated PRA in venous blood from the affected kidney. During the first week following creation of a coarctation in dogs in the present study, the femoral pressure was generally in the range of 75 to 90 mm Hg. Many of the animals showed transient elevation of PPRA at this time. It is possible that this mechanism may contribute to initiation of hypertension. However, this line of reasoning does not explain why the hypertension was progressive, nor why, in the long-term studies the femoral blood pressure rose to above control levels. The concept of a balance between decreased adrenergic stimulation and increased stimulation of intrarenal receptors in coarctation may offer an explanation of the species difference observed in the studies. The elevation of PPRA seen in the human subjects may reflect an increased influence of the intrarenal receptors upon renin secretion in the human as compared to the dog. Some work which has been recently done on renovascular hypertension may be relevant to the present study. Gavras et al.8 have shown that the administration of 1-sarcosine-8-alanine-angiotensin II (P113), a competitive inhibitor of angiotensin II, to rats with renal clip hypertension reversed the hypertension in the sodium-deplected animal, although not in the sodiumreplete animal. Ayers et al.2 have shown in studies 2 and 3

COARCTATION OF THE AORTA

Vol. 183 . No. 3

days postoperatively that in the dog with renal artery stenosis and contralateral nephrectomy administration of 1-sarcosine-8-alanine-angiotensin II (P113) or of SQ20881, a converting enzyme inhibitor, lowered the blood pressure and elevated the PPRA. This was felt to demonstrate a negative intrarenal feedback mechanism mediated by angiotensin II for control of renin release. Further studies42 in the chronic preparation showed that the increased intrarenal vascular resistance which is found in the renal hypertensive animal can be reversed by the inhibitor only when the animals are sodium-depleted. Brunner et al.6 found that angiotensin II blockade with P113 reduced elevated blood pressure and raised PPRA in patients with high-renin malignant hypertension and renovascular hypertension. For the present discussion, perhaps the most significant aspect of these studies is that in these chronic animal models the hypertension appears to be renin-dependent only in the sodium-depleted animal, while in the sodiumreplete animal other mechanisms were dominant. The same situation may be present in coarctation hypertension, and it would be of interest to determine if similar findings can be produced in coarctation hypertension.

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