Volume 101 Number 3 Two-dimensional echocardiography in A VS 259

diographic evaluation of ventricular septal aneurysms. Cir- culation 59:920, 1979.

5. Sahn DJ, Kirkpatrick SE, Friedman WF: Exhocardiograph- ic recognition of ventricular septal aneurysm. A case report. J. Clin Ultrasound 3:297, 1975.

6. Freedom RM, White RD, Pieroni DR, Varghese PJ, Krovetz LJ, Rowe RD: The natural history of the so-called aneu- rysm of the membranous ventricular septum in childhood. Circulation 49:375, 1974.

7. Kiss10 J, von Ramm OT, Thurstone FL: Cardiac imaging using a phased array ultrasound system. II. Clinical tech- nique and application. Circulation 53:262, 1976.

8. Silverman NH, Schiller NB: Apex echocardiography. A two-dimensional technique for evaluating congenital heart disease. Circulation 57:503, 1978.

9. Lange LW, Sahn DJ, Allen HD, Goldberg SJ: Subxiphoid cross-sectional echocardiography in infants and children with congenital heart disease. Circulation 59:513, 1979.

10. Aziz KU, Cole RB, Paul MH: Echocardiographic features of supracristal ventricular septal defect with prolapsed aortic valve leaflet. Am J Cardiol 43:854, 1979.

11. Larsen KA, Noer T: Cardiac aneurysm of the membranous portion of the interventricular septum. Acta Med Stand 166:401, 1960.

12. Baron MG, Wolf BS, Grishman A, Van Mierop LHS: Aneurysm of the membranous septum. Am J Roentgen01 91:1303, 1964.

13. Yarom R, Griffel B: Aneurysms of interventricular septum with subaortic stenosis. J Path01 Bacterial 88:93, 1964.

Effects elf angiotensin-converting enzyme inhibition on blood pressure and plasma renin activity in essential hypertension

Oral converting enzyme inhibitor SQ14225 was administered in 11 patients with essential hypertension, in order to investigate the role of the renin-angiotensin system in the regulation of blood pressure in essential hypertension. In the sodium-repleted state (150 mEq sodium intake for 6 days) in 11 patients, converting enzyme inhibitor decreased the average mean blood pressure from 113 ? 2 to 106 -t 2 mm Hg @ < 0.001). Plasma renin activity increased with sodium depletion (30 mEq sodium intake for 3 days after furosemkde treatment) from 1.26 I 0.07 to 3.26 -+ 0.48 ng/ml/hr @ < 0.001). In the sodium- depleted state the hypotensive effect of SQl4225 was more pronounced (mean blood pressure 108 i 2 to 93 f 3 mm Hg). The decrease in mean blood pressure caused by the inhibitor correlated to the basal plasma renin activity (r = -0.53, p < 0.02, n = 22 measurements). The results indicate that the renin-angiotensin system participates in the regulation of blood pressure in essential hypertension, even in the sodium-repleted state. This role of the renin-angiotensin system in blood pressure regulation becomes more crucial during sodium depletion. (AM HEART J 101:259, 1981.)

Toshiro Fujita, M.D., Nobuki Yamashita, M.D., Kamejiro Yamashita, M.D. &u-c&i,

Japan

Laragh’ has provided evidence supporting a possible role for the renin-angiotensin system in the patho- genesis and maintenance of essential hypertension. The recent progress in peptide chemistry of this system has contributed greatly to high blood pres- sure research. The pathogenetic role of angiotensin II has been investigated more precisely because of the availability of the angiotensin II competitive

From the Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Ibaraki, Japan.

Received for publication Aug. 4, 1980; accepted Sept. 25, 1980.

Reprint requests: Toshiro Fujita, M.D., Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Ibaraki- ken 305, Japan.

antagonist, saralasin, and the converting enzyme inhibitors.*-4 Unlike saralasin, the inhibitors have no intrinsic agonistic activity, since they act by block- ing the conversion of angiotensin I to angiotensin II, thereby eliminating the cardiovascular effects of circulating angiotensin 1I.j Recently, the new syn- thetic orally active angiotensin I-converting enzyme inhibitor, SQ14225 (captopril; n-3-mercapto-2- methylpropanoyl-L-proline), has proved to be a potent pharmacologic blocker of conversion of angiotensin I to the physiologically active pressor octapeptide, angiotensin II.“. 7 In this study SQ14225 was employed to investigate the role of the renin- angiotensin system in sodium-repleted and sodium- depleted patients with essential hypertension.

0002~8703/81/030259 + 05$00.50/O 0 1981 The C. V. Mosby Co.

260 Fujita Yamashita and Yamashita

Table I. Effect of converting enzyme inhibitor on mean blood pressure (mm Hg)

Patient No.

150 mEq sodium intake 30 mEq sodium intake

Basal Post CEP Difference Basal Post CEP Difference

Responder 1 122 116 -6 109 93 -16 2 95 90 -5 95 76 -19 3 112 106 -6 115 95 -20 4 113 102 -11 107 91 -16 5 124 102 -22 108 77 -31 6 119 111 -8 102 86 -16 7 112 106 -6 111 87 -24

Mean -t SEM 114 f 4 105 t 3 -9 * 2 107 t 2 86 i 3 -20 f 2

p value p < 0.005i p < O.OOli

Nonresponder 8 104 103 -1 100 94 -6 9 119 115 -4 117 107 -10

10 111 109 -3 104 99 -5 11 112 209 -3 122 116 -6

Mean f SEM 112 * 3 109 * 2 -3 f 1 111 f 5 104 * 5 -7 I 1

Total Mean ? SEM 113 f 2 106 & 2 -6 + 1 108 +- 2 93 + 3 -15 + 2

p value p < O.OOll. p < O.OOl§ p < O.OOl$ p < O.OOlB

*Post CEI = average mean blood pressure of 60, 90, and 120 minutes after converting enzyme inhibitor (CEI). tp = comparison with nonresponder by unpaired t test. ?@ = comparison with basal by paired t test. §p = comparison with 150 mEq sodium intake by unpaired t test

METHODS

Patients. Eleven male patients 35 to 54 years of age (mean +- SEM, 45.7 & 2.0 years), with mild or moderate essential hypertension were studied at the Institute of Clinical Medicine, University of Tsukuba. Informed con- sent was obtained from each of the participating patients according to the Declaration of Helsinki. All antihyper- tensive medication had been discontinued for at least 2 weeks before the study. The patients underwent the usual hypertensive evaluation, including serum electrolytes, uri- nalysis, intravenous pyelography, and in two cases angio- graphy to exclude primary causes of hypertension. Only those with normal renal function (serum creatinine < 1.5 mg/lOO ml) and diastolic blood pressure of at least 90 mm Hg on the fourth hospital day were considered eligible for participation in the study.

Sodium repletion. The patients were placed initially on sodium repletion with a diet containing 150 mEq sodium and 50 mEq potassium daily for 6 days (high-sodium period). On day 5, the patients remained supine for at least P hour while blood pressure was measured every 15 minutes. When the blood pressure stabilized, SQ14225,lOO mg, was administered orally, with 100 ml water. Blood pressure was measured by sphygmomanometer, 15, 30, 45, 60,90, and 120 minutes later. Blood was drawn for plasma renin activity (PRA) determination at 120 minutes after SQ14225.

Sodium depletion. Subsequently, all patients were submitted to depletion of sodium with a diet containing 30 mEq sodium and 50 mEq potassium daily for 3 days

(low-sodium period). To wash out sodium, furosemide was administered as an intravenous bolus at a dose of 40 mg in the morning of the first day of the low-sodium period. At the end of this 3-day period, the patients had the same blood pressure and PRA procedures repeated as during sodium repletion.

Classification of responders. Blood pressure was expressed as mean, i.e., diastolic + Y$systolic - diastolic). In the sodium-repleted state, patients whose average mean blood pressure value during the administration of SQ14225 decreased by 5% or more when compared to the value before its administration were classified as “respon- ders”; those whose average mean blood pressure did not change or fell by less than 5% were designated “nonrespon- ders.” PRA was measured by radioimmunoassay. Urinary electrolytes were measured by flame photometry. Stu- dent’s unpaired and paired t tests were used to determine statistical significance of differences between groups and between paired observations. Results are expressed as mean k SEM and were considered significant at the p < 0.05 level.

RESULTS

Sodium repletion. In all patients on the day before the study the 24-hour urine excretion of sodium was 146 f 6 mEq. The basal PRA (before the adminis- tration of the inhibitor) in the supine position was 1.26 -+ 0.07 ng/ml/hr.

Blood pressure. The effects of the inhibitor on

Volume 101 Number3 Captopril therapy in hypertension 261

Table II. Effect of converting enzyme inhibitor on plasma renin activity (ng/ml/hr)

Patient No.

150 mEq sodium intake 30 mEq sodium intake

Basal Post CEI* Basal Post CEI*

Responder 1 1.58 4.07 2 1.63 2.20 3 1.52 1.54 4 1.10 1.32

5 1.10 3.74 6 1.21 2.93 7 1.58 2.86

Mean k SEM 1.39 + 0.09 2.67 f 0.39

p value p < 0.05t p < 0.02t Nonresponder

8 1.10 1.32

9 1.32 1.28 10 0.88 1.21 11 0.99 1.19

Mean t SEM 1.07 t 0.09 1.25 + 0.03

Total subjects Mean t SEM 1.26 k 0.07 2.15 + 0.31

p value p < 0.001~

*Plasma renin activity (PRA) at 120 minutes after the converting enzyme inhibitor (CEI).

5.72 23.1

5.28 42.9 2.64 9.68 2.11 4.62 2.16 17.6 5.94 20.9 3.26 4.40

3.87 + 0.65 17.6 + 5.1

N.S.t N.S.1‘

1.21 1.98

3.70 3.85 1.94 4.07 1.89 4.91

2.19 + 0.53 3.70 f 0.62

3.26 +- 0.48 12.6 zk 3.63

p < O.OOlt. p < O.OOl$

tp = comparison with nonresponder by unpaired t test. $p = comparison with lbasal by paired t test.

mean blood pressure are shown in Table I. It can be seen that, although the average decrease in mean blood pressure was observed in all patients (-1 to -22 mm Hg), a substantial decrease (i.e., by more than 5% of control) in blood pressure occurred in 7 of 11 patients (Nos. 1 to 7). In the remaining four patients (Nos. 8 to ll), no decrease (less than 5% of control) in blood pressure was observed. The average decrement of mean blood pressure with SQ14225, as analyzed by paired t test, differed significantly between the responders and the nonresponders (-9 k 2 and -3 2 1, respectively, p < 0.05).

Basal PRA. In the seven patients who responded to the inhibitor, the basal PRA was 1.39 + 0.09 ng/ml/hr, whereas in the nonresponders the basal PRA was 1.07 k 0.09 ng/ml/hr 0, < 0.05). The 24- hour sodium excretion in the urine was 141 f 6 and 154 f 13 mEq, respectively @ > 0.05).

Sodium depletion Blood pressure. The effects of the inhibitor on

mean blood pressure during sodium depletion also are shown in Table I. During the sodium-depleted state, all patien.ts showed a marked decrease in blood pressure, including those who did not exhibit a hypotensive response during the sodium-repleted state.

Basal PRA. The basal PRA in each individual patient is shown in Table II. During sodium restric- tion, PRA was markedly increased from 1.26 -+ 0.07

to 3.26 + 0.48 ng/ml/hr (p < 0.001). Consequently, the percent decrease in mean blood pressure in all patients was significantly related to the basal PRA (r = -0.52, p < 0.02, n = 22 measurements) (Fig. 1).

PRA response to SQ14225. Even in the sodium- repleted state, when all values were averaged, PRA was increased during the administration of the inhibitor from 1.26 ? 0.07 to 2.15 +- 0.31 ng/ml/hr @ < 0.001) (Table II). During sodium depletion, the response of PRA to SQ14225 was more markedly in- creased-from 3.26 f 0.48 to 12.6 f 3.6 ng/ml/hr (p < 0.001). The responders had a greater mean increment of PRA with SQ14225 in comparison to the nonresponders. The response of PRA to furo- semide plus standing after 120 minutes was exam- ined in all 11 patients. In the responders, the mean ratio of postfurosemide to prefurosemide PRA value was significantly greater than the value in the nonresponders (4.18 + 0.87 and 1.68 + 0.29, respec- tively,p < 0.05). The increment of PRA with furo- semide for each patient is significantly correlated to the increment of PRA with SQ14225 on a low- sodium diet for that patient (r = 0.75, p < 0.01) (Fig. 2).

DISCUSSION

ReWative role of renin-angiotensin system in essential hypertension. In 11 patients with essential hyperten-

262 Fujita, Yamashita and Yamashita

BASAL PLASMA RENIN ACTIVITY bg/ml/hr)

Fig. I. Relationship between the average decrease in mean blood pressure and the basal plasma renin activity in 11 patients with essential hypertension.

sion the new orally active inhibitor of angiotension- converting enzyme, SQ14225, was administered dur- ing sodium repletion and during sodium depletion. The results of the present investigation clearly show that converting enzyme inhibition significantly decreases blood pressure in patients with essential hypertension, even in the sodium-repleted state, in 72% of the patients studied (Table I). During the sodium-repleted state, the responders to the inhibi- tor had significantly higher basal PRA in eompari- son to the nonresponders (Table II). These observations support the view that angiotensin II participates in the regulation of blood pressure in patients with essential hypertension, even in the sodium-repleted state, and while these patients exhi- bit “normal” or “low” renin values

Role of renin-angiotensin system during sodium depletion. The hypotensive effects of converting enzyme inhibitor were more pronounced in the sodium-depleted state (Table I). Even the nonre- sponders in the sodium-repleted state exhibited a marked hypotensive response to SQ14225 during salt restriction. As a group, the sodium-depleted patients had a significantly higher PRA than the nonre- sponders and responders during the sodium-repleted state (Table II). These findings support the concept that activation of the renin-angiotensin system is an important compensatory mechanism in blood pres- sure maintenance during sodium and volume deple- tion in patients with essential hypertension.

Correlation of PRA response to SQ14225 and to

g cJ -‘-’ 0 2 4 6 8 Response to Furosemide iPRAl20min/PRA0mm)

Fig. 2. Relationship between the mean increment of plas- ma renin activity (PRA) with SQ14225 during sodium depletion and that with furosemide in 11 patients with essential hypertension.

furosemide. During the administration of SQ14225, PRA was significantly increased .in all patients. The responders had a greater mean increment of PRA during SQ14225 administration, in comparison with the nonresponders. It is suggested that PRA increased partly because of interruption of the nega- tive feedback control of angiotensin II on renin secretion and partly because of reflex sympathetic stimulation induced by a fall in blood pressure. On the other hand, furosemide may stimulate renin secretion because of the changes of sodium ion concentration in the macula densa- There was a significant correlation between the increase in PRA induced by SQ14225 and the increase in PRA induced by furosemide (Fig. 2), suggesting that juxtaglomerular cells should react correspondingly to these two different mechanisms of stimulating renin secretion. Consideration of SO1 4225 hypotensive mechanisms. Since there is a significant correlation between the fall in mean blood pressure with SQ14225 and the basal PRA (Fig. 1) the main mechanism of hypoten- sive action of SQ14225 is to act as a blocker of conversion of angiotensin I to angiotensin II, a physiologically active pressor octapeptide. The con- verting enzyme inhibitor also blocks the degradation of bradykinin and thereby may potentiate the vasodilatory effects of bradykinin.“. 9 Furthermore, a recent report supports a possible role for prostaglan- din E (vasodilatory) accumulation in the fall of blood pressure after the inhibitor administration.‘”

Volume 101 Number 3

To clarify the mechanism of hypotensive action of SQ14225, it is therefore also necessary to investigate the role of kallikrein-kinin and prostaglandin sys- tems in the action of SQ14225. REFERENCES

Laragh JH: Vasoconstriction-volume analysis for under- standing and treating hypertension. The use of renin and aldosterone profiles. Am J Med 55:201, 1973. Hollenberg NK, Williams GH, Adams DF, Moore T, Brown C, Borucki LJ, Leng F, Bavli S, Solomon HS, Passan D, Dluhy R: Response to saralasin and angiotensin’s role in essential and renal hypertension. Medicine 58:115, 1979. Case DB, Wallace JM, Keim HJ, Weber MA, Sealey JE, Laragh JH: Possible role of renin in hypertension as sug- gested by renin-sodium profiling and inhibition of converting enzyme. N Engl J Med 298:641, 1977. Gavras H, Gavras I, Textor S, Volicer L, Brunner HR, Rucinska EJ: Effect of angiotensin converting enzyme inhibition on blood pressure, plasma renin activity and plasma aldosterone in essential hypertension. J Clin Endo- crinol Metab 46:220, 1978.

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Captopril therapy in hypertension 263

Case DB, Wallace JM, Keim MJ, Weber MA, Drayer JIM, White RP, Sealey JE, Laragh JM: Estimating renin partic- ipation in hypertension: Superiority of converting enzyme inhibitor over saralasin. Am J Med 81:790, 1976. Ondetti MA, Rubin B, Cushman DW: Design of specific inhibitors of angiotensin-converting enzyme: New class of orally active antihypertensive agents. Sceince 196:441, 1977. Gavras H, Brunner HR, Turini GA, Kershaw GR, Vukovich RA, Mckinstry DN: Antihypertensive effects of the oral angiotensin converting-enzyme inhibitor SQ14225 in man. N Engl J Med 298:991, 1978. Erdos, EG: Angiotensin I converting enzyme. Circ Res 38:247, 1976. Williams GH, Hollenberg NK: Accentuated vascular and endocrine response to SQ20881 in hypertension. N Engl J Med 249:148, 1977. Vinci JM, Horwits D, Zusman RM, Pisano JJ, Catt KJ, Keiser HR: The effect of converting enzyme inhibition with SQ20881 on plasma and urinary kinins, prostaglandin E,, and angiotensin II in hypertensive man. Hypertension 1:416, 1979.

A comparison of clinical electrophysislogic studies in different institutions

Although electrophysiologic studies have been used to evaluate tachycardia and AV conduction for over 10 years, there are no data comparing measurements obtained on the ‘same patient studied in two institutions. We compared the records of 27 patients who underwent electrophysiologic studies at two different institutions and one patient studied twice in the same institution by two different investigators. We sought to determine if basic intervals, observed tachycardia, and diagnoses were comparable. We found no significant difference between the reported sinus cycle length, atrial-His interval, and His- ventricular interval when the patients were evaluated as a group. However, there were important measurement differences between the two studies in individual patients. The cycle length of induced tachycardias having similar QRS morphology and AV relation was also similar for the group, but individual,patients again demonstrated important differences between the two studies. The diagnosis of the tachycardia varied in four patients. This report suggests that intracardiac recordings and the diagnosis of observed tachycardias are comparable among institutions studying the same patient when the group results alre compared. However, individual patients demonstrate important measurement differences betweeln the two institutiolns. (AM HEART J 101:263, 1981.)

Stephen C. Hammill, M.D., Edward L. C. Pritchett, M.D., George J. Klein, M.D.,* and John J. Gallagher, M.D. Durham, N.C.

From the Division of Cardiology, Duke University Medical Center, Durham, N.C.

Supported in part by Grants RR-30 from the General Clinical Research Centers Branch, Division of Health Resources, and HL15190 from the National Institutes of Health.

Dr. Pritchett is the recipient of NHLBI Young Investigator Research Award HL21347.

Programmed stimulation has been used to study tachycardia for over 12 years,l and recordings of the His bundle electrogram have been used to study AV conduction for over 10 years2 Application of these methods to clinical research has been extraordinari-

This work was done during Dr. Gallagher’s tenure as an Established Reprint requests: Stepben C. Hammill, M.D., P. 0. Box 3270, Duke Investigator of the American Heart Association. University Medical Center, Durham, NC 27710.

Received for publication July 3, 1980; accepted Sept. 18, 1980. *Present address: University Hospital, London, Ontario.

0002-8703/81/030263 + 05$00.50/O 0 1981 The C. V. Mosby Co.