PROSTAGLANDINS

INDOMETHACIN POTENTIATES

THE VASOCONSTRICTOR ACTIONS OF ANGIOTENSIN II

IN NORMAL MAN

Phillip Negus, Richard L. Tannen & Michael J. Dunn

Division of Nephrology, Department of Medicine

University of Vermont College of Medicine

Burlington, Vermont

ABSTRACT

The blood pressure response to graded infusions of angiotensin II was assessed under control conditions and following short term (16 hour) indomethacin treatment utilizing normal men equilibrated on a constant diet of normal sodium and potassium content. Although basal mean blood pressure was unchanged, the increase in blood pressure with all rates of angiotensin II infusion rang- ing from 200 to i000 ng/min was significantly greater with indomethacin treatment. Pre-infusion body weight and plasma renin activity were similar under the two conditions. These results suggest that prostaglandins modulate the systemic vasoconstrictor effects of angio- tensin II.

Supported by NIH Clinical Research Center Grant RR - 109. R. L. Tannen is an Established Investigator of the American Heart Association.

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PROSTAGLANDINS

INTRODUCTION

There is evidence that prostaglandins, particularly prostaglandins of the E series, may influence blood pres- sure control (I). It is also knownthat the vasoconstrictor agent angiotensin II stimulates release of prostaglandins from the kidney (2), spleen (3) and vascular endothelium (4). Indomethacin blocks prostaglandin synthesis and has aggravated hypertension in animal models (5-7) and in man (8). Therefore we speculated that blockade of prostaglan- din synthesis in normal man may potentiate the pressor response to systemic infusions of angiotensin II. The present study examines this hypothesis.

METHODS

Ten normal male volunteers, who gare informed and written consent, were hospitalized on the Clinical Re- search Ward for five days and ingested a constant diet containing daily 35 calories, 2 to 3 mEq of sodium and 1.5 to 2.0 mEq of potassium per kilogram body weight. Indomethacin was given on either the fourth or fifth study day, with 4 subjects receiving it on day four and six subjects on day five. A 50 mg dose was given at 10:00 p.m. the prior evening as well as at 8:00 a.m. and 12:00 noon of the actual study day.

In addition, on days four and five, at the same time of day (approximately 12:00 noon) an angiotensin infusion was carried out in identical fashion. With the patient in the supine position, utilizing a calibrated Harvard Infusion pump, 5% dextrose in water was infused at a rate of 0.2 ml/min for one hour, baseline blood pressure measured, and venous blood obtained for plasma renin activity. The infusion was then changed to 5% dextrose in water containing angiotensin II (500 ng/ml) and a sequence of 20 minute infusion periods was carried out with flow rates of 0.2, 0.4, 0.8 and 2.0 ml/min. Auscul- tatory blood pressure measurements were taken five times during the last five minutes of each infusion period, and the mean of these readings utilized for analytical purposes (9,10).

RESULTS

Infusions of angiotensin II were performed in i0 adult male subjects before and after administration of indomethacin. The baseline blood pressure prior to the angiotensin II infusion was unaffected by the indometha- cin, averaging 89.6 mm Hg on the control day and 88.8 mm Hg with indomethacin. As shown in Figure I, the increase of mean blood pressure was greater, at each dose level of angiotensin II, after 150 mg of indomethacin. The

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PROSTAGLANDINS

differences were statistically significant using paired analysis for the three highest rates of administration of angiotensin II. At the rates of 200, 400 and 1,000 ng angiotensin II per min., the pressor response was greater after indomethacin in 28 of 30 paired observations. In four of the ten studies the indomethacin period preceeded the control period; however, the results were not influ- enced by the sequence of the two periods. Most of the differences in mean blood pressure were the result of differences in diastolic blood pressure between the con- trol and indomethacin periods.

There were no differences in weight immediately prior to the angiotensin II infusion; mean control weight was 69.8 kg and after indomethacin was 69.9 kg. Plasma

35

30

25

Increose 2o of mean BP

(mm Hg)is

10

# J #

Indometha~n,///)

B~ y Control

Y 0 I I I I I I I I I I

0 100200 400

Angiotensin 1T (ng/min) Figure i. The increase (mean ± SEM) of mean BP (diasto-

lic + 1/3 pulse pressure) is plotted against the in- fusion rate of angiotensin II. Each dose of angio- tensin II was administered intravenously for 20 mins. Control = » • ; indomethacin ........ . Indo- methacin 150 mg was given in 3 divided doses over the prior 16 hours. Paired T test was used; * p < 0.025, • ~ p < 0.01. Ten subjects were studied.

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PROSTAGLANDINS

renin activity was low in the controls (1.3 ng AII/ml plasma/hr.) and was not affected by indomethacin (1.3 ng AII/ml plasma/hr.).

DISCUSSION

These a c u t e s t u d i e s have shown a s m a l l p o t e n t i a t i n g e f f e c t o f i n d o m e t h a c i n on t h e p r e s s o r r e s p o n s e t o s y s t e m - i c , i n t r a v e n o u s i n f u s i o n s o f a n g i o t e n s i n I I in no rma l man. A l t h o u g h t h e i n c r e m e n t o f mean b l o o d p r e s s u r e was s m a l l , t h e c h r o n i c c u m u l a t i v e e f f e c t o f i n d o m e t h a c i n a d m i n i s t r a - t i o n may be g r e a t e r . S i n c e we d i d n o t measu re p l a sma or u r i n a r y p r o s t a g l a n d i n s we a r e u n c e r t a i n o f t h e e x t e n t o f i n h i b i t i o n o f p r o s t a g l a n d i n s y n t h e s i s and hence t h e e x a c t mechanism o f t h i s a u g m e n t a t i o n o f t h e a n g i o t e n s i n I I d o s e - r e s p o n s e c u r v e i s unknown. N o n e t h e l e s s , F r o h l i c h e t a l . have r e c e n t l y shown t h a t 1S0 mg o f i n d o m e t h a c i n d a i l y f o r 2 days r e d u c e s p r o s t a g l a n d i n m e t a b o l i t e e x c r e t i o n in t h e u r i n e by more t h a n S0% ( 1 1 ) . P o s s i b l e e x p l a n a t i o n s f o r i n d o m e t h a c i n ' s a c t i o n s i n c l u d e a n t a g o n i s m o f v a s c u l a r and r e n a l p r o s t a g l a n d i n p r o d u c t i o n , sodium r e t e n t i o n by t he k i d n e y s and b i o c h e m i c a l e f f e c t s on n o n p r o s t a g l a n d i n - s y s t e m s such as p h o s p h o d i e s t e r a s e ( 1 2 ) . We a t t e m p t e d to e l i m i n a t e any e f f e c t s m e d i a t e d t h r o u g h sodium r e t e n t i o n by g i v i n g t he i n d o m e t h a c i n b r i e f l y (16 h o u r s ) . The e q u a l w e i g h t s b e f o r e and a f t e r i n d o m e t h a c i n s u g g e s t t h a t s i g n i - f i c a n t sodium r e t e n t i o n d id n o t o c c u r . Recen t s t u d i e s o f i n d o m e t h a c i n a d m i n i s t r a t i o n f o r 2-4 days t o no rma l men do n o t show any s o d i u m - r e t a i n i n g e f f e c t in t h e b a s a l s t a r e ( 8 , 1 5 ) even t h o u g h t h e d rug i n t e r f e r e s w i t h f u r o s e m i d e - n a t r i u r e s i s ( 8 ) . The s u b j e c t s i n g e s t e d a g e n e r o u s sodium i n t a k e in o r d e r to s u p p r e s s e n d o g e n o u s p r o d u c t i o n o f a n g i o - t e n s i n I I and t h e r e b y to enhance t he b a s a l or c o n t r o l p r e s s o r r e s p o n s e to a n g i o t e n s i n ( 9 , 1 0 ) . The f a i l u r e o f i n d o m e t h a c i n t o s u p p r e s s p l a sma r e n i n a c t i v i t y ( 8 , 1 5 ) i s u n d o u b t e d l y a r e s u l t o f t h e s e low r e n i n v a l u e s due t o h i g h sodium d i e t s .

Our results in normal men are consistent with prior work in animals and man. The vasoconstrictor response of the canine renal circulation to angiotensin II as well as to other vasoconstrictors is augmented by inhibition of prostaglandin synthesis with either indomethacin or meclofenamate (2,14). In rats and rabbits with renal artery stenosis and hypertension, chronic dosage with indomethacin further increases the blood pressure (5°7). Indomethacin also slightly increases blood pressure in normotensive and hypertensive humans after administration for 4 days (8). These studies by others and our results from the present study suggest that prostaglandin synthe- sis modulates the intensity of the vasoconstrictor and pressor effects of vaso-active materials and especially angiotensin II.

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i.

2.

3.

4.

5.

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,,

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