Clinical Science (1979) 57.46 1-463

SHORT COMMUNICA TION

Studies on the renin-angiotensin-aldosterone system in elderly hypertensive patients with an angiotensin I1 antagonist

T. O G I H A R A , T. H A T A , A N N A M A R U Y A M A , H. M I K A M I , M . N A K A M A R U , T . M A N D A I A N D Y. K U M A H A R A Deparlmenl of Medicine and Geriatrics, Osaka Clniversi*, Medical School, Fukushima-ku, Osaka, Japan

(Received 18 June 1979; accepted 29 June 1979)

Summary

Introduction

1. To characterize the renin-angiotensin-aldosterone system in elderly hypertensive patients, an angiotensin 11 antagonist, [Sar1,11e81angiotensin 11, was infused into individuals 60 years old and older with and without hypertension. 2. After infusion of [Sar1,11e8]angiotensin I1 in all of the elderly patients and subjects an agonistic pressor response was observed that was greater than in middle-aged hypertensive patients. 3. Pre-infusion plasma renin activity and plasma aldosterone concentration in hypertensive and normotensive elderly groups were suppressed in comparison with those in middle-aged hypertensive subjects. The increased agonistic effects of [Sar1,11e8]angiotensin I1 infusion on blood pressure in the elderly are presumably due to their hyporeninaemia. 4. The angiotensin-aldosterone system in elderly essential hypertensive patients is suppressed and is presumably not responsible for their elevated blood pressures.

To clarify the pathophysiology of essential hypertension in the elderly as well as to improve management of the disease, we studied the reninangiotensin-aldosterone system in individuals with and without hypertension using an angiotensin I1 antagonist, [Sar1,11e81angiotensin 11 ([Sar1,11e81ANGII).

Materials and methods

Twenty-two individuals 60 years old or older were studied. Twelve had hypertension (six men and six women, age 74 f 3 years (mean f S E M ) and 10 were normotensive (five men and five women, age 75 f 3 years). Ten patients kss than 60 years old with hypertension were also studied (five men and five women, age 42 f 2 years). All hypertensive patients had blood pressures greater than 160 mmHg systolic and/or 90 mmHg diastolic after lying supine for 2 min. Patients with secondary hypertension or severe cardiovascular complications were excluded. Antihypertensive medications were discontinued at least 2 weeks before the study. Diets were unrestricted. The subjects were kept supine during the test. [Sar1,11e81ANGII (Dai-ichi Pharmaceutical Co. Ltd, Tokyo) was infused at a rate of 600 ng min-I kg-l for 30 min 1 h after intravenous injection of 40 mg of frusemide (Ogihara, Hata,

Key words: aldosterone, angiotensin I1 antagonist, hypertension, renin. Abbreviations: ANGII, angiotensin 11. Correspondence: Dr Toshio Ogihara, Department of Medicine and Geriatrics, Osaka University Hospital, Fukushima-ku,Osaka 553, Japan. 46 1

T. Ogihara et al.

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Maruyama, Mikami, Nakamaru, Okada & Kumahara, 1978). Infusion of [Sar', Ile81ANGII at a rate of 600 ng min-I kg-I causes no appreciable change in mean blood pressure (the sum of the diastolic and one-third of the pulse pressure) in frusemide-treated normal subjects (Yamamoto, Doi, Ogihara, Ichihara, Hata & Kumahara, 1976), whereas in patients with angiotensinogenic hypertension there is a decrease in mean blood pressure of more than 10 mmHg (Ogihara, Hata, Mikami, Nakamaru, Mandai & Kumahara, 1976). Blood pressure was monitored before and during the infusion with an automated device (Non-stetho, Parama Ltd, Tokyo). The mean of five readings before the infusion of [Sarl,Ile*]ANGII was used for the control blood pressure. The blood pressure during the infusion was expressed as the mean of the blood pressures 10, 20 and 30 min after beginning the infusion. The change in the mean blood pressure was calculated as the difference between the control blood pressure and that during the infusion. Blood was drawn from each subject just before the infusion of [Sar1,11e81ANG11 for assay of plasma renin activity and plasma aldosterone concentration ([aldosteronel). Blood samples were drawn in cold vacuum tubes containing disodium EDTA to provide 1 mg/ml. Plasma renin activity and [aldosteronel were measured by radioimmunoassays with commercial kits (Ogihara, Yamamoto, Doi, Omori & Kumahara, 1973; Ogihara, Iinuma, Nishi, Arakawa, Takagi, Kurata, Miyai & Kumahara, 1977). Statistical significance

was assessed by the analysis of variance, correlation coefficients and Student's t-test (Siegel, 1956).

The Ethical Committee of the Department of Medicine and Geriatrics approved the protocol and informed consent was obtained from each subject after full explanation. Results Blood pressure rose significantly higher during the infusion of [Sar', Ile81ANGII in the elderly normotensive and hypertensive patients than it did in the middle-aged hypertensive patients (P < 0.01) (Fig. 1). Plasma renin activity and [aldosteronel were markedly suppressed in the elderly, compared with the middle-aged hypertensive patients: mean plasma renin activity, 0.9 f 0.3 vs 4.4 f 0.6 ng h-' ml-I (P< 0.01); mean [aldosteronel, 38 f 6 vs 112 k 6 pg/ml (P < 0.01). The two values were similar (P > 0.1) in the elderly with and without hypertension. Large correlation coefficients were observed between age, plasma renin activity, [aldosteronel and the change in mean blood pressure (A mean B.P.) with [Sar1,11e8]ANGII infusion: age vs plasma renin activity -0.85, age vs A mean B.P. 0.55; plasma renin activity vs A mean B.P. -0.72; age vs [aldosteronel -0.79; [aldosteronel vs A mean B.P. -0.58; plasma renin activity vs [aldosterone] 0.7 1. All correlations were highly significant (P< 0.01).

-r" E

E

v

e

(II

r -0

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8

5 C

0 5

10

15

20

25

30

Time (min)

FIG.1. Changes in mean blood pressure during the infusion of [Sar1,11e81ANGII(600 ng min-' kg-I). SEM values are indicated by vertical bars. 0, Aged hypertensive patients; A, aged normotensive subjects; 0 , younger

hypertensive patients.

Hypertension in old age

Discussion A reduction in blood pressure after infusion of an angiotensin I1 antagonist implies that blood pressure is maintained at least partially by the reninangiotensin system (Haber, 1976). On the other hand, angiotensin I1 antagonists cause agonist pressor responses in low reninaemic states such as low renin essential hypertension and primary aldosteronism (Ogihara et al., 1976; Carey, Vaughan, Ackerly, Peach & Ayers, 1978). Plasma renin activity and [aldosterone] decrease with age (Hayduk, Krause, Kaufmann, Huenges, Schillmoeller & Unbehaun, 1973; Weidmann, de Chatel, Schiffmann, Backmann, Beretta-Poccioli, Reubi, Ziegler & Vetter, 1977). Our data agree with these earlier reports. The pressor responses observed in our elderly hypertensive patients and normotensive subjects may be due to their hyporeninaemia. These results indicate that the renin-angiotensin-aldosterone system in elderly patients with essential hypertension does not differ from that in the non-hypertensive elderly subjects and is presumably not responsible for elevation of their blood pressure. Refennces CAREY, R.M., VAUGHAN,E.D., JR, ACKERLY,J.A., PEACH, M.J. & AYERS,C.R. (1978)The immediate pressor effect of saralasin in men. Journal of Clinical Endocrfnology and Metabolism, 46,3643.

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HABER,E. (1976)The role of renin in normal and pathological cardiovascularhomeostasis. Circulorlon, 54,849-861. HAYDUCK,K., KRAUSE,D.K., -UPMA", W., HUBNOES,R., SCHILLMOELLBR, U. & UNBEHAUN, V. (1973)Agbdepezldent changes of plasma renin concentration in humans. Clinical Science andMolecular Medicine, 45,273-278. O O ~ R A T., , HAT& T., MARUYAMA,A., M n w a , Y., NAKMURU,M., OKADA,Y. & KLIIWMU, Y. (1978)Blood pressure response to angiotcnsin 11antagonist in patients with acromegaly. Journal of Clinical EndorrinorogV and Metabolism, 48,159-162. OGIHARA, T., HATA,T., MIKAMI,H., NAKAMARU,M.,MANDAI, T. & KUMAHARA, Y. (1976) Effects of differins states of sodium depletion on blood pressure response to 1-sarcosine, 8-isoleucine angiotcnsin I1 in paticnu with hypertension of various etiologies. Clinical Pharmacology and Therapeutics, 23,556-572. OGIHARA,T., Iwulru, K., NISHI, K., AIUKAWA,Y., TAKAGI, A., KURATA,K., MIYAI,K. & KUMUHAP?, Y. (1977)A nonchromatographic nonuttrachon radmmmunoassay for serum aldosterone. Journal of Clinical Endocrinology and Metabolism, 45,726731. OGIHARA,T., Y A M A M O ~ T., , Doh K., 0Mort1, K. & KUMAHAFU, Y. (1973)Angiotensin I radioimmunoassay and its application for measurement of plasma renin actjviw. Japanese Journal of Nuclear Medicine, 10, 555-563 (in Japanese). SIEGEL,S. (1956)Nonparametric Statistics for the Behavioral Sciences, p. 229.McGraw-Hill, Kogakusha, Tokyo. WEIDMANN,P., DE CHATE~L R., SCHIPPMANN, A., BACKMA", E., BERETTA-POCCIOLI, C., REUBI,F. C., ZIEGLBR,W.H. & VETTER,W. (1977) Intmelations between age and plasma renin, aldosterone and cortisol, urinary catecholamines, and the body sodium volume state in normal man. Klinische Wochenscht@, 55,725-733. YAMAMOTO, T., DOI,K., OGIHARA, T., Icrn~R.4,K., HATA,T. & KUMAHARA, Y. (1976)Changes of blood pressure, plasma renin activity and plasma angiotensin I1 in hypertensives. Progress in Biochemical Pharmacology, 12,174-189.

Studies on the renin-angiotensin-aldosterone system in elderly hypertensive patients with an angiotensin II antagonist.

Clinical Science (1979) 57.46 1-463 SHORT COMMUNICA TION Studies on the renin-angiotensin-aldosterone system in elderly hypertensive patients with a...
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