CAPTOPRIL OR ATENOLOL IN ESSENTIAL HYPERTENSION

Lennart And&, Anders Svensson and Lennart Hansson morn the Hypertension Section, Department of Medicine, Ostra Hospital,

University of Goteborg, Sweden

Abstract Twenty-five patients with essential hypertension were randomly assigned to treatment with either captopril or atenolol. There were 15 males and 10 females and their mean age was 53 years, range 32 - 66 years. Systolic and diastolic blood pressures were significantly reduced by atenolo150 - 100 mg once daily. Captopril 25 - 50 mg 3 times daily caused a significant decrease in supine diastolic but not in systolic blood pressure. After the addition of hydrochlorothiazide (25 - 50 mg) to those who did not become normotensive (supine diastolic blood pressure less than 95 mm Hg) on captopril or atenolol alone, blood pressure was further reduced. Captopril combined with hydrochlorothiazide significantly reduced both supine and standing blood pressure by 31/17 mm Hg (p < 0.01) and 33/18 mm Hg (p < 0.001) respectively. Atenolol combined with hydrochlorothiazide caused a sig- nificant decrease of both recumbent and standing blood pressure by 21/10 mm Hg (p < 0.01) and 23/13 mm Hg (p < 0.05 systolic, p < 0.001 diastolic). The reduction of systolic blood pressure was significantly better with the captopril/hydrochlorthiazide combination, while there was no differ- ence between the groups as regards diastolic blood pressure reduction. Thus, hydrochlorothiazide potentiates the blood pressure lowering effect of captopril more than of atenolol. This could be due to a synergistic interaction between captopril and hydrochlorothiazide.

Key words: Captopril, atenolol, hydrochlorothiazide, blood pressure, heart rate, synergism.

Captopril is a selective blocker of the angiotensin I/angiotensin I1 converting enzyme (1). It is effect- ive in reducing blood pressure both in renovascular and essential hypertension (2,3,4).

The purpose of the present study was to evaluate the antihypertensive effect of captopril com- pared to atenolol with and without the addition of hydrochlorothiazide in patients with essential hypertension.

Material and methods Twenty-five patients with essential hypertension (15 males and 10 females) were recruited from the Hypertension Clinic. Their mean age was 53 years, range 32 - 66 years. Twenty-four patients were previously treated with a beta-adrenoceptor blocking drug alone or in combination with other drugs, while one patient was previously untreated. All antihypertensive drugs were withdrawn when the study started and there was an initial placebo period of two weeks, The resting supine diastolic blood

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pressure at the end of the placebo period was 100 - 125 mm Hg. The patients were then randomized to either captopril (n = 13) or atenolol (n = 12) treatment. Blood pressure, heart rate and side effects were recorded every second week and the therapeutic goal was to reach nomotension, which was de- fined as supine diastolic blood pressure of 90 mm Hg or less. In order to reach normotension, the dos- age of captopril and atenolol was increased in a stepwise design and hydrochlorothiazide was added if necessary. The initial dose of captopril was 25 mg x 3. This dose was doubled after 2 weeks if normotension was not obtained. After further 2 and 4 weeks, hydrochlorothiazide (25 mg x 1 and 50 mg x 1) was added if necessary. The last dose step was to increase captopril to 100 mg x 3 while hydrochlorothiazide was kept at 50 mg x 1. In the atenolol group the initial dosages were 50 mg x 1 and 100 mg x 1. Then hydrochlorothiazide 25 mg x 1 and 50 mg x 1 was added if necessary and in the final step atenolol was increased to 200 mg x 1 if needed.

All blood pressure and heart rate measurements were made under strictly standardized conditions after 5 minutes of supine rest and after 1 minute in the standing position. The mean of three measure- ments was used for blood pressure calculations. AU measurements were made by specially trained nurses and a mercury sphygmomanometer with a 12 cm wide cuff containing a 30 cm rubber balloon was used for blood pressure recordings. The disappearance (phase V) of the Korotkoff sounds was taken as the diastolic blood pressure.

Statistics Student’s t-test for paired and non paired data was used for statistical evaluation.

Results Captopril as single therapy (25 - 50 mg x 3) reduced supine blood pressure by 11/9 mm Hg. The de- crease in diastolic blood pressure was statistically significant (Table 1). Standing blood pressure was reduced by 12/6 mm Hg (Table 1). Atenolol as single therapy (50 - 100 mg x 1) caused a significant reduction in systolic and diastolic blood pressure both supine, 13/11 mm Hg, and standing, 13/11 mm Hg (Table 1). Heart rate did not change significantly after captopril but was reduced after ateno- lo1 (Table 1). After the addition of hydrochlorothiazide (25 - 50 mg) to those who were not normo- tensive on captopril or atenolol alone, a further reduction in blood pressure was achieved in both groups (Table 1).

The fall in systolic blood pressure was significantly better in the captopril/hydrochlorothiazide group, while there was no significant difference in diastolic blood pressure reduction between the groups. Heart rate was significantly reduced by atenolol alone and with the combination of atenolol and hydrochlorothiazide, while heart rate was slightly increased in the captopril/hydrochlorothiazide group (Table 1). The difference between the captopril/hydrochlorothiazide group and the atenolol/ hydrochlorothiazide group was statistically significant.

There were 3 patients who did not completefhe study. One patient on captopril had a total loss of taste and the drug was withdrawn. Her ability to taste reappeared after one month. Two patients were excluded from the atenolol group. One patient did not respond to atenolol in spite of earlier treatment with a beta-blocking drug. One patient had a serious bradyarrhythmia (sick sinus syn- drome) which was normalised when atenolol was withdrawn.

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Table 1

CAPTOPRIL

End placebo week 6 week 14

Blood pressure (mm Hg) 159/105 148/96** 128**/88** (supine) Blood pressure (mm Hg) 163/115 15 1 */ 109 130***/97*** (standing)

Heart rate (beatslmin) 76 76 83 (supine) Heart rate (beatslmin) 83 87 96** (standing) Dosage (mg) / No. of patients c 75 5 c 75 1

C150 8 C 75+H25 1 C 150+H25 5 C 150+H50 3 C300+H50 2

ATENOLOL

End placebo - week 6 week 14

Blood pressure (mm HC) 163/106 150*/95* 142”*/96** (supine) Blood pressure (mm Hg) 16311 13 150*/102*** 140*/100*** (standing) Heart rate (beats/min) 13 57** 58* (supine) Heart rate (beats/min) 80 62*** 64* (standing) Dosage (mg) /No. of patients A 50 2 A 50 1

A100 9 A 100 1 A 100+H25 1 A 100+H50 4 A200+H50 3

C = Captopril; A = Atenolol; H = Hydrochlorothiazide. *p < 0.05; **p < 0.01; ***p < 0.001.

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Discussion Captopril and atenolol as single drugs caused a significant reduction of blood pressure in this study. The variability in the captopril group was, however, more pronounced causing a significant decrease only in supine diastolic and in standing systolic blood pressure. When combined with hydrochloro- tliiazide the blood pressure lowering potency was greatly increased especially in the group treated with captopril. Thus, systolic blood pressure was significantly better reduced both supine and stand- ing by the combination of captopril and hydrochlorothiazide than with atenolol and hydrochloro- thiazide. The reason for this difference between the captopril/hydrochlorothiazide and atenolol/ hydrochlorothiazide combination is not quite clear.

Hydrochlorothiazide causes an increase in renin and thus activates the renin-angiotensin system. When captopril is present, however, this potentially disadvantageous effect of hydrochlorothiazide is blocked.

On the other hand, combined therapy with atenolol should be expected to reduce the beta, -ad- renoceptor mediated increase of renin release. The mechanisms by which captopril reduces blood pressure in essential hypertension are not known. There is no evidence that the renin-angiotensin system is of pathogenetic importance in essential hypertension (5). Furthermore, captopril can reduce blood pressure in nephrectomized patients (2) and the long-term blood pressure lowering effect of captopril can thus not be correlated to circulating levels of angiotensin 11.

There is evidence for a renin-angiotensin system also in the walls of the blood vessels (6) and in the central nervous system (7) and perhaps the blood pressure lowering effect of captopril could be ex- plained by an interference in these systems. In addition, captopril impairs the vascular smooth muscle contraction mediated by postjunctional alpha-adrenoceptors (8).

Still it is difficult to explain why captopril t hydrochlorothiazide appeared to have a more potent antihypertensive effect than atenolol t hydrochlorothiazide, particularly since most patients in this study previously had responded to treatment with a beta-adrenoceptor blocking drug, From a practic- al point of view it can be concluded that both the therapeutic combinations proved to give clinically relevant reductions in blood pressure. A clear statement that the one combination is better than the other must await confirmation from other studies.

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of orally active antihypertensive agents. Science 196: 441-444, 1977. 2. De BNyn J.H.B., Wenting G.J., Man In’t Veld A.J., Derkx F.H.M., Schalekamp M.A.D.H. Captopril affects blood

pressure equally in renovascular and essential hypertension and in the fluiddepleted anephric state. Clinical Science 59: 83s-86s, 1980.

3. Cody R.J., Tarazi R.C., Bravo E.L., Fouad F.M. Haemodynamics of orally-active converting enzyme inhibitor (SQ 14225) in hypertensive patients. Clinical Science and Molecular Medicine 55: 453-459,1978.

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5. Beevers D.G., Morton J.J., Nelson C.S., Padfield P.L., Titterington M., Tree M. Angiotensin I1 in essential hyper- tension. British Medical Journal 1: 415,1977.

6. Haber E. Specific inhibitors of renin. Clinical Science 59: 7s-19s, 1980. 7. Scholkens B.A., Jung W., Rascher W., Schomig A., Ganten D. Brain angiotensin I1 stimulates release of pituitary

hormones, plasma catecholamines and increases blood pressure in dogs. Clinical Science 59: 53s-56s. 1980. 8. De Joonge A., Wilffert B., Kalkman H.O., Van Meel J.C.A., Thoolen M.J.M.C., Timmermans P.B.M.W.M., Van

Zwieten P.A. Captopril impairs the vascular smooth muscle contraction mediated by postsynaptic alpha2-adreno- ceptors in the pited rat. European Journal of Pharmacology 74: 385-386, 1981.

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