Eur J Clin Pharmacol (1990) 38:541-546 European,Journalof C ( ] ~ { ~ ( ~ ( ~ @ Springer-Verlag1990

Effects of single doses of quinapril and atenolol on autonomic nervous function and exercise capacity in healthy volunteers* I. P6rsti 1, E Arvola 1, R S fiynfivfilammi1, A. K. Nurmi l, T. Mets~i-Ketel~it, K. K o s k e n v u o 2, L. A. Laitinen 3, V. M a n n i n e n 4, and H. Vapaatalo 1 Department of Biomedical Sciences,University of Tampere, Tampere, and 2 General Military Headquarters, 3 Research Institute of Military Medicine and 4 First Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland Received: July 25, 1989/Accepted in revised form: October 28, 1989

Summary. The effects of single oral doses of the angiotensin converting enzyme (ACE) inhibitor quinapril (CI906) 40mg and the cardioselective [3-adrenoceptor blocker atenolol 100 mg on sympathetic and parasympathetic function and on exercise capacity have been studied in 8 healthy young men. The trial followed a doubleblind, placebo controlled, randomized cross-over design, with at least one week between treatments. Blood pressure (BP) and heart rate (HR) at rest were slightly reduced by atenolol but were not affected by quinapril. Atenolol impaired the sympathetically mediated increases in H R and BP caused by standing, immersion of the hand into melting ice, the Valsalva manoeuvre and isometric forearm exercise. Quinapril did not influence those responses nor the vagally mediated bradycardia of the diving reflex. Atenolol, however, augmented the vagal bradycardia, presumably by sympathetic inhibition. In a dynamic bicycle ergometer test with a stepwise increasing work load, exercise performance was decreased by atenolol but not by quinapril. Inhibition of the renin-angiotensin system by quinapril was shown by a marked decrease in serum A C E activity and a several-fold increase in plasma renin activity (PRA). Atenolol produced a moderate reduction in PRA. Before or during exercise, plasma noradrenaline and adrenaline were not influenced by either drug. The results indicate that, unlike the atenolol-induced [~-adrenoceptor blockade, A C E inhibition by a single dose of quinapril had no clear effect on autonomic nervous function or exercise capacity.

pate in the reduction of BP [1]. A C E inhibitors act as indirect vasodilators, but they do not cause the increase in sympathetic tone and reflex tachycardia induced by most other vasodilator drugs [2]. AII stimulates the sympathetic nervous system at a central as well as a peripheral level [3]. The most important sites of stimulation are presynaptic receptors on the peripheral sympathetic nerve endings, at which AII augments noradrenaline release [4]. AII also has an inhibitory effect on central parasympathetic tone and peripheral cardiac vagal activity [5, 6]. The lack of tachycardia after A C E inhibition has been attributed to a decrease in sympathetic or to an increase in parasympathetic tone produced by withdrawal of the action of AII.

Table 1. Systolic and diastolic blood pressure (SBP and DBP, mmHg) and heart rate (HR, beats/min) at rest and 0,1, 2, 3, 4, 5 and 6 h after administration of placebo, quinapril and atenolol. Mean (SEM), * P < 0.05, ** P < 0.01 compared to placebo

0h

lh

2h

Key words: quinapril, atenolol, autonomic function, exercise capacity, plasma renin activity, plasma catecholamines

Angiotensin converting enzyme (ACE) inhibitors lower blood pressure (BP) by decreasing the formation of angiotensin II (AII). Other mechanisms may also partici-

* Preliminary results from this study were presented at the XX Congress of the Nordic Society of Military Medicine, Helsinki, 14-16 May,1987,and were published in 1988in Ann Milit Med Fenn, 63 (1-2)

3h

4h 5h 6h

SBP DBP HR SBP DBP HR SBP DBP HR SBP DBP HR SBP DBP Ha SBP DBP HR SBP DBP HR

placebo 123 (2.8) 68 (2.5) 64 (3.8) 122 (3.4) 71 (1.5) 58 (2.8) 123 (1.8) 68 (1.1) 53 (1.1) 120 (4.1) 68 (1.6) 56 (2.7) 121 (3.3) 69 (2.4) 58 (2.3) 122 (3.0) 69 (2.1) 58 (2.1) 121 (4.1) 69 (2.1) 55 (1.7)

Treatment quinapril 126 (3.4) 74 (1.8) 66 (2.6) 120 (3.5) 70 (2.6) 63 (2.4) 117 (4.5) 70 (2.3) 61 (2.8)* 120 (2.5) 69 (1.9) 56 (1.8) 125 (3.1) 71 (3.5) 58 (1.8) 120 (4.0) 69 (2.7) 63 (3.7) 122 (2.7) 68 (3.3) 60 (2.8)

atenolol 122 (4.4) 69 (2.2) 65 (2.9) 119 (5.0) 68 (3.7) 53 (2.1) 115 (3.6) 60 (2.4)** 50 (2.1) 114 (4.7) 66 (1.9) 46 (1.8)** 114 (4.2) 65 (2.0) 52 (3.0) 114 (5.1) 65 (3.3) 53 (2.5) 114 (3.7) 64 (2.2) 49 (1.2)**

542

I. POrsti et al.: Effects of quinapril and atenolol HR

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The effect of [}-adrenoceptor blocking drugs on the sympathetic nervous system is complex. They seem to have central and peripheral effects, and also to reduce reflex-mediated sympathetic nerve activity [7]. In addition, they may block presynaptic facilitatory [3-adrenoceptors, thereby reducing the amount of noradrenaline released per nerve impulse [8]. [}-blockers also impair exercise performance by their action on cardiac ~-adrenoceptors [9]. In contrast, ACE inhibitors do not seem to reduce exercise capacity [10, 11]. The purpose of the present investigation was to study the effects of a new ACE inhibitor quinapril (CI-906) and the cardioselective [3-blocker atenolol on autonomic nervous function and exercise performance in healthy male volunteers.

Fig. 1. Effect of orthostatic test 2 h after administration of placebo, quinapril and atenolol. BP and H R were recorded at rest and 2, 5 and 8 rain after standingup. Mean (SEM), * P < 0.05, • ** P < 0.001 compared to placebo

Diving test. The subjects sat quietly for 5 min and then immersed the

face in water at + 12 °C to the level of the ears. They were instructed not to take a deep breath before the test and to remain immersed for 20 s. The E C G was recorded continuously during the immersion. The results are expressed in heart periods (R-R intervals) at rest, immediately at the beginning and at the end of the immersion. Cold pressor test. The subject immersed one hand to the wrist in

melting ice for 2 rain. H R and BP in the contralateral arm were measured before, and after 1 and 2 rain of immersion. Valsalva manoeuvre. The subject blew through a mouthpiece connected to a modified sphygmomanometer. Forced expiration at 40 mm Hg was maintained for 20 s. The E C G was recorded continuously and for 30 s after ceasing to blow. A second BP reading was taken immediately after stopping the manoeuvre in order to measure the BP 'overshoot' which follows its termination. Forearm isometric exemise test. H R and BP were measured before

Subjects and methods The study was performed on 8 normotensive, moderately trained, non smoking volunteers aged 19-23 y. Ethical approval was given by the Medical Department of the General Military Headquarters. Each subject was screened by clinical history and physical examination, resting 12-lead electrocardiogram, determination of erythrocyte sedimentation rate, totalblood count, serum creatinine and electrolytes, liver enzymes, fasting blood glucose and urine tests for protein and glucose, all of which were normal. The patients abstained from all other medication for 7 days prior to the tests. No strenuous physical activity or alcohol was allowed for 24 h before the tests. Each subject was studied on three separate occasions, at least 7 days apart, at which a single oral dose of quinapri140 rag, atenolol 100 mg or placebo was given in a double-blind cross-over design. The participant ate a light breakfast and arrived in the laboratory at 08.00 h. An antecubital vein was cannulated for blood sampling. Urine was collected for 7 h from the time of drug ingestion. Supine heart rate (HR) and BP were measured before and 1, 2, 3, 4, 5 and 6 h after drug intake with an automatic BP203 Sphygmomanometer Y M II (Nippon Colin Co., Komaki-City, Japan). Tests were performed as follows: an orthostatic test at 2 h, a diving test at 3 h, a cold pressor test at 4 h, the Valsalva manoeuvre and an isometric exercise test at 5 h, and a dynamic exercise test at 6 h. Details of the tests are given below. Orthostatic test. After 10 min in the supine position, the subject stood

up. BP and E C G were measured 2, 5 and 8 min after standing.

and at intervals of I min for a period of 3 min during hand grip exercise at 30% of maximal voluntary contraction, using a hand dynamometer. Dynamic exercise test. The subject exercised on a bicycle ergometer

with a stepwise increasing workload; the initial workload of 50 W was increased by 50 W every 3 min. E C G and BP were recorded at the end of each 3-min period. BP was measured with an ordinary sphygmomanometer. The participant exercised until subjective exhaustion. Table2. P R A (ng A I . m l - ~ . h 1) and serum A C E activity ( n m o l . m l - l . m i n -~) before and 3 h after placebo, quinapril and atenolol, and corresponding urinary excretion of catecholamines and their metabolites (nmol.7h-t). Mean (SEM), * P