Cardiovascular Drugs and Therapy 4: 737-744, 1990 c Kluwer Academic Publishers, Boston. Printed in U.S.A.

Hemodynamic Effects of Pindolol and Atenolol at Rest and During Isometric Exercise: A Noninvasive Study with Healthy Volunteers Janne M. Rapola, Timo J. Pellinen, Pekka Koskinen, Lauri Toivonen, Markku S. Nieminen Helsinki University Central Hospital Cardiovascular Laboratory, First Department of Medicine

Summary. Hemodynamic effects of intravenous and oral pindolol and atenolol were assessed in ten healthy volunteers by left ventricular echocardiography and systolic time inte~'als. Measurements were made at rest and during hand-gripinduced isometric exercise. Drug doses were pindolol 0.015 mg/kg intravenously and 10 mg/day orally, atenolol 0.1 mg/kg intravenously, and 50 rag/day orally. Heart rate at rest was reduced by both drugs. The reduction caused by atenolol during oral treatment was significantly greater (p < 0.01). Intravenously only pindolol reduced mean arterial pressure. During oral treatment atenolol reduced the mean arterial pressure nonsignificantly. Both drugs lowered heart rate during isometric exercise, atenolol being significantly more effective. During oral treatment atenolol blunted the heart-rate reaction to exercise. Mean arterial pressure during isometric exercise rose slightly with both drugs after intravenous administration: During oral treatment only atenolol reduced the mean arterial pressure significantly. Intravenous atenolol reduced cardiac contractility at rest, indicated by significant decreases in fractional shortening, ejection fraction, and the mean velocity of circumferential fiber shortening. In contrast, intravenous pindolol and oral therapy with either drug did not change contractility. Intravenous atenolol raised total peripheral resistance. The preejection period/left ventricular ejection time ratio decreased with intravenous pindolol, while atenolol increased it. In conclusion, atenolol had more negative inotropic and chronotropic effects, especially after acute intravenous administration. Only atenolol reduced cardiac output and increased peripheral resistance. After repeated oral administration, these effects were less apparent.

Key Words. Pindolol,

atenolol, echocardiography, systolic time intervals, isometric exercise

Pindolol and atenolol are both commonly used betaadrenergie blocking agents. Their clinical pharmacology, hemodynamic effects, and efficacy in the treatmerit of both hypertension and coronary artery disease have been well documented [1-8]. Despite their common beta-adrenerg-ie antagonism, they have properties that clearly differentiate them fi'om each other.

Pmdolol is a potent nonselective beta blocker with partial agonist activity or intrinsic sympathomimetic activity (ISA) [9-11]. Of the beta blockers in clinical use, the ISA of pindolol in relation to the betaantagonistic effect is the strongest [12]. The betablocking activity of pindolol in relation to propranolol varies in the literature, the most commonly used ratio being 6:1 [6,9,13]. Because of the relatively strong ISA of pindolol, it does not markedly reduce the resting heart rate or cardiac output, nor does it increase peripheral vascular resistance [2,7,14,15]. Its effect on plasma renin activity is minimal, and it causes a reduction in the plasma norepinephrine level [2]. In states of minimal adrenergic tone, e.g., during the night, pindolol may even cause an elevation in the resting heart rate [16]. Despite its strong ISA, pindolol has been documented to be an effective antianginal [7] and antihypertensive [3,4,8,14] drug. Atenolol is a betaa selective agent without ISA [1719]. Its beta-blocking activity in relation to propranolol is considered to be 1:1 [6,17]. Atenolol causes marked reductions in heart rate and blood pressure, both at rest and during exercise [1-3,15,20]. Its effect on peripheral vascular resistance is a slight increase, especially after acute beta blockade [14]. During longterm use, this effect seems to decrease [2,14,20]. During acute beta blockade stroke volume is markedly decreased, but after long-term administration the effect is a slight increase [14]. Cardiac output decreases markedly both acutely and after long-term administration [14]. In the present investigation, we studied the hemodynamic effects of pindolol and atenolol in young healthy subjects. Circulatory effects of these drugs

Address for correspondenceand reprint requests: Markku S. Nieminen, MD. CardiovascularLaboratory,UniversityCentral Hospital, 00290 HelsinM, Finland. 737

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after acute intravenous and repeated oral administration were studied at rest and during isometric exercise. The hemodynamic measurements were made noninvasively using echocardiography and systolic time intervals. The aims of this study were to investigate the hemodynamic effects of the two different types of beta blockers in different physiologic situations and to evaluate the validity of these noninvasive methods as tools for clinical pharmacologic investigation.

Methods

Subjects After screening 20 volunteers, ten clinically healthy subjects were selected for the study on the basis of repeatedly good echocardiogTaphic recordings, the criteria being distinct echo lines fl'om both the interventricular septum and left ventricular endocardium and epicardium. All subjects had normal exercise capacity and no significant medical history. Basic laboratory parameters, ECG, and chest x-ray were normal. Six subjects were female and four male. The mean age (_+ 1 SD) was 23 + "2 years and weight 65 -+ 5-kg.

Study design All examinations were performed in a fasting state in the morning. After 15 minutes supine rest, the baseline recordings were performed. Thereafter isometric exercise was undertaken and the recordings were repeated. After the baseline was obtained, the patients were randomized to receive either 0.015 my/ kg pindolol or 0.1 mg/kg atenolol intravenously. Five minutes later the recordings were performed again at rest and during isometric exercise. After 10 minutes, a second similar dose was given IV and the recordings were repeated 5 minutes later. The same drug was continued orally for 1 week, and the examinations were repeated 2 hours arm" the last oral dose. After a washout period of 1 week, the same subjects entered the protocol with the other drug. Oral dosages were 10 mg pindolol and 50 mg atenolol as a single daily close. The drugs were administered double blindly.

Isometric exercise Isometric exercise was induced by hand grip. A standard electrodynamically adjusted hand-gril) device was used. Before the study the device was calibrated individually for each subject by measuring the maximum level of contraction. During the study the subjects were working at 30~ of the previously measured maximum. Measurements were begun after 3 minutes hand grip and completed during the fourth minute.

Clinical and hemodynamic measurements

The subjects were in the supine position with a slight left lateral tilt. The brachial cuff blood pressure was measured and the mean blood pressm'e was calculated. M-mode echocardiograms of the leR ventricle were taken with an h'ex System II using a probe with a fl'equency of 2.25 MHz. Simultaneous electrocardio~'aphic and phonocardiographic recordings were made. ARm" eehocardiographic recording, indirect carotid artery pressm'e tracings were made with simultaneous ECG and phonocardiogTam. All tracings were recorded with a strip-chart recorder using paper speeds of 50 mm/s for the eehoeardiogTam and 100 mm/s for the carotid artery pressure curve. The echocardiograms were recorded from the fourth left intercostal space fl'om a premarked site. The transducer was directed posteriorly just below the mitral leaflets, so that the echo beam passed through the septum and posterolateral wall as perpendicularly as possible. Satisfactory perpendicularity was indicated by tracings in which endoeardial, myocardial, and epicardial echoes were linear. Repeated measurements in each subject were always made from the same site, using the mitral leaflets as an anatomic landmark.

Hemodgnamic calculations M-mode echocardiograms were traced for computer analysis on a digitizing board connected to a PDP 11 computer. Five consecutive cardiac cycles were traced and averaged. A computer progTam similar to that introduced by Upton and Gibson [21] was used. The analysis of left ventricular dimensions were made according to the European standardization recommendations [22]. Left ventricular end-diastolic diameter (LVEDD) was measured at the beginning of the QRS complex and the end-systolic diameter (LVESD) at the first deflection of the second heart sound. The program calculates left ventricular end-diastolic volume (LVEDV) and end-systolic volume (LVESV) according to the Teicholz formula [23], which has been shown to correlate well with invasively assessed volumes in normal subjects [24-2611. Stroke volume (SV) was calculated as the difference L V E D V - LVESV. Ejection fraction (EF) was calculated as 100 x SV/ L V E D V and fl'actional shortening (FS) as 100 x (LVEDD LVESD)/LVEDD. The program was able to calculate the first derivative of the instantaneous left ventricular dimensional change. During ventricular contraction (time fl'om the first to the second heart sound), the mean derivative of the velocity of dimensional change represents the mean velocity of circumferential fiber shortening and the peak value of this derivative represents the maximum velocity of circumferential fiber shortening (VCF max) [21]. -

Hemmly~amic Etl'ects ql'Pindol.I atM Ate~olol

739

Table l. Hemodynamic e(lOcts qf pit~dolol ,*ld alenolol at rest Control

[ intravenous

II intravenous

Oral

PbMolol HR (beats/min) MAP (mmHg) RPP (mmHg/min) LVEDD (ram) CO (l/• EF(~) FS(~) VCF max (circ/s) TPR (dyn s/c• r') PEP/LVET

63 • 87 • 6700 47.3 3.50 56 • 29 • 1.75 2100 0.31

12

57

8

84 •

• 1100 + 4.5 • 0.70 6 4 • 0.24 • 500 • 0.04

+ 7" 7 ~'

57 :

6"

59 •

7

,'~4 •

6"

54 •

8

6400 • 51111 48.1 _+ 4.8 3.45 + 0.50 58 • s 31 • 5 1.75 * 0.31 2000 • 3[J0 0.:~,0 • o.04

I;3011 + 51111 4s.II - 5.4 3.42 : 0.7o 57 - 5 3o ~ 3 1.72 _~ 0.2s 200o + :r o.29 ~ o.o4"

6500 = 700 45.0 _~ 4.9 3.41 = 0.57 56 + 5 29 • 3 1.67 • 0.23 2010 = 330 I).32 _+ 0.05

56 • 7" 83 § 9 621)!/ • 700" 4~.2 : 4.7 3.2(I = 0.62 54 : 7 28 ~ 5 1.62 • 0.23

55 = 7" S5 ~ 8 61110 • 7o0:' 47.,~ _- 5.7 2.95 = o.5.q~' 52 = ~9' 27 : 4" 1.60 * 0.25

49 • 7~' 78 : 1() 5100 = 1000( 49.3 • 4.9 :-1.15 z 0.53 5,~ • 6 31 = 4 1.71 _~ 0.27

2200 + 500

24011 •

2001) ~ 5 0 0

0.32 • 0.o~;

o.33 = ().o5'

Atcnolol HR (beats/min) MAP (mmHg) RPP (mmHg/min) LVEDD (ram) CO (l/• EF (~) FS ((~) VCF max(cite/s) TPR

(dyn s/c•

PEP/LVET

62 • 9 85 + 8 6900 • 900 48.6 • 5.8 3.70 + (I.73 56 • 6 29 + 4 1.73 + 0.27 191)0 • 4ol) 0.30 + 0.o5

5(10"

o.30 + o.04

;' = p < 0 . 0 5 , ~' = p < o . 0 1 , " = p . : 0.11111. A b b r e v i a t i o n s a c c o r d i n g to t e x t in M e t h o d s .

C a r d i a c o u t p u t (CO) w a s m e a s u r e d b y m u l t i p l y i n g SV by heart rate (HR). Mean arterial pressure (MAP) w a s d e f i n e d as: M A P = D B P + 1 / 3 ( S B P DBP), w h e r e S B P = s y s t o l i c blood p r e s s u r e a n d D B P = diastolic blood pressure. Total peripheral resistance w a s c a l c u l a t e d fl'om t h e f o r m u l a : T P R ( d y n x s / c • s) = 80 x M A P / C O . L e f t v e n t r i c u l a r m i d s y s t o l i c p o s t e r i o r wall s t r e s s w a s c a l c u l a t e d as follows: wall s t r e s s ( d y n / c m z) = S B P x M S D / 2 M S W T x (1 - M S D / 8 • ( M S D + M S W T ) x 1332, w h e r e M S D is m i d s y s t o l i e d i a m e t e r a n d M S W T m i d s y s t o l i c wail t h i c k n e s s of t h e left v e n t r i c u l a r p o s t e r i o r wall. M i d s y s t o l e w a s defined as t h e m i d d l e of t h e a c o u s t i c s y s t o l e . T h e r a t e p r e s s u r e p r o d u c t ( R P P ) w a s c a l c u l a t e d as S B P x H R . T h e s y s t o l i c t i m e i n t e r v a l s w e r e m e a s u r e d fl'om t e n cons e c u t i v e c a r d i a c c y c l e s b y c o n v e n t i o n a l m e t h o d s [27]. T h e p r e e j e c t i o n p e r i o d ( P E P ) w a s m e a s u r e d b y subt r a c t i n g t h e left v e n t r i c u l a r e j e c t i o n t i m e ( L V E T ) from the QS2 interval. LVET was measured from the c a r o t i d a r t e r y t r a c i n g . T h e P E P / L V E T r a t i o w a s calc u l a t e d a n d u s e d as a m e a s u r e of c o n t r a c t i l i t y [28].

Statistical analysis T h e s t a t i s t i c a l s i g n i f i c a n c e of d i f f e r e n c e s w a s t e s t e d b y a n a l y s i s of v a r i a n c e w i t h r e p e a t e d m e a s m ' e s comp a r i n g t h e m e a n s o b s e r v e d a t b a s e l i n e , a f t e r t h e first a n d s e c o n d i n t r a v e n o u s dose, a n d a f t e r oral t r e a t m e n t . W h e n a s i g n i f i c a n t effect w a s o b s e r v e d b y t h e

a n a l y s i s of v a r i a n c e , t h e p a i r e d t t e s t w a s u s e d to t e s t t h e significance of c h a n g e s . T h e e q u a l i t y of all b a s e l i n e m e a s u r e m e n t s w a s e v a l u a t e d by t h e p a i r e d t t e s t . W h e n c o m p a r i n g t h e e f f e c t s of t h e d i f f e r e n t d r u g s , t h e b a s e l i n e m e a s u r e m e n t s w e r e u s e d as c o v a r i a t e s to e l i m i n a t e a n y effect of s l i g h t d i f f e r e n c e s in b a s e l i n e values. T h e p v a l u e of 0.05 w a s u s e d for t h e level of significance. R e p r o d u c i b i l i t y of t h e s t u d y v a r i a b l e s was a s s e s s e d by c a l c u l a t i n g coefficients of v a r i a t i o n for all b a s e l i n e m e a s u r e m e n t s . I n d i v i d u a l v a l u e s w e r e c a l c u l a t e d as a p e r c e n t a g e by d i v i d i n g t h e s t a n d a r d d e v i a t i o n w i t h t h e m e a n of t h e t w o b a s e l i n e m e a s u r e m e n t s . G r o u p coefficients of v a r i a t i o n w e r e o b t a i n e d b y a v e r a g i n g i n d i v i d u a l values.

Results B o t h t e s t d r u g s w e r e well t o l e r a t e d , no s i g n i f i c a n t side effects o c t • a n d all s u b j e c t s c o m p l e t e d t h e t r i a l as p l a n n e d . No d i f f e r e n c e s in b a s e l i n e v a l u e s w e r e o b s e r v e d . M e a n coefficients of v a r i a t i o n for all v a r i a b l e s w e r e less t h a n 1 0 ~ , e x c e p t for c a r d i a c outp u t a n d p e r i p h e r a l r e s i s t a n c e . C o e f f i c i e n t s of v a r i a t i o n i b r t h e s e w e r e 13c/c a n d 17c~, r e s p e c t i v e l y .

H e m o d g n a m i c effects a t rest T h e r e s u l t s a r e listed in T a b l e 1. B o t h d r u g s c a u s e d a r e d u c t i o n in h e a r t r a t e b o t h a c u t e l y (i.e., a f t e r i n t r a -

740

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Table 2. Hcmodlpmmic tJ~'ecls qf pimloh~l mid ttlemdol durblg i,somelrl'c exercise Control

I intravenous

1I i n t r a v e n o u s

Oral

t;2 + 7

Pimh~tol HR (beats/•

65 + 11/

63 + .q

61 •

MAP (mmHg) RPP ImmHg/min)

101 • 11 81110 = 1100

103 • 12 8 3 0 0 _+ 1200

1118 + 12 ~' 821111 + 71111

1114 • I2 771111 • 90o

LVEDD

.1.%0 + 5 . 2

(ram)

7

4 8 . 7 + 5.4

48.9 + 4 . 7

4.%5 •

CO (1/min) E F (r/r)

3 . 8 0 + {I..q0 54 • 7

3 . 7 7 • 0.65 54 • 9

3.7(; + I}.5I 54 § S

3 . 6 3 • 0.~;8 54 + 7

4

5.1~:'

F S (5'~1

2~ •

28 + 6

2,"; + 5

28 + 5

V C F i]lax (ell'c/s) TPR (dyn s!em:')

1.67 _+ 11.35 2 2 0 0 • 600

1.62 • 0 . 2 6 2 3 0 0 • 500

1.58 + 0 , 2 3 2at)I1 + 400

1.61 • 0 . 2 8 24110 + 500

PEP/LVET

0.35 •

11.32 + 0.04

0.32 + 11.115

11.31 + 0.03

11.05

.-th'm~h~l HR (beats/mini

(~l~ _+ 12

(;(I •

59 + lOh

50 + s t'

MAP (mmHg) RPP (• LVEDD (ram)

99 + 12 811111 m 111){1 4 8 . 8 _+ 5.2

lO3 ~ 12 7600 • 1/10 4 9 . o + 5.3

lO5 + 16 7500 + 1400 48.4 +_ 5.5

92 + .q" 5 9 0 0 + 900" 4.q.3 • 5.4

CO (1/mini E F (r FS t%)

3.71 + 0.t;,s 52 • 5 27 _+ 3

3.25 + 0.46" 5O • 6 25 + 4

3.114 • 0.54 ~' 49 + t; 25 • 3

3.(I.q • 0.1jiP 55 + 1; 29 _+ ,t

VCF max tcirc/s) TPR (dyn s/c• PEP/LVET

1.54 + 0.24 2 1 0 0 • 500 o.34 • ll.I)5

1.41 + 0 . 1 9 ~' 2 6 0 0 _+ 501P o . 3 7 + tl.06

1.47 + 0.21; 2S00 + 500 h 11.?,7 = 0 . 0 7

1.55 • 0 . 2 3 2 5 0 0 • 700 O.34 +_ 0 . 0 3

~' =

p

Hemodynamic effects of pindolol and atenolol at rest and during isometric exercise: a noninvasive study with healthy volunteers.

Hemodynamic effects of intravenous and oral pindolol and atenolol were assessed in ten healthy volunteers by left ventricular echocardiography and sys...
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