European Journal of Clinical Pharmacology
Europ. J. clin. Pharmacol. 11,423-427 (1977)
© by Springer-Verlag 1977
Effect of Certain Antiadrenergic Agents on Systolic Time Intervals in Essential Hypertension E. Q. Roland, M.E. Safar, CI. E. Lelguen, N.E. Aboras, Y.A. Weiss, and P.M. Milliez Haemodynamic Laboratory, Hypertension Research Center, Hospital Broussais, Paris, France
Summary. Systolic time intervals, including preejection period (PEP) and left ventricular ejecion time (LVET), were studied in patients with permanent essential hypertension before and after intra-venous administration of propranolol 0.2mg/kg (11 patients), clonidine 0.002mg/kg (10 patients) and methyldopa 2 m g / k g (12 patients). With propranolol, diastolic blood pressure was unchanged and the heart rate decreased, whilst PEP and LVET were significantly prolonged (P < 0.001). Clonidine caused a fall in blood pressure (P < 0.001), heart rate was slightly reduced, PEP was prolonged (P < 0.001) and there was a significant decrease in LVET at 5 rain. With methyldopa, no significant effect was observed after intravenous injection, but 7 days oral administration produced the identical effect as clonidine. These observations suggest that certain antihypertensive drugs may impair left ventricular performance and depress myocardial contractility. Key words: Systolic time intervals, propranolol, clonidine, methyldopa, essential hypertension.
The majority of the haemodynamic studies of antihypertensive drugs have been based on blood pressure, cardiac output and blood volume determinations [1]. However, characterization of contractile state may also be of major importance in assessment of cardiac function before and after treatment [6]. Several indices of myocardial contractility have been obtained by left heart catheterization. These invasive technics cannot easily be performed in hypertensive man before and after therapy. Many reports have confirmed that determination of systolic time intervals can provide a valid approach for estimation of variations in the contractile state of the left ven-
tricular myocardium [7-15]. In addition, determination of the length of preejection period (PEP) after beta adrenergic blockade can serve as useful index of adrenergic influences on cardiac dynamics [12, 16]. The purpose of the present study was to investigate the effects of 3 of the most widely used antihypertensive drugs, propranolol, clonidine and methyldopa. All 3 drugs can reduce sympathetic tone and so they might change cardiac performance as measured by systolic time intervals.
Material and Methods Patients
Thirty three male hypertensive patients were included in the present study; ages 25 to 51 years (average: 39 years); and weight 56 to 82 kgs (average 75 kg). The patients were hospitalized for a 10 days period. Antihypertensive treatment was discontinued at least 4 weeks before the study. In all patients diastolic blood pressure was equal to or higher than 95 mmttg on the third day of hospitalization. Before the study a complete clinical and laboratory evaluation had been carried out, including physical examination, routine laboratory tests, determination of urinary catecholamines, measurement of plasma electrolytes, and intravenous pyelography and/or renal arteriography. All the patients were diagnosed as having moderate essential hypertension : creatinine clearance was normal (greater 90 ml/min), the optic fundi showed no haemorrhages, exudates and/or papilloedema. None of the patients had clinical signs of congestive heart failure, coronary insufficiency, valvular heart disease or stroke.
424
E. Q. Roland et al.: Antiadrenergic Agents on Systolic Time Intervals
Table 1. Systolic (SBP) and diastolic blood pressure (DBP), heart rate (HR) and systolic time intervals before (control) and 5 rain, 10 min, 15 min, 30 rain after propranolol 0,2 mg/kg i. v. in 11 hypertensive patients. (Means ± standard error of the mean; *P < 0,05; **P < 0.01; ***P < 0.001; t P < 0.02, in comparison with the control period) Control SBP (mmHg) DBP (mmHg) HR (b/mn) QS2 (ms) LVET (ms) PEP (ms) APEP (ms) SLVET (ms) PEP/LVET
160 --- 7 98 _+ 4
5 min
10 min
144 + 7**
143 + 8*
143 ± 8t
101 + 3
100 + 4
101 + 5
100 ± 5
75 + 4
60 ± 3***
61 + 3***
61 + 3***
59 ± 3***
395 + 11
438 + 10'**
435 ± 11"**
434 ± 10"**
434 ± 11"**
269 ± 8
293 ± 8***
290 ± 7**
287 ± 7**
287 ± 8**
126 ± 5
145 ± 5***
150 + 7***
147 ± 6***
147 ± 6***
26 ± 5
39 ± 5***
44 ± 6***
41 ± 6**
40 ± 5***
-16 + 4 0.4705 ± 0.0183
-18 ± 5 0.4961 ±0.0210
- 2 4 ± 5* 0.5265' ±0.0244
Experimental Procedure The patients were maintained on a constant sodium diet (110 mEq/day) and classified into 3 groups according to the 3 drugs. Patients were studied on the third day of hospitalization. Measurements were made before administration of the chozen drug and after 5 rain, 10 min, 15 min and 30 min. The drugs were administered intravenously over 1 rain at the following dosages:
- Clonidine - Methyldopa
30 min
146 ± 6**
The electrocardiagram of each patient was reviewed. All had regular sinus rhythm without evidence of left or right bundle branch block. Moderate left ventricular hypertrophy was observed in 4 cases.
- Propranolol
15rain
0,2 mg/kg 0,002 mg/kg 2 mg/kg
according to previous reports [1-5, 16]. Since ant±hypertensive effect of methyldopa does not cur rapidly [1], the intravenous injection was lowed by a 7 days oral administration (6 mg/kg day) and a further set of recording.
the ocfolper
Determination of Systolic Time Intervals [7, 9, 10, 13, 14, 181 The systolic time intervals were measured from simultaneous recordings of the electrocardiogram, phonocardiogram, and carotid arterial pulse using a
-23 ± 5 0.5179" ±0.0241
- 2 7 ± 5** 0.5154"* +0.0200
multichannel system (Telco Paris). An ink-jet, direct writing Siemens Oscillomink E recorder at a paper speed of 100 mm/s was used. It was necessary clearly to demonstrate the onset of ventricular depolarization in the electrocardiographic lead; usually lead it was taken. A heart sound microphone was placed over the upper part of the precordium in the optimal position for obtaining the initial high frequency vibrations of the second heart sound. The carotid pulse was determined with an Telco pulse sensor fixed at the point of maximal pulsation of the carotid artery. Measurements in all patients were made in the supine position and after a 15 rain rest. A sphygmomanometer cuff was applied to the subject's arm and diastolic blood pressure was taken as the fourth phase of Korotkoff's sounds, each time the systolic intervals were recorded. Care was taken to ensure that the beginning and end of the determinations always coincided with the same phase of respiration. The following intervals of the left ventricular systolic cycle were measured or calculated: QS2: The total electromechanical interval was measured from the onset of the QRS complex to the initial high frequency vibration of the aortic component of the second heart sound. LVET: Left ventricular ejection time measured from the beginning of the upstroke to the trough of the incisura of the carotid arterial pulse tracing. PEP: The pre-ejection period was derived by subtracting LVET from the QS2 interval. The PEP/LVET ratio was also calculated.
E. Q. Roland et al.: Antiadrenergic Agents on Systolic Time Intervals
425
Table 2. Systolic and diastolic blood pressure, heart rate and systolic time intervals before and 5 rain, 10 min, 15 min, 30 rain after intravenous clonidine (2 Ixg/kg) in 10 hypertensive patients. Abbreviations as in Table 1
Control SBP (mmHg) DBP (mmHg) HR (b/ran) OS2 (ms) LVET (ms) PEP (ms) APEP (ms) ALVET (ms) PEP/LVET
5 rain
10 min
15 min
30 rain
161_+ 8
136 ± 5***
131 _ 5***
130 ± 3***
133 ± 6***
105 ± 5
95 ± 5***
95 ± 5***
95 ± 5***
95 ± 5***
70 ± 3
69 ± 3
67 ± 3
67 ± 3
66 ± 3+
402 ± 8
400 ± 7
404 ± 6
407 ± 6
411 ± 7**
275 ± 9
263 ± 9**
267 _+ 9
267 ± 9
269 ± 9
127 ± 5
137 _+ 5***
137 ± 5**
140 ± 6***
142 ± 5***
24 ± 5
33 ± 6**
33 ± 6**
37 ± 7**
38 ± 5***
-20 ± 7 0.4689 ±0.0306
- 3 3 ± 7** 0.5306*** ±0.0393
- 3 2 ± 7** 0.5234** _+0.0390
- 3 4 ± 7** 0.5365** ±0.0404
- 34 ± 7*** 0.5406*** _+0.0368
Table 3. Effects of intravenous methyldopa (2 mg/kg) in 12 hypertensive patients. Abbreviations as in Table 1
Control SBP (mmHg) DBP (mmHg) HR (b/mn) QSz (ms) LVET (ms) PEP (ms) zSPEP (ms) ALVET (ms) PEP/LVET
5 rain
10 min
15 min
30 rain
163 _+ 6
159 + 7
156 _+ 6
158 ± 6*
160 + 6
103 _+ 4
102 + 4
101 _+ 4
102 _+ 3
102 + 3
77 _+ 3
78 + 4
74 ± 4
74 + 3t
386 + 6
387 ± 9
389 + 7
391 + 7*
392 _+ 7*
262 _+ 5
265 -+ 6
265 _+ 6
264 + 5
265 _+ 5
123 ± 3
121 _ 3
124 + 3
127 ± 3
127 _+ 4
23 + 3
21+2
24+3
26+3
25 + 4
-21 _ 3 0.4704 +0.0153
--15 + 3** 0.4564 +0.0105
-22 + 3 0.4720 _+0.0146
-24 + 3 0.4835 +0.0144
--24 + 3* 0.4802 +0.0154
A l l intervals w e r e calculated as the average of m e a s u r e m e n t s m a d e to the n e a r e s t 5 msec o n 10 c o n s e c u t i v e h e a r t beats. H e a r t rate ( H R ) was derived f r o m the a v e r a g e R - R interval. P E P a n d L V E T w e r e c o r r e c t e d for h e a r t rate according to the s t a n d a r d f o r m u l a given b y Weissler et al., [10]. Statistical significance was d e t e r m i n e d b y S t u d e n t ' s p a i r e d t-test. Results
D e t a i l e d results are p r e s e n t e d in T a b l e s 1, 2, a n d 3. A s s h o w n in T a b l e 1, p r o p r a n o l o l c a u s e d a sign±f±-
73 _+ 3**
cant fall in systolic b l o o d p r e s s u r e (P < 0.01) a n d a n n o n - s i g n i f i c a n t c h a n g e in diastolic b l o o d pressure. H e a r t rate was significantly r e d u c e d (P < 0 . 0 0 l ) . P E P a n d L V E T were p r o l o n g e d (P < 0.001) in all p a t i e n t s by p r o p r a n o l o l . T h e c o r r e c t e d v a l u e A P E P was also p r o l o n g e d (P < 0.001), b u t the A L V E T i n t e r v a l was o n l y slightly increased. T h e P E P / L V E T ratio was i n c r e a s e d after p r o p r a n o l o l . C l o n i d i n e ( T a b l e 2) p r o d u c e d a statistically sign i f i c a n t fall in systolic a n d diastolic b l o o d p r e s s u r e (P < 0.001) a n d p r o l o n g a t i o n in P E P (P < 0.001) a n d A P E P (P < 0.001). A slight t e n d e n c y to decrease h e a r t rate a n d to s h o r t e n L V E T were o b -
426
E. Q. Roland et al.: Antiadrenergic Agents on Systolic Time Intervals
Table 4. Effects of methyldopa after 7 days oral administration (6 mg/kg per day). Abbreviations as in Table 1
sersed. The PEP/LVET ratio was increased after clonidine (P < 0.001). No significant effect was found when methyldopa was administered intravenously (late measurements 30 min after injection in Table 3). After 7 days oral adminstration methyldopa produced almost the same effects as clonidine (Table 4).
modynamic parameters were not measured. However, the changes in systolic time intervals can be discussed on the basis of previous results in the literature. Prolongation of the pre-ejection period might have been due to direct or reflex depression of the myocardium, as suggested by reports from dogs and man [2, 5, 24, 25]. Nevertheless, in this study the significant fall in left ventricular ejection time, which occured 5 min after clonidine, indicates a decrease in stroke volume, as has been reported previously [2, 5]. Therefore, changes in preload could also account for the prolongation of PEP. Methyldopa caused almost identical effects to those of clonidine. However, changes in the systolic intervals were observed only during long term treatment, when they corresponded to a fall in blood pressure quite like that obtained with clonidine. Hypertension is often accompanied both by cardiac hypertrophy and by prolonged systolic ejection [7, 20]. The former carries with it an increased demand for myocardial flow, while the latter shortens diastole and lessens the time available for myocardial p~rfusion. These relationships may be modified if hypertension is treated with a drug causing both prolongation in ejection time and decreased myocardial contractility. Such observations could be of importance in the mechanism of the cardiac complications observed during antihypertensive therapy [26, 27, 281.
Comments
References
Control SBP (mmHg) DBP (mmHg) HR (b/ran) QS2 (ms) LVET (ms) PEP (ms) APEP (ms) ALVET (ms) PEP/LVET
After 7 days
154 + 12
124 + 9**
95 + 5
84 _+ 6*
74 + 3
64 + 4**
395 + 10
432 + 6**
264 + 6
287 + 6t
130 + 9
146 _+ 9t
29 + 9
40 + 9*
-23 + 5 0.4951 +0.0426
-21 + 5 0.5131 +0.0415
The 3 drugs studied all prolonged the preejection period (PEP). In agreement with previous reports [7, 8, 10, 11, 13, 14, 19, 20, 21], this could be related to changes in various haemodynamic factors; heart rate, left ventricular preload and afterload, and myocardial contractility. In the present results, systolic time intervals were corrected for heart rate according to the Weissler formula [10]. A fall in diastolic blood pressure could not account for the prolongation of PEP observed in all patients, even though it might have been expected to become shorter with decreasing arterial pressure [20, 22]. Thus, the demonstrated prolongation might have been due mainly to changes in preload and/or myocardial contractility. Propranolol is known to have only slight effect on stroke volume [4]. So, preload is largely unaffected. Therefore, the substantial prolongation of PEP after propranolol must reflect a decrease in ventricular contractility, as previously suggested [16, 17, 23]. With clonidine, the increase in PEP is more difficult to elucidate, since certain other hae-
1. Dollery, C.T., Harrington, H., Hodge, J.V.: Haemodynamic studies with methyldopa. Effect on cardiac output and response to pressor amines. Brit. Heart J., 25, 670 (1963) 2. Mc Raven, D.R., Kroetz, F.W., Kiochos, J.M., Kirkendall, W.M.: The effect of clonidine on haemodynamic in hypertensive patients. Amer. Heart J. 81, 482 (1971) 3. Sannerstedt, R., Conway, J.: Haemodynamic effects of methyldopa at rest and during exercise in patients with arterial hypertension. Acta reed. scand. 171, 75 (1962) 4. Ulrych, M., Frolich, F.D., Dustan, H.P.: Immediate haemodynamic effects of beta adrenergic blockade with propranolol in normotensive and hypertensive man. Circulation 37, 311 (1968) 5. Kroetz, F.W., Mc Raven, D.R., Kioschios, J.M., Kirkendall, W.M.: The acute effects of catapres on cardiac haemodynamics of hypertensive man. In: Catapres in Hypertension. Ed. M.E. Conolly, p. 59. London: Butterworths 1970 6. Braunwald, E.: On the difference between the heart's output and its contractile state. Circulation 43, 171 (1971) 7. Ahmed, S.S., Levinson, G.E., Schwartz, C.J., Ettinger, P.O.: Systolic time intervals as measure of the contractile state of the left ventricular myocardium in man. Circulation 46, 559 (1972) 8. TaUey, R.C., Meyer, J.F., Mc Nay, J.L.: Evaluation of the preejecion period as an estimate of myocardial contractility in dogs. Amer. J. Cardiol. 27, 384 (1971)
427
E. Q. Roland et al.: Antiadrenergic Agents on Systolic Time Intervals 9. Kumar, S., Spodick, D.N.: Study of the mechanical events of the left ventricle by atraumatic techniques: comparison of methods of measurements and their significance. Amer. Heart J. 80, 401 (1970) 10. Weis~ler, A.M., Harris, W.F., Schoenfeld, C.D.: Systolic time intervals in heart failure in man. Circulation 37, 149 (1968) l l . Weissler, A.M., Peeler, R.G., Roehill, W.M., Durham, N.C.: Relationships between left ventricular ejection time, stroke volume, and heart rate in normal individuals and patients with cardiovascular disease. Amer. Heart J. 62, 367 (1961) 12. Weissler, A.M., Harris, W.S., Schoenfeld, C.D.: Bedside technics for the evaluation of ventricular function in man. Amer. J. Cardiol. 23, 577 (1969) 13. Martin, C.E., Shaver, J.A., Thompson, M.E., Reddy, P.S., Leonard, J.J.: Direct correlation of external systolic time intervals with internal indices of left ventricular function in man. Circulation 44, 419 (1971) 14. Tavel, M.E., Campbell, R.W., Feigenbaum, H., Steinmetz, E.F.: The apexcardiogram and its relationship to haemodynamic events with the left heart. Brit. Heart J. 27, 829 (1965) 15. Metzger, C., Chough, C.B., Kroetz, F.W., Leonard, J.J.: True isovolumic contraction time: its correlation with two external indices of ventricular performance. Amer. J. Cardiol. 25, 434 (1970) 16. Harris, W.S., Schoenfeld, C.D., Weissler, A.M.: Effects of adrenergic receptor activation and blockade on the systolic preejection period, heart rate and arterial presure in man. J. clin. Invest. 46, 1704 (1967) 17. Hunt, D., Sloman, G., Clark, R.M., Hoffman, G.: Effects of beta adrenergic blockade on the systolic time intervals. Amer. J. reed. Sci. 259, 97 (1970) 18. Spodick, D.N., Kumar, S.: Left ventricular ejection period, measurements by atraumatic techniques: results in normal young man and comparison of methods of calculation. Amer. Heart J. 76, 70 (1968) 19. Matsuura, T., Goodyer, A. V.N.: Effect of a pressure load on left ventricular systolic time intervals. Amer. J. Physiol. 224, 80 (1973) 20. Shaver, J.A., Kroetz, F. W., Leonard, J.J., Raley, H. W.: The effect of steady state increases in systemic arterial pressure on
the duration of left ventricular ejection time. J. clin. Invest. 47, 217 (1968) 21. Stafford, R.W., Harris, W. S., Weissler, A.M.: Left ventricular systolic time intervals as indices of postural circulatory stress in man. Circulation 41, 485 (1970) 22. Sawayama, T., Ochia, M., Marumoto, S., Matsuura, T., Niki, I.: Influence of amylnitrite inhalation on the systolic time intervals in normal subjects and in patients with ischemic heart disease. Circulation 40, 327 (1969) 23. Bodem, G., Brammell, H.L., Weil, J.V., Chidsey, C.A.: Pharmacodynamic studies of beta adrenergic antagonism induced in man by propranolol and practolol. J. clin. Invest. 52, 747 (1973) 24. Boissier, J.R., Giudicelli, J.F., Fichelle, J., Schmitt, H., Schmitt, H.: Cardiovascular effects of 2-(2,6 dichlorophenyl amino) - 2 imidazoline hydrochloride (ST155). I. Pcripherical sympathetic system. Eur. J. Pharmacol. 2, 333 (1968) 25. Schmitt, H., Schmitt, H., Fenard, S.: Action of a adrenergic blocking drugs on the sympathetetic centres and their interactions with the central sympatho inhibitory effect of clonidine Arzneimittelforsch. 23, 40 (1973) 26. Dustan, H.P.: Atherosclerosis complicating chronic hypertension Circulation 50, 871 (1974) 27. Veterans Administration Cooperative Study Group on Antihypertensive Agents: Effects of treatment on morbidity in hypertension: I. Results in patients with diastolic blood pressures averaging 115 through 129mmHg. J. Amer. Med. Ass. 202, 1028 (1967) 28. IBID II. Results in patients with diastolic blood pressure averaging 90 though l l 4 m m H g . J. Amer. Med. Ass. 213, 1143 (1973)
Received: June 18, 1976, first revised form: October 22, 1976, second revised form: February 4, 1977, accepted: February 18, 1977 Prof. Ag. M. E. Safar H6pital Broussais 96 rue Didot F-75674 Paris Cedex 14 France
Europ. J. clin. Pharmacol. 11,423-427 (1977)
© by Springer-Verlag 1977
Effect of Certain Antiadrenergic Agents on Systolic Time Intervals in Essential Hypertension E. Q. Roland, M.E. Safar, CI. E. Lelguen, N.E. Aboras, Y.A. Weiss, and P.M. Milliez Haemodynamic Laboratory, Hypertension Research Center, Hospital Broussais, Paris, France
Summary. Systolic time intervals, including preejection period (PEP) and left ventricular ejecion time (LVET), were studied in patients with permanent essential hypertension before and after intra-venous administration of propranolol 0.2mg/kg (11 patients), clonidine 0.002mg/kg (10 patients) and methyldopa 2 m g / k g (12 patients). With propranolol, diastolic blood pressure was unchanged and the heart rate decreased, whilst PEP and LVET were significantly prolonged (P < 0.001). Clonidine caused a fall in blood pressure (P < 0.001), heart rate was slightly reduced, PEP was prolonged (P < 0.001) and there was a significant decrease in LVET at 5 rain. With methyldopa, no significant effect was observed after intravenous injection, but 7 days oral administration produced the identical effect as clonidine. These observations suggest that certain antihypertensive drugs may impair left ventricular performance and depress myocardial contractility. Key words: Systolic time intervals, propranolol, clonidine, methyldopa, essential hypertension.
The majority of the haemodynamic studies of antihypertensive drugs have been based on blood pressure, cardiac output and blood volume determinations [1]. However, characterization of contractile state may also be of major importance in assessment of cardiac function before and after treatment [6]. Several indices of myocardial contractility have been obtained by left heart catheterization. These invasive technics cannot easily be performed in hypertensive man before and after therapy. Many reports have confirmed that determination of systolic time intervals can provide a valid approach for estimation of variations in the contractile state of the left ven-
tricular myocardium [7-15]. In addition, determination of the length of preejection period (PEP) after beta adrenergic blockade can serve as useful index of adrenergic influences on cardiac dynamics [12, 16]. The purpose of the present study was to investigate the effects of 3 of the most widely used antihypertensive drugs, propranolol, clonidine and methyldopa. All 3 drugs can reduce sympathetic tone and so they might change cardiac performance as measured by systolic time intervals.
Material and Methods Patients
Thirty three male hypertensive patients were included in the present study; ages 25 to 51 years (average: 39 years); and weight 56 to 82 kgs (average 75 kg). The patients were hospitalized for a 10 days period. Antihypertensive treatment was discontinued at least 4 weeks before the study. In all patients diastolic blood pressure was equal to or higher than 95 mmttg on the third day of hospitalization. Before the study a complete clinical and laboratory evaluation had been carried out, including physical examination, routine laboratory tests, determination of urinary catecholamines, measurement of plasma electrolytes, and intravenous pyelography and/or renal arteriography. All the patients were diagnosed as having moderate essential hypertension : creatinine clearance was normal (greater 90 ml/min), the optic fundi showed no haemorrhages, exudates and/or papilloedema. None of the patients had clinical signs of congestive heart failure, coronary insufficiency, valvular heart disease or stroke.
424
E. Q. Roland et al.: Antiadrenergic Agents on Systolic Time Intervals
Table 1. Systolic (SBP) and diastolic blood pressure (DBP), heart rate (HR) and systolic time intervals before (control) and 5 rain, 10 min, 15 min, 30 rain after propranolol 0,2 mg/kg i. v. in 11 hypertensive patients. (Means ± standard error of the mean; *P < 0,05; **P < 0.01; ***P < 0.001; t P < 0.02, in comparison with the control period) Control SBP (mmHg) DBP (mmHg) HR (b/mn) QS2 (ms) LVET (ms) PEP (ms) APEP (ms) SLVET (ms) PEP/LVET
160 --- 7 98 _+ 4
5 min
10 min
144 + 7**
143 + 8*
143 ± 8t
101 + 3
100 + 4
101 + 5
100 ± 5
75 + 4
60 ± 3***
61 + 3***
61 + 3***
59 ± 3***
395 + 11
438 + 10'**
435 ± 11"**
434 ± 10"**
434 ± 11"**
269 ± 8
293 ± 8***
290 ± 7**
287 ± 7**
287 ± 8**
126 ± 5
145 ± 5***
150 + 7***
147 ± 6***
147 ± 6***
26 ± 5
39 ± 5***
44 ± 6***
41 ± 6**
40 ± 5***
-16 + 4 0.4705 ± 0.0183
-18 ± 5 0.4961 ±0.0210
- 2 4 ± 5* 0.5265' ±0.0244
Experimental Procedure The patients were maintained on a constant sodium diet (110 mEq/day) and classified into 3 groups according to the 3 drugs. Patients were studied on the third day of hospitalization. Measurements were made before administration of the chozen drug and after 5 rain, 10 min, 15 min and 30 min. The drugs were administered intravenously over 1 rain at the following dosages:
- Clonidine - Methyldopa
30 min
146 ± 6**
The electrocardiagram of each patient was reviewed. All had regular sinus rhythm without evidence of left or right bundle branch block. Moderate left ventricular hypertrophy was observed in 4 cases.
- Propranolol
15rain
0,2 mg/kg 0,002 mg/kg 2 mg/kg
according to previous reports [1-5, 16]. Since ant±hypertensive effect of methyldopa does not cur rapidly [1], the intravenous injection was lowed by a 7 days oral administration (6 mg/kg day) and a further set of recording.
the ocfolper
Determination of Systolic Time Intervals [7, 9, 10, 13, 14, 181 The systolic time intervals were measured from simultaneous recordings of the electrocardiogram, phonocardiogram, and carotid arterial pulse using a
-23 ± 5 0.5179" ±0.0241
- 2 7 ± 5** 0.5154"* +0.0200
multichannel system (Telco Paris). An ink-jet, direct writing Siemens Oscillomink E recorder at a paper speed of 100 mm/s was used. It was necessary clearly to demonstrate the onset of ventricular depolarization in the electrocardiographic lead; usually lead it was taken. A heart sound microphone was placed over the upper part of the precordium in the optimal position for obtaining the initial high frequency vibrations of the second heart sound. The carotid pulse was determined with an Telco pulse sensor fixed at the point of maximal pulsation of the carotid artery. Measurements in all patients were made in the supine position and after a 15 rain rest. A sphygmomanometer cuff was applied to the subject's arm and diastolic blood pressure was taken as the fourth phase of Korotkoff's sounds, each time the systolic intervals were recorded. Care was taken to ensure that the beginning and end of the determinations always coincided with the same phase of respiration. The following intervals of the left ventricular systolic cycle were measured or calculated: QS2: The total electromechanical interval was measured from the onset of the QRS complex to the initial high frequency vibration of the aortic component of the second heart sound. LVET: Left ventricular ejection time measured from the beginning of the upstroke to the trough of the incisura of the carotid arterial pulse tracing. PEP: The pre-ejection period was derived by subtracting LVET from the QS2 interval. The PEP/LVET ratio was also calculated.
E. Q. Roland et al.: Antiadrenergic Agents on Systolic Time Intervals
425
Table 2. Systolic and diastolic blood pressure, heart rate and systolic time intervals before and 5 rain, 10 min, 15 min, 30 rain after intravenous clonidine (2 Ixg/kg) in 10 hypertensive patients. Abbreviations as in Table 1
Control SBP (mmHg) DBP (mmHg) HR (b/ran) OS2 (ms) LVET (ms) PEP (ms) APEP (ms) ALVET (ms) PEP/LVET
5 rain
10 min
15 min
30 rain
161_+ 8
136 ± 5***
131 _ 5***
130 ± 3***
133 ± 6***
105 ± 5
95 ± 5***
95 ± 5***
95 ± 5***
95 ± 5***
70 ± 3
69 ± 3
67 ± 3
67 ± 3
66 ± 3+
402 ± 8
400 ± 7
404 ± 6
407 ± 6
411 ± 7**
275 ± 9
263 ± 9**
267 _+ 9
267 ± 9
269 ± 9
127 ± 5
137 _+ 5***
137 ± 5**
140 ± 6***
142 ± 5***
24 ± 5
33 ± 6**
33 ± 6**
37 ± 7**
38 ± 5***
-20 ± 7 0.4689 ±0.0306
- 3 3 ± 7** 0.5306*** ±0.0393
- 3 2 ± 7** 0.5234** _+0.0390
- 3 4 ± 7** 0.5365** ±0.0404
- 34 ± 7*** 0.5406*** _+0.0368
Table 3. Effects of intravenous methyldopa (2 mg/kg) in 12 hypertensive patients. Abbreviations as in Table 1
Control SBP (mmHg) DBP (mmHg) HR (b/mn) QSz (ms) LVET (ms) PEP (ms) zSPEP (ms) ALVET (ms) PEP/LVET
5 rain
10 min
15 min
30 rain
163 _+ 6
159 + 7
156 _+ 6
158 ± 6*
160 + 6
103 _+ 4
102 + 4
101 _+ 4
102 _+ 3
102 + 3
77 _+ 3
78 + 4
74 ± 4
74 + 3t
386 + 6
387 ± 9
389 + 7
391 + 7*
392 _+ 7*
262 _+ 5
265 -+ 6
265 _+ 6
264 + 5
265 _+ 5
123 ± 3
121 _ 3
124 + 3
127 ± 3
127 _+ 4
23 + 3
21+2
24+3
26+3
25 + 4
-21 _ 3 0.4704 +0.0153
--15 + 3** 0.4564 +0.0105
-22 + 3 0.4720 _+0.0146
-24 + 3 0.4835 +0.0144
--24 + 3* 0.4802 +0.0154
A l l intervals w e r e calculated as the average of m e a s u r e m e n t s m a d e to the n e a r e s t 5 msec o n 10 c o n s e c u t i v e h e a r t beats. H e a r t rate ( H R ) was derived f r o m the a v e r a g e R - R interval. P E P a n d L V E T w e r e c o r r e c t e d for h e a r t rate according to the s t a n d a r d f o r m u l a given b y Weissler et al., [10]. Statistical significance was d e t e r m i n e d b y S t u d e n t ' s p a i r e d t-test. Results
D e t a i l e d results are p r e s e n t e d in T a b l e s 1, 2, a n d 3. A s s h o w n in T a b l e 1, p r o p r a n o l o l c a u s e d a sign±f±-
73 _+ 3**
cant fall in systolic b l o o d p r e s s u r e (P < 0.01) a n d a n n o n - s i g n i f i c a n t c h a n g e in diastolic b l o o d pressure. H e a r t rate was significantly r e d u c e d (P < 0 . 0 0 l ) . P E P a n d L V E T were p r o l o n g e d (P < 0.001) in all p a t i e n t s by p r o p r a n o l o l . T h e c o r r e c t e d v a l u e A P E P was also p r o l o n g e d (P < 0.001), b u t the A L V E T i n t e r v a l was o n l y slightly increased. T h e P E P / L V E T ratio was i n c r e a s e d after p r o p r a n o l o l . C l o n i d i n e ( T a b l e 2) p r o d u c e d a statistically sign i f i c a n t fall in systolic a n d diastolic b l o o d p r e s s u r e (P < 0.001) a n d p r o l o n g a t i o n in P E P (P < 0.001) a n d A P E P (P < 0.001). A slight t e n d e n c y to decrease h e a r t rate a n d to s h o r t e n L V E T were o b -
426
E. Q. Roland et al.: Antiadrenergic Agents on Systolic Time Intervals
Table 4. Effects of methyldopa after 7 days oral administration (6 mg/kg per day). Abbreviations as in Table 1
sersed. The PEP/LVET ratio was increased after clonidine (P < 0.001). No significant effect was found when methyldopa was administered intravenously (late measurements 30 min after injection in Table 3). After 7 days oral adminstration methyldopa produced almost the same effects as clonidine (Table 4).
modynamic parameters were not measured. However, the changes in systolic time intervals can be discussed on the basis of previous results in the literature. Prolongation of the pre-ejection period might have been due to direct or reflex depression of the myocardium, as suggested by reports from dogs and man [2, 5, 24, 25]. Nevertheless, in this study the significant fall in left ventricular ejection time, which occured 5 min after clonidine, indicates a decrease in stroke volume, as has been reported previously [2, 5]. Therefore, changes in preload could also account for the prolongation of PEP. Methyldopa caused almost identical effects to those of clonidine. However, changes in the systolic intervals were observed only during long term treatment, when they corresponded to a fall in blood pressure quite like that obtained with clonidine. Hypertension is often accompanied both by cardiac hypertrophy and by prolonged systolic ejection [7, 20]. The former carries with it an increased demand for myocardial flow, while the latter shortens diastole and lessens the time available for myocardial p~rfusion. These relationships may be modified if hypertension is treated with a drug causing both prolongation in ejection time and decreased myocardial contractility. Such observations could be of importance in the mechanism of the cardiac complications observed during antihypertensive therapy [26, 27, 281.
Comments
References
Control SBP (mmHg) DBP (mmHg) HR (b/ran) QS2 (ms) LVET (ms) PEP (ms) APEP (ms) ALVET (ms) PEP/LVET
After 7 days
154 + 12
124 + 9**
95 + 5
84 _+ 6*
74 + 3
64 + 4**
395 + 10
432 + 6**
264 + 6
287 + 6t
130 + 9
146 _+ 9t
29 + 9
40 + 9*
-23 + 5 0.4951 +0.0426
-21 + 5 0.5131 +0.0415
The 3 drugs studied all prolonged the preejection period (PEP). In agreement with previous reports [7, 8, 10, 11, 13, 14, 19, 20, 21], this could be related to changes in various haemodynamic factors; heart rate, left ventricular preload and afterload, and myocardial contractility. In the present results, systolic time intervals were corrected for heart rate according to the Weissler formula [10]. A fall in diastolic blood pressure could not account for the prolongation of PEP observed in all patients, even though it might have been expected to become shorter with decreasing arterial pressure [20, 22]. Thus, the demonstrated prolongation might have been due mainly to changes in preload and/or myocardial contractility. Propranolol is known to have only slight effect on stroke volume [4]. So, preload is largely unaffected. Therefore, the substantial prolongation of PEP after propranolol must reflect a decrease in ventricular contractility, as previously suggested [16, 17, 23]. With clonidine, the increase in PEP is more difficult to elucidate, since certain other hae-
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Received: June 18, 1976, first revised form: October 22, 1976, second revised form: February 4, 1977, accepted: February 18, 1977 Prof. Ag. M. E. Safar H6pital Broussais 96 rue Didot F-75674 Paris Cedex 14 France
