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Modification of arterial baroreflexes by captopril in essential hypertension
Modification of Arterial Baroreflexes by Captopril in Essential Hypertension
GIUSEPPE MANCIA. MD GIANFRANCO PARATI, MD GUIDO POMIDOSSI, MD GUIDO GRASSI, MD GIOVANNI BERTINIERI, MD NUNZIO BUCCINO, MD ALBERT0 FERRARI, MD LUISA GREGORINI, MD LUCIA RUPOLI, MD ALBERT0
ZANCHETTI,
MD
Milano, Italy
Captopril lowers blood pressure without increasing heart rate and plasma norepinephrine, which suggests that this drug may potentiate arterial baroreflexes. In eight subjects with untreated essential hypertension, blood pressure was monitored intraarterially and the effects of baroreceptor stimulation OCdeactivation were assessed by measuring (1) the slopes of the relations between increase or reduction in systolic pressure (intravenous phenylephrine or nitroglycerin) and the resulting lengthening or shortening in R-R interval, and (2) the increase or decrease in mean arterial pressure induced by increasing and decreasing carotid transmural pressure (neck chamber). The measurements were made before and after a hypotensive oral dose of captopril(50 mg). Before captopril, the slopes of the R-R interval changes with increase and reduction in systolic pressure were 8 and 4 ms/mm Hg, respectively. The slopes of the mean arterial pressure changes with increase and reduction in carotid transmural pressure were 0.51 and 0.40 mm Hg, respectively. After captopril, the responses to baroreceptor stimulation were unaltered but those to baroreceptor deactivation were augmented. The pressor and heart rate responses to hand-grip and cold exposure were unchanged by captopril. Administration of captopril is accompanied by a baroreflex potentiation which involves the lower portion of the stimulus-response curve of the reflex. This phenomenon (which may originate at the afferent baroreceptor fibers or centrally) may avoid a reduction in the tonic baroreflex influence during captopril-induced hypotension, thus contributing to the hemodynamic effects of the drug.
Recent observations’-5 suggest that a variety of mechanisms play a role in the antihypertensive effect of captopril. This drug inhibits angiotensin-converting enzyme activity and in this way reduces the circulating levels of angiotensin II and aldosterone. However, it also increases circulating bradykinin2J and perhaps prostaglandinq4 and affects norepinephrine at the nerve terminals in a manner that is believed to impair sympathetic vascular control.5 A hemodynamic feature of captopril is that it reduces arterial blood pressure without a concomitant increase in heart rates-s and plasma norepinephrine level,g which suggests that under this circumstance baroreceptor inhibition of autonomic nerve activity may be preserved rather than reduced and that baroreflex potentiation may represent another antihypertensive mechanism of the drug. In the present study on hypertensive subjects we examined arterial baroreceptor control of heart rate and blood pressure before and after administration of a hypotensive dose of captopril. From the lstituto di Patologia Medica I, Universiti
di Milano. Centro di Ricerche Cardiovascolari CNR, Milako, Italy. Address for reprints: Professor Giuseppe Mancia, lstitutodi Patologia Medica I, Centro Ricerche CardiovascolariCNR,Universiti di Milano, Via F. Sforza 35, 20122 Milano, Italy.
Methods Study patients: Our study was performed on eight in-hospital patients with essential hypertension whose ages ranged from 32 to 58 years (mean 49). The subjects (seven men and one woman) had mild or moderate hypertension and were selected for the study if (1) no cardiac or renal failure was present, (2) no
April 21, 1982
The American Journal of CARDIOLOGY
Volume 49
1415
MODIFICATION OF ARTERIAL BAROREFLEXES BY CAPTOPRIL-MANCIA
mmHg
b/min
1
150
l30-
ET AL.
1200.
loo-
._
80 . . . . . . .
a I a
120 #!%
800-
110
150 TOO-
90
:A Captoprrl
no arug
4oJ
I no drug
I Captopril
FIGURE 1. Effects of captopril administration on resting mean arterial pressure (left) and heart rate (right) in eight patients. Ctosed cIrclea and solid lines represent data from single subjects, with each value derived from 12 measurements (see text). Open circles and dashed lines represent beats.
means
(f
standard
errors) for the group as a whole.
b =
signs or symptoms of coronary or cerebral vascular insufficiency had ever occurred, (3) no major disease other than hypertension had been diagnosed, (4) no treatment with antihypertensive drugs had been given in the preceding 2 weeks, and (5) informed consent to the study was obtained. Except for two instances the subjects were under no sodium restriction before the study. Measurements: Pulsatile arterial blood pressure was measured by a catheter introduced percutaneously into a femoral artery (after local anesthesia with 2 percent procaine solution) and connected to a strain-gauge transducer. Mean arterial pressure was obtained from the pulsatile signal both by electronic damping and by continuous integration of the blood pressure tracing over consecutive 10 second periods. Heart rate was obtained by a cardiotachometer which was triggered by lead II of an electrocardiogram. The same lead was used to measure (at high speed recording) R-R intervals. Techniques for studying arterial baroreflexes: Arterial baroreflexes were studied by two techniques. The first technique, which was suited for evaluating baroreceptor control of heart rate, was that described by Gribbin et al.1° and by Pickering et al.” In brief, arterial hlood’pressure was increased or reduced by an intravenous bolus of phenylephrine (50 to 100 pg) or nitroglycerin (50 to 100 pg), that is, a vasopressor or a vasodepressor drug with little direct cardiac effect. In this way arterial baroreceptors were either stimulated above or deactivated below the existing level of activity, the reflex responses consisting, respectively, of a lengthening or a shortening of the R-R interval. The second technique employed the variable pressure neck chamber, which was suited for the evaluation of the blood
1416
170 Systolic
April 21, 1962
The American Journal of CARDlDLDGY
Blood
h
no
*--
Captopril
190 Pressure
drug
210 (mmtig)
FIGURE 2. Effects of captopril on the linear regressions between increases in systolic blood pressure and lengthening of the R-R interval induced by phenylephrine, and between reductions in systolic pressure and shortening of the R-R interval induced by nitroglycerin. Data are shown as means (* standard errors) of single regression lines obtained in each of the eight subjects. The circles between the regression slopes represent average control values (rt standard errors) for systolic pressure and R-R interval. Note that the regression slope obtained by increasing systolic pressure was similar before and after captopril, whereas the regression slope obtained by reducing systolic pressure was steeper in the latter than in the former circumstance.
pressure control exerted by the carotid sinuses.12 In brief, a rigid collar was applied to the patients. The upper and lower openings of the collar were provided with rubber valve systems which allowed pneumatic pressure around the neck to be made almost instantaneously negative or positive with respect to atmospheric pressure. In this way an increase or a reduction in carotid transmural pressure was obtained with resulting stimulation or deactivation, respectively, of the carotid baroreceptors above or below the existing level of activity. The changes in pneumatic pressure were maintained steady for 120 seconds, and their magnitude was measured by connecting the interior of the collar with a pressure transducer. Isometric exercise and cold exposure: Isometric exercise consisted of steadily gripping a spring with one hand for 90 seconds. The spring was connected to a dynamometer which allowed the strength of the grip to be measured. The exercise was always performed at 40 percent of the subject’s maximal strength (established by a short trial at the beginning of the study). Exposure to cold was obtained by immersing one hand of the subject in water at 4OC for 60 seconds. Protocol: The subjects were studied supine according to the following steps: (1) the catheters were inserted and the neck chamber fitted; (2) after 20 minutes two injections of phenylephrine and two injections of nitroglycerin were made in a random order, with each injection separated from the preceding one by 10 to 15 minutes; (3) three different positive and three different negative neck chamber pressures were applied in a random order, each separated from the preceding one by 5 minutes; (4) hand-grip was performed followed after 5 minutes by the cold pressor test; (5) 50 mg of captoprii was administered orally; (6) after 60 to 90 minutes steps 2,3 and 4 were repeated.
Volume 49
MODIFICATION OF ARTERIAL BAROREFLEXES BY CAPTOPRIL-MANCIA
EARLY
STEADY
(n=8)
STATE
d YAP
A MAP
mmHg
mmHg
ET AL.
(n=8)
*
A NTP 20
20
+30
drug
-
no
o-e
Captoprll
*
mmtig
p
-30
FIGURE 3. Effects of reducing or increasing neck tissue pressure (NTP) on mean arterial pressure (MAP) before and after administration of captopril. Data are shown as means (4~ standard errors) from the eight subjects in the preceding figures. Increase or reduction in neck tissue pressure which was obtained through positive and negative neck chamber pressure applications was accompanied by carotid baroreceptor stimulation or deactivation, respectively.
In each subject an intravenous bolus of angiotension I (20 pglkg) was injected before captopril; 20 and 40 pg/kg doses of angiotension I were also injected 15 and again 150 minutes after the administration of captopril. The peak pressor effects of the injections were used as a measure of the inhibition of
the converting enzyme activity induced by the drug. Data analysis: The effects of captopril on resting
mean arterial pressure and heart rate were calculated by averaging in each subject the 12 control values before the various tests (vasoactive drug injections, neck chamber pressure applications, hand-grip and cold exposure) before and after administration of the drug. The data obtained by injection of phenylephrine and nitroglycerin were calculated during the ramp phase of the pressure changes induced by these drugs.lOJ1 Each systolic blood pressure value was related to the subsequent R-R interval. Significant linear regressions were always found between these two variables (r never less than 0.66, p never more than O.Ol), which allowed the regression slopes to be taken as measures of the baroreflex sensitivity. The neck chamber data were calculated by the method described in previous studies.13 The alterations in baroreceptor activity were expressed as changes in tissue pressure outside the carotid sinuses. These were derived from the positive and negative changes in neck chamber pressure reduced by 14 and 36 percent, respectively, to account for the imperfect pressure transmission through the neck tissues.14 The early and late (or steady state) reflex effects were evaluated by comparing a control value for mean arterial pressure (the average of the 30 seconds preceding the change in neck tissue pressure) with the values measured both between the 5th and the 15th seconds and during the last 30 seconds of the change in neck tissue pressure. Heart rate changes were disregarded because with the neck chamber we
employed they were always mild and transient.
Mean arterial pressure and heart rate effects of hand-grip and cold exposure were evaluated by comparing the average values in the 10 seconds preceding and in the last 10 seconds
of these maneuvers. Data from single subjects were averaged to obtain means (& standard errors) for the group as a whole. Comparisons before and after captopril administration were made by paired t test. A p value less than 0.05 was taken as the minimal level of statistical significance.
Results Pressor effects of angiotensin I: Before captopril, injection of 20 pg/kg of angiotensin I caused an increase in mean arterial pressure in the eight patients which averaged 23.0 f 3.1 mm Hg. Fifteen minutes after captopril the increase in mean arterial pressure induced by 20 ,uglkg of angiotensin I was 1.8 f 1 mm Hg and by 40 pglkg of angiotensin I 2.2 f 1.3 mm Hg; 150 minutes after captopril the mean increases in arterial pressure induced by the two doses of the drug were 1.9 f 1.5 and 3.7 f 1.8 mm Hg, respectively. Thus the pressure responses to angiotensin I were abolished or greatly reduced by captopril. Resting values (Fig. 1): Captopril induced a reduction in resting mean arterial pressure in seven of the eight subjects; the reduction in resting mean arterial pressure in the group as a whole was statistically significant (p
April 21, 1982
The American Journal of CARDIOLOGY
Volume 49
1417
MODIFICATION
OF
ARTERIAL BAROREFLEXES
180,
i
I
E -
ET AL.
Hand-grip and cold (Fig. 4): Hand-grip caused a marked increase in mean arterial pressure and an increase in heart rate in the eight subjects which were similar before and after administration of captopril. This ,was also the case for cold exposure, and the pressor and tachycardic effects of cold exposure were not significantly affected by the drug.
7
I -I
G
BY CAPTOPRIL-MANCIA
160
Discussion
J
,
1
100,
,
3
601
1
a c
-
C
CPT no
drug
0-o
HG
Captopril
FIGURE 4. Hentodynamic effects of cold exposure (left) and hand-grip (right) before and after administration of captopril. Data are shown as means (i standard errors) from the eight subjects in the preceding figures. b = beats; C = control: CPT = cold pressor test; HG = handgrip.
Phenylephrine and nitroglycerin (Fig. 2): Regression lines were obtained relating the drug-induced changes in systolic blood pressure and the R-R interval before and after captopril. The average regression slope obtained by increasing systolic pressure by phenylephrine was virtually identical before and after captopril. On the other hand, the average regression slope obtained by reducing systolic pressure by nitroglycerin was significantly (p <0.05), although not markedly, greater after captopril despite the fact that the hypotension should have reduced the tonic activity of the baroreceptors. Neck chamber (Fig. 3): Negative pneumatic neck pressure caused a reduction in mean arterial nressure. the magnitude of which increased with the increasing degree of the negative pressure application. The early blood pressure reductions were greater than the late or steady state ones. All reductions. however. did not differ significantly before and after administration of captopril. Positive neck wessure caused an increase in mean arterial pressure, the magnitude of which increased as the degree of the positive pressure application increased. In this instance the early responses were small and the pressure increases showed maximal development in the late or steady state phase. During this phase the responses were distinctly greater after than before captopril, the difference being significant at each degree of positive pressure applications.
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April 21, 1982
The American Journal of CARDIOLOGY
The question examined in this study was whether in hypertensive human subjects arterial baroreflexes are affected by therapeutic doses of captopril. The results show that they are. At the dose used, captopril reduced arterial blood pressure and drastically inhibited angiotensin-converting enzyme activity. The bradycardia and hypotension that followed baroreceptor stimulation were similar before and after administration of the drug. However, the tachycardia, and particularly the hypertension that followed deactivation of baroreceptors below their tonic level of activity, were greater after captopril administration. Thus, at least after acute administration, captopril increases the effectiveness of the cardiovascular control exerted by arterial baroreceptors in the range between the threshold and the tonic activity level of the reflex. Mechanisms of captopril potentiation of baroreflexes: Several hypotheses can be made about the mechanisms that are responsible for the baroreflex potentiation by captopril and the sites where this phenomenon occurs. One is that captopril acts on the efferent site of the reflex arch by enhancing the cardiovascular effects of the autonomic nerves. This is unlikely, however, because norepinephrine output and vascular responses to sympathetic nerve stimulation as well as vascular effects of norepinephrine infusion seem to be reduced after administration of captopril.5,15,16 Furthermore, when in our subjects the autonomic nerves were engaged by hand-grip and cold, the effects on heart rate and blood pressure were not greater after than before the drug. Another hypothesis is that captopril acts on the afferent portion of the reflex arch by eliminating the vasoconstrictor effect of angiotensin II and increasing arterial compliance and the baroreceptor firing rate. This possibility cannot be excluded, but it should be emphasized that a drug such as prazosin, which might influence baroreceptor sensitivity by affecting arterial compliance,17 does not cause any baroreflex potentiation in man.38Jg A third and more likely hypothesis is that this effect of captopril takes place at a central leuet. Animal studieszo,zl have shown the existence of receptors in the area postrema which can be stimulated by circulating angiotensin II and can thus increase blood pressure and also antagonize baroreflexes. It can be surmised that this stimulation might be reduced by captopril by preventing angiotensin II formation, and that this is the reason baroreceptor cardiovascular control is potentiated. It remains to be explained why the baroreflex potentiation observed with captopril is limited to the effects of baroreceptor deactivation, whereas the effects of baroreceptor stimulation are unchanged by the drug.
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MODIFICATION
The most likely explanation is that captopril displaces the set-point of the stimulus-response curve of the baroreflex toward a more central position, at a greater distance from the threshold (thus accounting for the greater pressor reaction to reflex deactivation) but still in the steep portion of the curve (thus accounting for an unchanged depressor reaction to reflex stimulation). Clinical implications: A few comments can also be made on the practical implication of the increased baroreflex effectiveness caused by captopril. Because of this ahenomenon. the tonic inhibitorv influence of the reflex might be preserved or enhanced during ad-
OF ARTERIAL
BAROREFLEXES
BY CAPTOPRIL-MANCIA
ET AL.
ministration of captopril, despite the tendency of the hypotension to reduce baroreceptor activity. This might prevent reflex tachycardia and sympathetic activation, and be responsible for the stable (and even reduced) heart rate and norepinephrine values observed with administration of the drug. In addition, the preserved, or enhanced, baroreflexes (along with the unaltered responses to exercise and cold) suggest that clinical doses of captopril do not interfere with circulatory homeostasis. This may explain why orthostatic hypotension and reduction in exercise abilitv” are seldom described during treatment with this drug.22-2s
References 1. Case DB, Wallace JM, Keim HJ, Weber MS, Sealey JE, Laragh JH. Possible role of renin in hypertension as suggested by reninsodium profiling and inhibition of converting enzyme. N Engl J Med 1977;296:641-6. 2. Marks ES, Bing RF, Thurston H, Swales JD. Vasodepressor property of the converting enzyme inhibitor captopril (SQ 14225): the role of factors other than renin-angiotensin blockade in the rat. Clin Sci 1980;58:1-6. 3. Carretero OA, Scicli AG, Maitra SR. Role of kinins in the pharmacological effects of converting enzyme inhibitors. In: Angiotensin Converting Enzyme Inhibitors. Horovitz ZP, ed. Baltimore, Munich: Urban & Schwarzenberg, 1981;105-21. 4. Grant RR, Swatiz SL, Hollenberg NK, et al. Role of prostaglandins in the hypotensive response to captopril in essential hypertension (abstr). Clin Res 1979;27:592A. 5. Clough DP, Collis MG, Conway J, Hatton R, Veddie J. Interaction of angiotensin-converting enzyme inhibitors with the function of the sympathetic nervous system. Am J Cardiol 1982;49:1410-4. 6. Cody RJ, Tarazi RL, Bravo EL, Fouad FM. Hemcdynamics of orally active converting enzyme inhibitors (SQ 14225) in hypertensive patients. Clin Sci Mol Med 1978;55:453-9. 7. Muirhead EE, Prewith RR. Brooks B, Brosius WL. Anti-hypertensive action of the orally active converting enzyme inhibitor (SC 14225) in spontaneously hypertensive rats. Circ Res 1978;43:Suppl 1:1-53-l-59. a. Fagard R, Amery A, Reibrouck T, Lijnen P, Billiet L. Acute and chronic systemic and pulmonary hemodynamic effects of angiotensin converting enzyme inhibition with captopril in hypertensive patients. Am J Cardiol 1980;46:295-300. 9. Muiesan G, Alicandri CL, Agabfff-Rosei E. Angiotensin-converting enzyme inhibition, catechoiamines and hemodynamics in essential hypertension. Am J Cardiol 1982;49: 1420-4. 10. Gribbfn B, Pickering TG, Sleight P, Peto R. Effect of age and high blood pressure on baroreflex sensitivity in man. Circ Res 1971; 29:424-31. 11. Pickering TG, Gribbin B, Sleight P. Comparison of reflex heart rate response to rising and falling arterial pressure in man. Cardiovasc Res 1972;6:277-83. 12. Mancia G, Ferrari A, Gregorini L, et al. Control of blood pressure by carotid sinus baroreceptors in human beings. Am J Cardiol
i979;44:895-902. 13. Mancia G, Ludbrook J, Ferrarf A, Gregorini L, Zanchetti A. Baroreceptor reflexes in human hypertension. Circ Res 1978; 43:170-7. 14. Ludbrook J, Mancia 0, Ferrari A, Zanchetti A. The variable pressure neck-chamber method for studying carotid barorefiex in man. Clin Sci Mel Med 1977;53:165-7 1. 15. Mimran A, Caseflas D, Ghevfllard C, DuPont M, Jover 8. Evidence for a postsynaptic action of captopril in isolated perfused rabbit kidney. Am J Cardiol 1982;49: 1540- 1. 16. Antonaccio MJ, Kerwin L. Evidence for prejunctional inhibition or norepinephrine release by captopril in spontaneously hypertensive rats. Eur J Pharmacol 1980;68:209-12. 17. Cambridge D, Davey MJ, Massingham R. The pharmacology of antihypertensive drugs with special reference to vasodilators, alpha-adrenergic blocking agents and prazosin. Med J Aust [Suppl] 1977;2:2-6. 18. Mancia G, Ferrari A, Gregorini L, Zanchetti A. Clonidine and carotid baroreflex in essential hypertension. Hypertension 1979; 1: 362-70. 19. Mancia G, Ferrari A, Gregorini L, et al.: Effects of prazosin on autonomic control of circulation in essential hypertension. Hypertension i980;2:700-7. 20. Barnes KL, Ferrario CM, Conomy JP. Comparison of the hemodynamic changes produced by electrical stimulation of the area postrema and nucleus tractus solitarii in the dog. Circ Res 1979; 45: 136-43. 21. Ferrario CM, Barnes KL, Szilagyl SE, Brosnihan KB. Physiological and pharmacological characterization of the area postrema pressor pathways in the normal dog. Hypertension 1979;1:235-45. 22. Bravo EL, Tarazi RC, Fouad FM. Hemodynamic effects of longterm captopril therapy in hypertensive man. In Ref 3, 263-72. 23. Brunner HR, Turini GA, Waeber 8, Gavras H. Clinical pharmacological studies with captopril. In Ref 3, p 351-68. 24. Atkinson AB, Robertson JfS. Benefits vs risks of captopril therapy. In: Recent Advances in Hypertension Therapy: Captopril. Brunner HR, Gross F, eds. Amsterdam: Excerpta Medica, 198150-63. 25. Fagard RH, Lijnen PJ, Amery AK. Hemodynamic response to captopril at rest and during exercise in hypertensive patients. Am J Cardiol 1982;49: 1569-7 1.
April 21, 1982
The American Journal of CARDIOLOGY
Volume 49
1419
GIUSEPPE MANCIA. MD GIANFRANCO PARATI, MD GUIDO POMIDOSSI, MD GUIDO GRASSI, MD GIOVANNI BERTINIERI, MD NUNZIO BUCCINO, MD ALBERT0 FERRARI, MD LUISA GREGORINI, MD LUCIA RUPOLI, MD ALBERT0
ZANCHETTI,
MD
Milano, Italy
Captopril lowers blood pressure without increasing heart rate and plasma norepinephrine, which suggests that this drug may potentiate arterial baroreflexes. In eight subjects with untreated essential hypertension, blood pressure was monitored intraarterially and the effects of baroreceptor stimulation OCdeactivation were assessed by measuring (1) the slopes of the relations between increase or reduction in systolic pressure (intravenous phenylephrine or nitroglycerin) and the resulting lengthening or shortening in R-R interval, and (2) the increase or decrease in mean arterial pressure induced by increasing and decreasing carotid transmural pressure (neck chamber). The measurements were made before and after a hypotensive oral dose of captopril(50 mg). Before captopril, the slopes of the R-R interval changes with increase and reduction in systolic pressure were 8 and 4 ms/mm Hg, respectively. The slopes of the mean arterial pressure changes with increase and reduction in carotid transmural pressure were 0.51 and 0.40 mm Hg, respectively. After captopril, the responses to baroreceptor stimulation were unaltered but those to baroreceptor deactivation were augmented. The pressor and heart rate responses to hand-grip and cold exposure were unchanged by captopril. Administration of captopril is accompanied by a baroreflex potentiation which involves the lower portion of the stimulus-response curve of the reflex. This phenomenon (which may originate at the afferent baroreceptor fibers or centrally) may avoid a reduction in the tonic baroreflex influence during captopril-induced hypotension, thus contributing to the hemodynamic effects of the drug.
Recent observations’-5 suggest that a variety of mechanisms play a role in the antihypertensive effect of captopril. This drug inhibits angiotensin-converting enzyme activity and in this way reduces the circulating levels of angiotensin II and aldosterone. However, it also increases circulating bradykinin2J and perhaps prostaglandinq4 and affects norepinephrine at the nerve terminals in a manner that is believed to impair sympathetic vascular control.5 A hemodynamic feature of captopril is that it reduces arterial blood pressure without a concomitant increase in heart rates-s and plasma norepinephrine level,g which suggests that under this circumstance baroreceptor inhibition of autonomic nerve activity may be preserved rather than reduced and that baroreflex potentiation may represent another antihypertensive mechanism of the drug. In the present study on hypertensive subjects we examined arterial baroreceptor control of heart rate and blood pressure before and after administration of a hypotensive dose of captopril. From the lstituto di Patologia Medica I, Universiti
di Milano. Centro di Ricerche Cardiovascolari CNR, Milako, Italy. Address for reprints: Professor Giuseppe Mancia, lstitutodi Patologia Medica I, Centro Ricerche CardiovascolariCNR,Universiti di Milano, Via F. Sforza 35, 20122 Milano, Italy.
Methods Study patients: Our study was performed on eight in-hospital patients with essential hypertension whose ages ranged from 32 to 58 years (mean 49). The subjects (seven men and one woman) had mild or moderate hypertension and were selected for the study if (1) no cardiac or renal failure was present, (2) no
April 21, 1982
The American Journal of CARDIOLOGY
Volume 49
1415
MODIFICATION OF ARTERIAL BAROREFLEXES BY CAPTOPRIL-MANCIA
mmHg
b/min
1
150
l30-
ET AL.
1200.
loo-
._
80 . . . . . . .
a I a
120 #!%
800-
110
150 TOO-
90
:A Captoprrl
no arug
4oJ
I no drug
I Captopril
FIGURE 1. Effects of captopril administration on resting mean arterial pressure (left) and heart rate (right) in eight patients. Ctosed cIrclea and solid lines represent data from single subjects, with each value derived from 12 measurements (see text). Open circles and dashed lines represent beats.
means
(f
standard
errors) for the group as a whole.
b =
signs or symptoms of coronary or cerebral vascular insufficiency had ever occurred, (3) no major disease other than hypertension had been diagnosed, (4) no treatment with antihypertensive drugs had been given in the preceding 2 weeks, and (5) informed consent to the study was obtained. Except for two instances the subjects were under no sodium restriction before the study. Measurements: Pulsatile arterial blood pressure was measured by a catheter introduced percutaneously into a femoral artery (after local anesthesia with 2 percent procaine solution) and connected to a strain-gauge transducer. Mean arterial pressure was obtained from the pulsatile signal both by electronic damping and by continuous integration of the blood pressure tracing over consecutive 10 second periods. Heart rate was obtained by a cardiotachometer which was triggered by lead II of an electrocardiogram. The same lead was used to measure (at high speed recording) R-R intervals. Techniques for studying arterial baroreflexes: Arterial baroreflexes were studied by two techniques. The first technique, which was suited for evaluating baroreceptor control of heart rate, was that described by Gribbin et al.1° and by Pickering et al.” In brief, arterial hlood’pressure was increased or reduced by an intravenous bolus of phenylephrine (50 to 100 pg) or nitroglycerin (50 to 100 pg), that is, a vasopressor or a vasodepressor drug with little direct cardiac effect. In this way arterial baroreceptors were either stimulated above or deactivated below the existing level of activity, the reflex responses consisting, respectively, of a lengthening or a shortening of the R-R interval. The second technique employed the variable pressure neck chamber, which was suited for the evaluation of the blood
1416
170 Systolic
April 21, 1962
The American Journal of CARDlDLDGY
Blood
h
no
*--
Captopril
190 Pressure
drug
210 (mmtig)
FIGURE 2. Effects of captopril on the linear regressions between increases in systolic blood pressure and lengthening of the R-R interval induced by phenylephrine, and between reductions in systolic pressure and shortening of the R-R interval induced by nitroglycerin. Data are shown as means (* standard errors) of single regression lines obtained in each of the eight subjects. The circles between the regression slopes represent average control values (rt standard errors) for systolic pressure and R-R interval. Note that the regression slope obtained by increasing systolic pressure was similar before and after captopril, whereas the regression slope obtained by reducing systolic pressure was steeper in the latter than in the former circumstance.
pressure control exerted by the carotid sinuses.12 In brief, a rigid collar was applied to the patients. The upper and lower openings of the collar were provided with rubber valve systems which allowed pneumatic pressure around the neck to be made almost instantaneously negative or positive with respect to atmospheric pressure. In this way an increase or a reduction in carotid transmural pressure was obtained with resulting stimulation or deactivation, respectively, of the carotid baroreceptors above or below the existing level of activity. The changes in pneumatic pressure were maintained steady for 120 seconds, and their magnitude was measured by connecting the interior of the collar with a pressure transducer. Isometric exercise and cold exposure: Isometric exercise consisted of steadily gripping a spring with one hand for 90 seconds. The spring was connected to a dynamometer which allowed the strength of the grip to be measured. The exercise was always performed at 40 percent of the subject’s maximal strength (established by a short trial at the beginning of the study). Exposure to cold was obtained by immersing one hand of the subject in water at 4OC for 60 seconds. Protocol: The subjects were studied supine according to the following steps: (1) the catheters were inserted and the neck chamber fitted; (2) after 20 minutes two injections of phenylephrine and two injections of nitroglycerin were made in a random order, with each injection separated from the preceding one by 10 to 15 minutes; (3) three different positive and three different negative neck chamber pressures were applied in a random order, each separated from the preceding one by 5 minutes; (4) hand-grip was performed followed after 5 minutes by the cold pressor test; (5) 50 mg of captoprii was administered orally; (6) after 60 to 90 minutes steps 2,3 and 4 were repeated.
Volume 49
MODIFICATION OF ARTERIAL BAROREFLEXES BY CAPTOPRIL-MANCIA
EARLY
STEADY
(n=8)
STATE
d YAP
A MAP
mmHg
mmHg
ET AL.
(n=8)
*
A NTP 20
20
+30
drug
-
no
o-e
Captoprll
*
mmtig
p
-30
FIGURE 3. Effects of reducing or increasing neck tissue pressure (NTP) on mean arterial pressure (MAP) before and after administration of captopril. Data are shown as means (4~ standard errors) from the eight subjects in the preceding figures. Increase or reduction in neck tissue pressure which was obtained through positive and negative neck chamber pressure applications was accompanied by carotid baroreceptor stimulation or deactivation, respectively.
In each subject an intravenous bolus of angiotension I (20 pglkg) was injected before captopril; 20 and 40 pg/kg doses of angiotension I were also injected 15 and again 150 minutes after the administration of captopril. The peak pressor effects of the injections were used as a measure of the inhibition of
the converting enzyme activity induced by the drug. Data analysis: The effects of captopril on resting
mean arterial pressure and heart rate were calculated by averaging in each subject the 12 control values before the various tests (vasoactive drug injections, neck chamber pressure applications, hand-grip and cold exposure) before and after administration of the drug. The data obtained by injection of phenylephrine and nitroglycerin were calculated during the ramp phase of the pressure changes induced by these drugs.lOJ1 Each systolic blood pressure value was related to the subsequent R-R interval. Significant linear regressions were always found between these two variables (r never less than 0.66, p never more than O.Ol), which allowed the regression slopes to be taken as measures of the baroreflex sensitivity. The neck chamber data were calculated by the method described in previous studies.13 The alterations in baroreceptor activity were expressed as changes in tissue pressure outside the carotid sinuses. These were derived from the positive and negative changes in neck chamber pressure reduced by 14 and 36 percent, respectively, to account for the imperfect pressure transmission through the neck tissues.14 The early and late (or steady state) reflex effects were evaluated by comparing a control value for mean arterial pressure (the average of the 30 seconds preceding the change in neck tissue pressure) with the values measured both between the 5th and the 15th seconds and during the last 30 seconds of the change in neck tissue pressure. Heart rate changes were disregarded because with the neck chamber we
employed they were always mild and transient.
Mean arterial pressure and heart rate effects of hand-grip and cold exposure were evaluated by comparing the average values in the 10 seconds preceding and in the last 10 seconds
of these maneuvers. Data from single subjects were averaged to obtain means (& standard errors) for the group as a whole. Comparisons before and after captopril administration were made by paired t test. A p value less than 0.05 was taken as the minimal level of statistical significance.
Results Pressor effects of angiotensin I: Before captopril, injection of 20 pg/kg of angiotensin I caused an increase in mean arterial pressure in the eight patients which averaged 23.0 f 3.1 mm Hg. Fifteen minutes after captopril the increase in mean arterial pressure induced by 20 ,uglkg of angiotensin I was 1.8 f 1 mm Hg and by 40 pglkg of angiotensin I 2.2 f 1.3 mm Hg; 150 minutes after captopril the mean increases in arterial pressure induced by the two doses of the drug were 1.9 f 1.5 and 3.7 f 1.8 mm Hg, respectively. Thus the pressure responses to angiotensin I were abolished or greatly reduced by captopril. Resting values (Fig. 1): Captopril induced a reduction in resting mean arterial pressure in seven of the eight subjects; the reduction in resting mean arterial pressure in the group as a whole was statistically significant (p
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180,
i
I
E -
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Hand-grip and cold (Fig. 4): Hand-grip caused a marked increase in mean arterial pressure and an increase in heart rate in the eight subjects which were similar before and after administration of captopril. This ,was also the case for cold exposure, and the pressor and tachycardic effects of cold exposure were not significantly affected by the drug.
7
I -I
G
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Discussion
J
,
1
100,
,
3
601
1
a c
-
C
CPT no
drug
0-o
HG
Captopril
FIGURE 4. Hentodynamic effects of cold exposure (left) and hand-grip (right) before and after administration of captopril. Data are shown as means (i standard errors) from the eight subjects in the preceding figures. b = beats; C = control: CPT = cold pressor test; HG = handgrip.
Phenylephrine and nitroglycerin (Fig. 2): Regression lines were obtained relating the drug-induced changes in systolic blood pressure and the R-R interval before and after captopril. The average regression slope obtained by increasing systolic pressure by phenylephrine was virtually identical before and after captopril. On the other hand, the average regression slope obtained by reducing systolic pressure by nitroglycerin was significantly (p <0.05), although not markedly, greater after captopril despite the fact that the hypotension should have reduced the tonic activity of the baroreceptors. Neck chamber (Fig. 3): Negative pneumatic neck pressure caused a reduction in mean arterial nressure. the magnitude of which increased with the increasing degree of the negative pressure application. The early blood pressure reductions were greater than the late or steady state ones. All reductions. however. did not differ significantly before and after administration of captopril. Positive neck wessure caused an increase in mean arterial pressure, the magnitude of which increased as the degree of the positive pressure application increased. In this instance the early responses were small and the pressure increases showed maximal development in the late or steady state phase. During this phase the responses were distinctly greater after than before captopril, the difference being significant at each degree of positive pressure applications.
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The question examined in this study was whether in hypertensive human subjects arterial baroreflexes are affected by therapeutic doses of captopril. The results show that they are. At the dose used, captopril reduced arterial blood pressure and drastically inhibited angiotensin-converting enzyme activity. The bradycardia and hypotension that followed baroreceptor stimulation were similar before and after administration of the drug. However, the tachycardia, and particularly the hypertension that followed deactivation of baroreceptors below their tonic level of activity, were greater after captopril administration. Thus, at least after acute administration, captopril increases the effectiveness of the cardiovascular control exerted by arterial baroreceptors in the range between the threshold and the tonic activity level of the reflex. Mechanisms of captopril potentiation of baroreflexes: Several hypotheses can be made about the mechanisms that are responsible for the baroreflex potentiation by captopril and the sites where this phenomenon occurs. One is that captopril acts on the efferent site of the reflex arch by enhancing the cardiovascular effects of the autonomic nerves. This is unlikely, however, because norepinephrine output and vascular responses to sympathetic nerve stimulation as well as vascular effects of norepinephrine infusion seem to be reduced after administration of captopril.5,15,16 Furthermore, when in our subjects the autonomic nerves were engaged by hand-grip and cold, the effects on heart rate and blood pressure were not greater after than before the drug. Another hypothesis is that captopril acts on the afferent portion of the reflex arch by eliminating the vasoconstrictor effect of angiotensin II and increasing arterial compliance and the baroreceptor firing rate. This possibility cannot be excluded, but it should be emphasized that a drug such as prazosin, which might influence baroreceptor sensitivity by affecting arterial compliance,17 does not cause any baroreflex potentiation in man.38Jg A third and more likely hypothesis is that this effect of captopril takes place at a central leuet. Animal studieszo,zl have shown the existence of receptors in the area postrema which can be stimulated by circulating angiotensin II and can thus increase blood pressure and also antagonize baroreflexes. It can be surmised that this stimulation might be reduced by captopril by preventing angiotensin II formation, and that this is the reason baroreceptor cardiovascular control is potentiated. It remains to be explained why the baroreflex potentiation observed with captopril is limited to the effects of baroreceptor deactivation, whereas the effects of baroreceptor stimulation are unchanged by the drug.
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The most likely explanation is that captopril displaces the set-point of the stimulus-response curve of the baroreflex toward a more central position, at a greater distance from the threshold (thus accounting for the greater pressor reaction to reflex deactivation) but still in the steep portion of the curve (thus accounting for an unchanged depressor reaction to reflex stimulation). Clinical implications: A few comments can also be made on the practical implication of the increased baroreflex effectiveness caused by captopril. Because of this ahenomenon. the tonic inhibitorv influence of the reflex might be preserved or enhanced during ad-
OF ARTERIAL
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ministration of captopril, despite the tendency of the hypotension to reduce baroreceptor activity. This might prevent reflex tachycardia and sympathetic activation, and be responsible for the stable (and even reduced) heart rate and norepinephrine values observed with administration of the drug. In addition, the preserved, or enhanced, baroreflexes (along with the unaltered responses to exercise and cold) suggest that clinical doses of captopril do not interfere with circulatory homeostasis. This may explain why orthostatic hypotension and reduction in exercise abilitv” are seldom described during treatment with this drug.22-2s
References 1. Case DB, Wallace JM, Keim HJ, Weber MS, Sealey JE, Laragh JH. Possible role of renin in hypertension as suggested by reninsodium profiling and inhibition of converting enzyme. N Engl J Med 1977;296:641-6. 2. Marks ES, Bing RF, Thurston H, Swales JD. Vasodepressor property of the converting enzyme inhibitor captopril (SQ 14225): the role of factors other than renin-angiotensin blockade in the rat. Clin Sci 1980;58:1-6. 3. Carretero OA, Scicli AG, Maitra SR. Role of kinins in the pharmacological effects of converting enzyme inhibitors. In: Angiotensin Converting Enzyme Inhibitors. Horovitz ZP, ed. Baltimore, Munich: Urban & Schwarzenberg, 1981;105-21. 4. Grant RR, Swatiz SL, Hollenberg NK, et al. Role of prostaglandins in the hypotensive response to captopril in essential hypertension (abstr). Clin Res 1979;27:592A. 5. Clough DP, Collis MG, Conway J, Hatton R, Veddie J. Interaction of angiotensin-converting enzyme inhibitors with the function of the sympathetic nervous system. Am J Cardiol 1982;49:1410-4. 6. Cody RJ, Tarazi RL, Bravo EL, Fouad FM. Hemcdynamics of orally active converting enzyme inhibitors (SQ 14225) in hypertensive patients. Clin Sci Mol Med 1978;55:453-9. 7. Muirhead EE, Prewith RR. Brooks B, Brosius WL. Anti-hypertensive action of the orally active converting enzyme inhibitor (SC 14225) in spontaneously hypertensive rats. Circ Res 1978;43:Suppl 1:1-53-l-59. a. Fagard R, Amery A, Reibrouck T, Lijnen P, Billiet L. Acute and chronic systemic and pulmonary hemodynamic effects of angiotensin converting enzyme inhibition with captopril in hypertensive patients. Am J Cardiol 1980;46:295-300. 9. Muiesan G, Alicandri CL, Agabfff-Rosei E. Angiotensin-converting enzyme inhibition, catechoiamines and hemodynamics in essential hypertension. Am J Cardiol 1982;49: 1420-4. 10. Gribbfn B, Pickering TG, Sleight P, Peto R. Effect of age and high blood pressure on baroreflex sensitivity in man. Circ Res 1971; 29:424-31. 11. Pickering TG, Gribbin B, Sleight P. Comparison of reflex heart rate response to rising and falling arterial pressure in man. Cardiovasc Res 1972;6:277-83. 12. Mancia G, Ferrari A, Gregorini L, et al. Control of blood pressure by carotid sinus baroreceptors in human beings. Am J Cardiol
i979;44:895-902. 13. Mancia G, Ludbrook J, Ferrarf A, Gregorini L, Zanchetti A. Baroreceptor reflexes in human hypertension. Circ Res 1978; 43:170-7. 14. Ludbrook J, Mancia 0, Ferrari A, Zanchetti A. The variable pressure neck-chamber method for studying carotid barorefiex in man. Clin Sci Mel Med 1977;53:165-7 1. 15. Mimran A, Caseflas D, Ghevfllard C, DuPont M, Jover 8. Evidence for a postsynaptic action of captopril in isolated perfused rabbit kidney. Am J Cardiol 1982;49: 1540- 1. 16. Antonaccio MJ, Kerwin L. Evidence for prejunctional inhibition or norepinephrine release by captopril in spontaneously hypertensive rats. Eur J Pharmacol 1980;68:209-12. 17. Cambridge D, Davey MJ, Massingham R. The pharmacology of antihypertensive drugs with special reference to vasodilators, alpha-adrenergic blocking agents and prazosin. Med J Aust [Suppl] 1977;2:2-6. 18. Mancia G, Ferrari A, Gregorini L, Zanchetti A. Clonidine and carotid baroreflex in essential hypertension. Hypertension 1979; 1: 362-70. 19. Mancia G, Ferrari A, Gregorini L, et al.: Effects of prazosin on autonomic control of circulation in essential hypertension. Hypertension i980;2:700-7. 20. Barnes KL, Ferrario CM, Conomy JP. Comparison of the hemodynamic changes produced by electrical stimulation of the area postrema and nucleus tractus solitarii in the dog. Circ Res 1979; 45: 136-43. 21. Ferrario CM, Barnes KL, Szilagyl SE, Brosnihan KB. Physiological and pharmacological characterization of the area postrema pressor pathways in the normal dog. Hypertension 1979;1:235-45. 22. Bravo EL, Tarazi RC, Fouad FM. Hemodynamic effects of longterm captopril therapy in hypertensive man. In Ref 3, 263-72. 23. Brunner HR, Turini GA, Waeber 8, Gavras H. Clinical pharmacological studies with captopril. In Ref 3, p 351-68. 24. Atkinson AB, Robertson JfS. Benefits vs risks of captopril therapy. In: Recent Advances in Hypertension Therapy: Captopril. Brunner HR, Gross F, eds. Amsterdam: Excerpta Medica, 198150-63. 25. Fagard RH, Lijnen PJ, Amery AK. Hemodynamic response to captopril at rest and during exercise in hypertensive patients. Am J Cardiol 1982;49: 1569-7 1.
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