(Hypertension. 1995;26:425-431.)
© 1995 American Heart Association, Inc.
Articles |
Differential Modulation of Baroreceptor Sensitivity by Long-term Antihypertensive Treatment
Presented in part at the 8th International Symposium on SHR and Related Studies, Osaka, Japan, October 18-20, 1994, and published in abstract form (Clin Exp Pharmacol Physiol. 1994[suppl 1]:S30).
From the Department of Internal Medicine, Keio University, School of Medicine, Tokyo, Japan.
Correspondence to Takao Saruta, MD, Department of Internal Medicine, Keio University, School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160, Japan.
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Abstract |
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Abstract We investigated the effects of long-term oral treatment with four different classes of antihypertensive drugs (a thiazide diuretic [trichlormethiazide, 10 mg/kg per day]; a ß-blocker [atenolol, 90 mg/kg per day]; a calcium channel antagonist [nicardipine, 150 mg/kg per day]; and an angiotensin-converting enzyme inhibitor [enalapril maleate, 10 mg/kg per day]) on aortic baroreceptor activity in spontaneously hypertensive rats with chronic hypertension (36 weeks of age). Treatment with each of the four drugs, given from 10 to 36 weeks of age, similarly decreased arterial pressure (171±2 to 144±1 mm Hg, P<.01) and similarly decreased the threshold pressure for baroreceptors (116±3 to 103±1 mm Hg, P<.05). The four antihypertensive drugs also potentiated the maximal gain of the pressure-activity relation in these rats (untreated, 1.08±0.05% maximum/mm Hg); however, nicardipine and enalapril (1.77±0.04% and 1.70±0.06% maximum/mm Hg, respectively) augmented the maximal gain to a greater extent (P<.05 to .01) than did trichlormethiazide or atenolol (1.49±0.05% and 1.42±0.02% maximum/mm Hg, respectively). When the initiation of treatment was delayed to 28 weeks of age, no differences were found in the effects on either threshold pressure (104±1 mm Hg) or maximal gain (1.36±0.03% maximum/mm Hg) for all four drugs. These findings suggest that in the treatment of chronic hypertension (1) baroreceptor resetting to a lower pressure level is similarly induced with the four drugs, and (2) baroreceptor sensitivity is augmented more by early and long-term treatment with calcium channel antagonists or angiotensin-converting enzyme inhibitors than by diuretics or ß-blockers.
Key Words: pressoreceptors • rats, inbred SHR • angiotensin-converting enzyme inhibitors • calcium channel blockers • diuretics • adrenergic beta antagonists • aorta
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Introduction |
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Hypertension has been associated with impaired baroreceptor function, which leads to a disturbance of control in the sympathetic and parasympathetic nervous systems. This impairment is already present in the early phase of hypertension1 2 3 when chronic structural changes are induced less by hypertension in the aorta and carotid sinuses, in which the baroreceptors are situated.2 4 5 We have recently demonstrated that in young hypertensive SHR (10 weeks of age) 2 weeks of antihypertensive treatment (from 8 to 10 weeks of age) with four different classes of drugs (a thiazide diuretic, a ß-blocker, a calcium channel antagonist, and an ACE inhibitor) similarly potentiated baroreceptor function, suggesting that the BP reduction by itself (as opposed to specific actions of the drugs) may directly potentiate the function of the baroreceptor.3
During the development and progression of hypertension several structural alterations, such as medial hypertrophy and endothelial damage, occur in the vessel wall.4 5 These vascular structural changes are associated with the altered function of the vessel, which may have substantial effects on baroreceptor activity.6 7 Moreover, a number of studies conducted to examine the effects of antihypertensive treatment on vascular properties have revealed differences among several antihypertensive drugs in their ability to improve vascular structure and function.8 9 10 11 12 We inferred that in the chronic stage of hypertension the modulation of baroreceptor activity in response to antihypertensive treatment may differ from that in the early stage and different drugs may modify baroreceptor activity differently.
To test this hypothesis we evaluated the effects of antihypertensive treatment on aortic baroreceptor activity in SHR with chronic hypertension (36 weeks of age) using four widely used drugs (trichlormethiazide, atenolol, nicardipine, and enalapril). In addition, to determine whether the modulation of baroreceptor activity is influenced by the timing of treatment initiation, we started antihypertensive treatment either in the early stage of hypertension (10 weeks of age) to attenuate the full development of hypertension for 26 weeks or in the chronic stage (28 weeks of age) to moderately reverse high BP for 8 weeks.
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Methods |
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Rats
Male SHR and WKY (8 weeks of age) were obtained from Charles River Japan Co (Atsugi, Japan). All experimental procedures were in accordance with institutional animal care guidelines.
Experiment 1
WKY (n=13) were fed a normal diet (0.38% NaCl; Nippon Clea).
SHR were divided into an untreated group (n=13) that
was fed a normal diet and four treated groups (n=10
in each group) that received one of four drugs mixed in the diet as
follows: trichlormethiazide (10 mg/kg per day; Schering Corp), atenolol
(90 mg/kg per day; Zeneca PLC), nicardipine (150 mg/kg
per day; Yamanouchi Pharmaceutical Co), or enalapril maleate (10 mg/kg
per day; Merck Sharp & Dohme). Antihypertensive treatment was initiated
at the developmental phase of hypertension (10 weeks of age) and was
continued for 26 weeks to the chronic hypertensive stage (36 weeks of
age). Aortic baroreceptor function was examined at 10 and 36 weeks of
age in untreated SHR and WKY and at 36 weeks of age in treated SHR.
Experiment 2
WKY (n=16) were fed a normal diet. SHR were divided into an
untreated group (n=16) that was fed a normal diet and four treated
groups (n=8 in each group) that were given one of four drugs mixed in
the diet as in experiment 1. Antihypertensive therapy was initiated
after the progression of hypertension (28 weeks of age) and was
continued for 8 weeks to 36 weeks of age. Aortic baroreceptor function
was examined at 28 and 36 weeks of age in untreated SHR and WKY and at
36 weeks of age in treated SHR.
Arterial and Venous
Catheterization
Polyethylene catheters prepared from PE-10 (Clay Adams) fused
with PE-50 tubing were placed into the abdominal aorta and
inferior vena cava through the femoral artery and vein,
respectively, with rats under ether anesthesia. One day
after catheterization arterial pressure was
recorded in conscious rats (AP-611G, Nihon Kohden Co). The rats
were then anesthetized with pentobarbital sodium (30 mg/kg IV;
Abbott Laboratories), which was supplemented (5 mg/kg IV) as needed to
maintain the absence of eyelid and paw-pinch reflexes.
Recording and Quantification of Aortic Nerve
Activity
Procedures for recording aortic nerve activity were
described previously.3 13 Briefly, after a midline
cervical incision was made, the left aortic nerve was isolated and
placed on multistrand stainless wire electrodes (A-M Systems, Inc) with
the use of a dissecting microscope (SMZ, Nikon). The nerve and
electrodes were fixed with Wacker Sil-Gel 604 (Wacker-Chemie). The
electrodes were connected to a high-impedance probe (JB101J, Nihon
Kohden) that was connected to a differential amplifier (AVB-10, Nihon
Kohden) with a band-pass filter of 50 to 3000 Hz. The amplified
activity was rectified and integrated by a root-mean-square integrator
(EI-601G, Nihon Kohden) with a time constant of 28 milliseconds and
further filtered at 0.08 Hz for quantification.3 13 14 15 16 17 The
background noise was determined when nerve activity had been eliminated
by decreasing MAP by nitroglycerin infusion; this value
was subtracted from all experimental values of nerve activity.
Amplification and filtering used to record nerve activity were
identical for all rats in the present study. Aortic nerve activity
was measured during changes in MAP. To lower MAP by 50 to 70 mm Hg in
approximately 20 seconds, nitroglycerin (2.2 mmol/L)
was infused at rates of 0.1 to 0.39 mL/min. To raise MAP by 50 to 70
mm Hg in approximately 20 seconds, phenylephrine (4.9
mmol/L) was infused at rates of 5.86 to 11.5 µL/min.
Data Analysis
Pth was designated as the MAP at which aortic nerve
activity firing disappeared and integrated voltage equaled noise, and
Psat was designated as the MAP at which aortic nerve
activity no longer increased (even though the arterial
pressure continued to increase).3 18 The data for aortic
nerve activity were normalized in two ways. The maximal value of aortic
nerve activity was defined as 100% in one method,1 3 19
and the value of the aortic nerve activity at baseline MAP was defined
as 100% in the other.3 13 20 We plotted aortic nerve
activity at MAP intervals of 5 mm Hg and fitted the data to a logistic
function curve by using a nonlinear regression program (PROC
NLIN, SAS Institute Inc). Four parameters were
derived from the following equation21 22 : Aortic Nerve
Activity=P4+P1/{1+exp[P2(P3-MAP)]},
where P1 is the aortic nerve activity range; P2
is the slope coefficient (independent of the range); P3 is
the MAP at the midpoint of the curve (BP50); and
P4 is the lower plateau of aortic nerve activity. The
sensitivity of aortic nerve activity was defined as the
Gmax of the logistic function curve and was calculated as
Gmax=P1 · P2/4.3 13 14 15 18 20
Statistical Analysis
Results are given as mean±SEM. Statistical difference was
evaluated by unpaired t test or ANOVA followed by
Scheffé's F test. A value of P<.05 was
considered statistically significant.
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Results |
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Experiment 1
MAP
MAP did not differ significantly between the conscious and anesthetized states in all rats (Tables 1 and 2). The MAP of untreated SHR was higher than that of untreated WKY at 10 weeks of age and was further increased at 36 weeks (P<.01). Antihypertensive treatment with each of the four drugs beginning at 10 weeks of age attenuated the development of hypertension in 36-week-old SHR to a similar extent.
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Baseline and Maximal Aortic Nerve Activities
At 10 weeks of age baseline aortic nerve activity was greater but
maximal aortic nerve activity was similar in untreated SHR compared
with untreated WKY (Table 1). These findings are
compatible with our previous data.3 At 36 weeks baseline
and maximal values of aortic nerve activity were comparable among
untreated SHR and WKY (Table 2). Although the maximal
aortic nerve activities in the four treated SHR groups were slightly
greater than values in untreated SHR, the difference did not reach
statistical significance.
Pth, Psat, and
BP50
Fig 1 shows the changes in aortic nerve
activity in response to changes in arterial pressure in
36-week-old rats. Pth, Psat, and
BP50 values in untreated SHR were greater than those in
untreated WKY at 10 weeks of age (Table 1) and were
further increased (P<.01) at 36 weeks (Table 2). Each of the four antihypertensive drugs equally
attenuated the increase in Pth, which in turn
correlated with the attenuation of hypertension (Table 2 and Fig 2). All four antihypertensive drugs also diminished the
increase in Psat, but nicardipine and
enalapril restrained the increase in Psat to a greater
extent than did trichlormethiazide or atenolol (Table 2). The four drugs also attenuated the increase in
BP50, which tended to be lower in
nicardipine- and enalapril-treated SHR than in
trichlormethiazide- and atenolol-treated SHR (Table 2).
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), untreated SHR (
), and SHR treated from 10 to 36 weeks
of age (
) in experiment 1. Gmax was depressed in
untreated SHR compared with untreated WKY. Although Gmax
values in all treated SHR groups were greater than in untreated SHR,
Gmax values in nicardipine- and
enalapril-treated SHR were greater than those in trichlormethiazide-
and atenolol-treated SHR. Values are mean±SEM.
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Gmax of the MAP–Aortic Nerve Activity
Curve
Analysis with normalization to the maximal aortic nerve
activity showed that Gmax in untreated SHR was smaller than
that in untreated WKY at 10 weeks of age (Table 1) and
was further decreased (P<.01) at 36 weeks (Table 2). The decline in Gmax of SHR was partially
prevented by treatment with trichlormethiazide or atenolol in
proportion to the BP-lowering effects (Table 2 and Fig 2). In contrast, treatment with
nicardipine or enalapril preserved
Gmax, leading to a greater Gmax than
expected by the BP level (Table 2 and Fig 2). Thus,
Gmax was greater in nicardipine- and
enalapril-treated SHR than in trichlormethiazide- and atenolol-treated
SHR. Logistic analysis with normalization to the baseline nerve
activity also showed that Gmax in nicardipine-treated
(4.51±0.12% baseline/mm Hg) and enalapril-treated (4.20±0.17%
baseline/mm Hg) SHR was greater (P<.05 to .01) than in
trichlormethiazide-treated (3.64±0.18% baseline/mm Hg) and
atenolol-treated (3.49±0.11% baseline/mm Hg) SHR.
Experiment 2
MAP
MAP was comparable between the conscious and anesthetized
states in all rat groups (Tables 3 and 4). The MAP of untreated SHR at 28 weeks
of age was higher than that of age-matched untreated WKY and was
similar to that of untreated SHR at 36 weeks. Antihypertensive
treatment with each of the four drugs beginning at 28 weeks of age
similarly decreased MAP in SHR at 36 weeks.
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Baseline and Maximal Aortic Nerve Activities
At both 28 and 36 weeks of age baseline and maximal aortic nerve
activities were similar among untreated SHR and WKY (Tables 3 and 4).
Although the maximal aortic nerve activities in the four treated SHR
groups were slightly greater than those in untreated SHR, the
difference did not reach statistical significance.
Pth, Psat,
and BP50
Fig 3 shows the changes in aortic nerve
activity in response to changes in arterial pressure in
36-week-old rats. Pth, Psat, and
BP50 values in untreated SHR were greater than values in
age-matched untreated WKY at both 28 and 36 weeks of age (Tables 3 and 4). Antihypertensive therapy with the four drugs similarly reduced
Pth, Psat, and BP50
in association with the BP reduction (Table 4 and Fig 2). No differences in Pth,
BP50, and Psat were found among the four
groups of treated SHR.
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Gmax of the MAP–Aortic Nerve Activity
Curve
Analysis with normalization to the maximal aortic
nerve activity showed that Gmax in untreated SHR at 28
weeks of age was smaller than that in age-matched untreated WKY and was
similar to that in untreated SHR at 36 weeks (Tables 3 and 4).
Gmax of SHR was similarly potentiated by antihypertensive
therapy with the four drugs in proportion to the BP reduction (Table 4
and Fig 2). Logistic function analysis with
normalization to the baseline nerve activity showed a similar increase
in Gmax for trichlormethiazide-treated (3.52±0.13%
baseline/mm Hg), atenolol-treated (3.46±0.20% baseline/mm Hg),
nicardipine-treated (3.61±0.13% baseline/mm Hg), and
enalapril-treated (3.69±0.17% baseline/mm Hg) SHR compared with
untreated SHR (2.12±0.10% baseline/mm Hg).
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Discussion |
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The present study is the first to demonstrate the effects of four different classes of antihypertensive drugs (a thiazide diuretic [trichlormethiazide], a ß-blocker [atenolol], a calcium channel antagonist [nicardipine], and an ACE inhibitor [enalapril]) on the correlation between BP and arterial baroreceptor activity in the long-term treatment of chronic hypertension.
Baroreceptor Resetting to Lower Pressures
It has been shown that acute baroreceptor resetting, as examined
by changes in Pth during short-term (15 minutes)
hypotension, is affected differently depending on which
antihypertensive drug is used in normotensive rats.23 24
In contrast, the present study demonstrated that long-term
antihypertensive treatment with four different drug classes decreased
Pth to a similar extent in SHR with highly developed
hypertension (36 weeks of age) regardless of whether treatment was
begun early (from 10 weeks) or late (from 28 weeks). These results
extended those of our previous work which showed that 2 weeks of
treatment with each of the four drugs decreased Pth to a
similar extent in young hypertensive SHR (10 weeks of
age).3 Moreover, the decrease in Pth
correlated well with the BP-lowering effect. These findings confirm
earlier studies showing that the capacity for baroreceptor
Pth to reset to a lower level remains unchanged in chronic
hypertension.19 25 26 27 They provide additional information
indicating that irrespective of depressor mechanisms and the timing of
treatment, the prevailing BP is the major determining factor for
baroreceptor Pth during chronic antihypertensive therapy.
On the other hand, the decrease in Psat in response to the
lowering of BP differed among the four drugs when treatment was started
at a young age. This indicates that a shift in the
pressure–baroreceptor activity curve at higher pressures was in part
modulated by nondepressor mechanisms. The lower Psat with
the similar Pth values in nicardipine- and
enalapril-treated SHR, compared with those in trichlormethiazide- and
atenolol-treated SHR, led to a narrowed range of pressure over which
baroreceptor activity changed, making the pressure-activity curve
steeper. These findings are consistent with the
Gmax obtained by logistic function analysis.
Baroreceptor Sensitivity
The depressed baroreceptor sensitivity in chronic renovascular
hypertension is reported to be restored even after a brief (60 to 120
minutes) reversal of hypertension.19 27 Regarding
long-term (4 to 40 weeks) antihypertensive treatment, combinations of
vasodilators, diuretics, and adrenergic antagonists
potentiate the baroreceptor sensitivity in SHR.28 29 30 We
previously demonstrated that 2 weeks of treatment of young hypertensive
SHR (10 weeks of age) with a single administration of the four classes
of drugs (a thiazide diuretic, a ß-blocker, a calcium channel
antagonist, and an ACE inhibitor) potentiates
baroreceptor sensitivity (Gmax of the pressure-activity
curve) to a similar extent.3 In the present study
attenuation of hypertension with each of the four drugs started early
(10 weeks of age) preserved the baroreceptor sensitivity in the chronic
stage of hypertension (36 weeks of age) although the extent of
preservation was variable among the four drugs. Delayed treatment
from 28 to 36 weeks of age with the four drugs similarly restored
baroreceptor sensitivity in association with the BP reduction. The
present results combined with previous studies indicate that
lowering BP itself is the major contributor to recovery of the
depressed baroreceptor sensitivity in hypertension. Furthermore, it is
remarkable that only early and long-term treatment with
nicardipine and enalapril augmented baroreceptor
sensitivity to an extent greater than that expected by the BP reduction
(Fig 2). This additional effect of
nicardipine and enalapril may reflect the early
initiation of treatment (10 versus 28 weeks of age). However, the
duration of early treatment was longer than that of delayed treatment
(26 versus 8 weeks), so the relative roles of time of treatment
initiation versus treatment duration could not be exactly
distinguished. Nevertheless, the present findings indicate that the
pharmacological actions of calcium channel antagonists and
ACE inhibitors, in addition to the BP-lowering effect, can
at least in part modify baroreceptor sensitivity by interacting with
some factors that occur during the progression of hypertension. We will
discuss candidates for such factors below.
First, it is possible that degeneration of the baroreceptors may be caused by chronic hypertension. Angell-James31 reported that degenerative changes were observed by light microscopy in some of the baroreceptor nerve endings of renal hypertensive rabbits. In contrast, studies by Krauhs32 and Andresen et al2 demonstrated no morphological differences between the baroreceptors of SHR and WKY by electron microscopic examinations. In the present study the maximal value of whole aortic baroreceptor activity was not decreased in untreated SHR compared with untreated WKY, suggesting that degeneration of the baroreceptors, if it exists, may be minimal. Second, sustained hypertension induces changes in the aortic medial layer (such as smooth muscle hypertrophy and increased collagen content) that affect baroreceptor sensitivity through changes in vessel distensibility and/or mechanical coupling of the baroreceptors to the vessel.2 7 28 32 ACE inhibitors and calcium channel antagonists have been shown to prevent these medial changes to a greater extent than ß-blockers, diuretics, and vasodilators,8 9 10 12 33 34 35 probably by acting directly on vascular smooth muscle.36 37 38 39 These beneficial effects on the aortic media may have contributed to the preserved baroreceptor sensitivity observed after early treatment with enalapril and nicardipine. Moreover, this hypothesis is supported by the finding that these pronounced effects on Gmax were not observed in delayed therapy because it may be difficult to regress hypertensive medial changes that already exist by antihypertensive treatment.4 28 40 41 Finally, recent studies have shown that several substances released from the endothelium42 43 are involved in the modulation of baroreceptor activity in a paracrine manner. Prolonged antihypertensive therapy begun early with ACE inhibitors and calcium channel antagonists can effectively prevent hypertensive endothelial damage,11 12 potentially leading to the preservation of baroreceptor sensitivity. As discussed above, it appears likely that enalapril and nicardipine act on vascular components rather than on the baroreceptors themselves to potentiate the baroreceptor sensitivity to an extent greater than that expected by the attenuation of hypertension. However, further experiments are needed before the exact site or sites of action are known.
Study Limitations
In the present study we recorded multifiber activity that
likely represents activity of myelinated
baroreceptor afferents. Therefore, we could not evaluate the possible
effects of hypertension and treatment of hypertension on the activity
of baroreceptor unmyelinated fibers in this study.
Furthermore, multifiber recordings do not enable as precise a
determination of threshold pressure as do single-fiber
recordings. Additionally, we used the mean
Pth, but Krieger6 observed that an
exact coincidence exists between the systolic Pth and the
diastolic pressure level. These methodological factors
might have contributed to the present results showing that the
extent of decreases in the mean Pth was smaller than
decreases in MAP produced by the drugs.
Summary
In the treatment of hypertension, baroreceptor resetting to
a lower pressure level was similarly induced by administration of four
different classes of drugs, whereas baroreceptor sensitivity was
potentiated to a greater extent by administration of
nicardipine or enalapril than by trichlormethiazide or
atenolol when initiated in the early stage of hypertension and
continued over the long term.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by research grants (Nos. 05770480 and 06770873) from the Ministry of Education, Science and Culture, Japan. The authors thank Haruko Kihara for her excellent secretarial assistance.
Received February 8, 1995; first decision March 10, 1995; accepted May 19, 1995.
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