(Hypertension. 1996;27:209-218.)
© 1996 American Heart Association, Inc.
Articles |
Comparison of Early and Late Start of Antihypertensive Agents and Baroreceptor Reflexes
From the Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
Correspondence to Takao Saruta, MD, Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160, Japan.
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Abstract |
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Abstract Along with arterial blood pressure reduction, maintenance of the integrity of baroreceptor reflex function contributes to preserving end-organ function in the treatment of hypertensive patients. The purpose of this study was to investigate the effects of antihypertensive agents (trichlormethiazide, atenolol, nicardipine, and enalapril) on baroreceptor reflex function by comparing early and late starts of treatment. We administered each agent to spontaneously hypertensive rats (SHR) as early-start groups from 10 to 36 weeks of age and as late-start groups from 28 to 36 weeks of age. We evaluated the gain of the reflex control of renal sympathetic nerve activity and heart rate using ramp infusions of phenylephrine and nitroglycerin in untreated SHR at 10, 28, or 36 weeks of age and in treated SHR at 36 weeks of age. In 28- and 36-week-old untreated SHR, the renal sympathetic nerve activity gain was not altered and the heart rate gain was decreased (from -2.3±0.3 to -1.3±0.3 and -1.2±0.3 beats per minute [bpm]/mm Hg, P<.05, respectively) compared with 10-week-old SHR. Early and late start of therapy produced arterial pressure reductions (-18±4 and -12±5 mm Hg, P<.05, respectively). In the early-start groups, the renal sympathetic nerve activity gain was improved markedly in nicardipine- and enalapril-treated SHR (-4.2±0.2% and -4.9±0.2% of control/mm Hg, P<.01, respectively), and the heart rate gain was improved markedly in atenolol- and enalapril-treated SHR (-4.1±0.2 and -4.4±0.2 bpm/mm Hg, P<.01, respectively). In the late-start groups, the renal sympathetic nerve activity gain was improved moderately in nicardipine- and enalapril-treated SHR (-3.8±0.2% and -2.9±0.2% of control/mm Hg, P<.05, respectively). The heart rate gain was improved slightly only in nicardipine-treated SHR (-1.9±0.2 bpm/mm Hg, P<.05). These results demonstrate that an early start of antihypertensive treatment improves baroreceptor reflex function markedly compared with a late start of treatment. This supports the hypothesis that a possible critical phase sensitive to intervention with antihypertensive treatment exists during the development of hypertension and indicates that the early start of antihypertensive treatment would be required in clinical practice.
Key Words: diuretics • receptors, adrenergic, beta • calcium channel blockers • angiotensin-converting enzyme inhibitors • baroreflex • rats, inbred SHR
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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The final goal in the management of hypertension is prevention of end-organ damage. To accomplish this, antihypertensive agents are used to reduce hypertension. Although various types of agents are available, evidence has shown that in terms of arterial pressure reduction, there are no large differences among the major classes of antihypertensive agents, ie, diuretics, ß-blockers,
1-blockers, calcium channel antagonists, and
angiotensin-converting enzyme
inhibitors.1 Antihypertensive agents are known
to have various effects on the sympathetic nervous system,
renin-angiotensin system, baroreceptor reflex
mechanism, and regional and systemic hemodynamics.
Since the baroreceptor reflex mechanism could modify perfusion pressure
and/or blood flow to end organs, more attention to the effects of
antihypertensive agents on the reflex function has been needed. We have
shown that short-term treatment with four currently used agents
(trichlormethiazide, atenolol, nicardipine, and
enalapril) restored the impaired baroreceptor reflex control of RSNA
and HR in the early hypertensive stage of SHR.2 However,
it remains unknown whether an early start of antihypertensive treatment
is favorable with regard to reflex function compared with a late start
and which types of agents improve the reflex function under
long-term treatment. To confirm the hypothesis that a possible
critical phase sensitive to intervention with antihypertensive
treatment exists during the development of hypertension3
and to simulate clinical settings more closely, we examined the effects
of four currently used antihypertensive agents on baroreceptor reflex
function in SHR by comparing the early start of antihypertensive
treatment from 10 to 36 weeks of age with the late start of treatment
from 28 to 36 weeks of age. |
Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Experiments were conducted in 8-week-old male Okamoto SHR purchased from Charles River Japan Co. All surgical and experimental procedures followed institutional animal care guidelines. Rats were housed singly in cages in a room with a constant temperature and 12-hour light/dark cycle.
Surgical Procedures
For all surgical preparations, ether
anesthesia was
used as the preanesthetic agent, and the rats were anesthetized
with pentobarbital sodium (161.12 µmol/kg [40 mg/kg] IP,
supplemented by 40.28 µmol/kg [10 mg/kg], as needed; Abbott
Laboratories). Sterile techniques were used, and
procaine-penicillin (50 000 U/kg IM) diluted in isotonic sterile
saline was given postoperatively.
Arterial and Venous
Catheterization
The left femoral vein was catheterized with two
modified
polyethylene tubes made from PE-10 tubing (Clay Adams) fused with PE-50
tubing (Clay Adams) for infusion of either phenylephrine or
nitroglycerin; the left femoral artery was also
catheterized. The catheters were led subcutaneously to the back of the
neck and fixed and then flushed with sterile, heparinized (1000 U/mL)
isotonic saline.
Renal Nerve Electrode Implantation
RSNA recording techniques
were used to obtain multifiber
recordings of postganglionic RSNA as described
previously.2 4 5 With the rat in a
shielded cage, the left
kidney was exposed via a retroperitoneal approach through a left flank
incision. With the use of a dissecting microscope (SMZ, Nikon), a renal
nerve was identified and carefully isolated.
Polytetrafluoroethylene-coated
multistrand stainless steel wire electrodes (A-M Systems, Inc) were
placed on the nerve. To insulate the electrodes and nerve from
surrounding tissue, parafilm (American Can Co) was placed beneath the
nerve. The nerve and electrode assembly was covered with silicon gel
(SilGel 604, Wacker-Chemie) to prevent the nerve from drying. A ground
lead was fixed to the tissue close to the electrodes. When the gel had
hardened, the electrodes were looped in the flank area. The flank
incision was closed, and the electrodes were exteriorized at the back
of the neck. The electrodes were protected with a handmade stockinette
jacket, and the rats were allowed to recover.
Data Analysis
After surgical preparation, the rats were
housed in individual
cages. A minimum of 24 hours later, each conscious rat was placed in a
nonrestraining holder that permitted forward and backward movement. The
arterial catheter was connected to a transducer (TP-200T,
Nihon Kohden Co) for measurement of arterial pressure, MAP
(AP-611G, Nihon Kohden), and HR (AT-601G, Nihon Kohden). The RSNA
recording 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 (low, 50
Hz; high, 3 kHz). Amplified (x10 000 to x20 000) and filtered RSNA
was monitored on an oscilloscope (VC-10, Nihon Kohden). The root mean
square (RMS) of RSNA was defined as the whole-nerve activity
obtained by rectifying and integrating the activity with an RMS
integrator (EI-601G, Nihon Kohden) that had a time constant of 28
milliseconds, and mean RSNA was defined as the RMS of RSNA further
filtered at 0.08 Hz for quantification. The RSNA remaining after
maximum inhibition by phenylephrine infusion (4.9 mmol/L,
at 12.86 µL/min) was similar to the background noise observed at 30
minutes postmortem; this value was subtracted from all experimental
values of RSNA. Arterial pressure, MAP, HR, original renal
neurogram, mean RSNA, and the RMS of RSNA were recorded on a
thermal array recorder (RTA-1300, Nihon Kohden). Data were stored
in a multichannel data recorder (A-89, Sony Inc).
Analysis of Baroreceptor Reflex Function
After 60 minutes had
been allowed for arterial
pressure to settle, arterial pressure, MAP, HR, and RSNA
were recorded. Baroreceptor reflex curves of RSNA and HR versus MAP
were generated by measurement of the RSNA and HR responses to increases
and decreases in MAP produced with intravenous ramp
infusions of phenylephrine or nitroglycerin
alternately. To raise MAP by 40 mm Hg for 1 to 2 minutes,
phenylephrine (4.9 mmol/L) was infused at 2.34 to 6.43
µL/min. To lower MAP by 40 mm Hg in 10 to 15 seconds,
nitroglycerin (2.2 mmol/L) was infused at 0.1 to 0.4
mL/min. At least 30 minutes were allowed between drug infusions. The
initial baseline values for MAP, RSNA, and HR were taken as their
5-minute averages before the infusion of each drug. The initial
baseline value of integrated mean RSNA was defined as 100% before drug
infusion. For data analysis, RSNA and HR were collected at MAP
intervals of 5 mm Hg.
Data for the RSNA-MAP and HR-MAP relations after infusion of phenylephrine and nitroglycerin were fitted to a logistic function curve with the use of a nonlinear regression program (PROC NLIN, SAS Institute Inc) on a computer (PS/2 model 50Z, IBM Co). The best fit of the curve was obtained with the above computer program. Four parameters were derived from the following equation: RSNA or HR=P4+P1/[1+eP2(MAP-P3)], where P1 is the RSNA or HR range, P2 is the slope coefficient (independent of the range), P3 is the MAP at half the RSNA or HR range, and P4 is the lower plateau of RSNA or HR. The curve was forced through the average initial baseline values of MAP, RSNA, and HR. In the present study, the goodness of fit, which was determined by the percentage of the total sums of squares that were accounted for by the model, was greater than 95%. The baroreceptor reflex gain index was defined as the maximum gain of the logistic function curve Maximum Gain=-P1·P2/4. We defined several appropriate terms according to our previous study.2
Experimental Protocols
Experiment 1: Comparison of
Arterial Baroreceptor
Reflexes in 10-, 28-, and 36-Week-Old Untreated SHR
Untreated
8-week-old SHR (n=24) were randomly assigned to
one of three groups. Each group was fed a normal commercial diet (20
g/d, 0.38% NaCl; Nippon Clea) for 2, 20, or 28 weeks and received
water ad libitum. Each group was evaluated for baroreceptor reflex
function at 10, 28, or 36 weeks of age.
Experiment 2:
Effects of Early-Start Antihypertensive Treatment on
Arterial Baroreceptor Reflexes
SHR (n=66) were randomly
assigned to one of two groups: one for
early start of treatment and another for late start. In the
early-start group (n=32), antihypertensive agents were administered
for 26 weeks from 10 to 36 weeks of age. Rats of the
early-start group were randomly assigned to one of four
subgroups and given trichlormethiazide (26.3 µmol/kg [10 mg/kg]
per
day; Schering Co), atenolol (337.9 µmol/kg [90 mg/kg] per day;
Zeneca PLC), nicardipine (290.7 µmol/kg [150 mg/kg]
per day; Yamanouchi Pharmaceutical Co), or enalapril maleate (20.3
µmol/kg [10 mg/kg] per day; Merck Sharp & Dohme) mixed in
the diet.
A specific reduction in arterial pressure, defined as
clinically effective (ie, 10 to 15 mm Hg as MAP) or as the prevention
of excessive reduction in arterial pressure that may lead
to a J-shaped phenomenon,6 was
targeted according to our previous study.2
Experiment 3: Effects of Late-Start Antihypertensive
Treatment on
Arterial Baroreceptor Reflexes
In the late-start group (n=34),
antihypertensive agents were
administered for 8 weeks, from 28 to 36 weeks of age. Rats in the
late-start group were randomly assigned to one of four subgroups
and given the same agents as rats in the early-start groups.
Statistical Analysis
Initial baseline values of MAP and HR
and the
parameters obtained from logistic function curves were
compared by one-way ANOVA with repeated measures followed by
Scheffé's F test. Values are expressed as mean±SEM; a
value of
P<.05 was considered statistically significant.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Experiment 1
Twenty-eight– and 36-week-old SHR had greater MAP values (P<.01) and lower HR values (P<.05) than 10-week-old SHR (Table 1
).
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Comparison of RSNA-MAP
Relation in 10-, 28-, and 36-Week-Old
Untreated SHR
The operating point of the curve was shifted to the
right (ie,
upward resetting) in 28- and 36-week-old compared with
10-week-old SHR (Fig 1, top). The RSNA gain, RSNA
range, upper plateau, and range of reflex sympathetic excitation and
inhibition were not altered in 28- and 36-week-old compared with
10-week-old SHR. The BP50 was increased in 28- and
36-week-old compared with 10-week-old SHR (P<.01)
(Table 2).
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), 28-week-old (
), and 36-week-old
(x) untreated SHR. Symbols indicate the operating point,
ie, baseline level, of RSNA-MAP or HR-MAP relation. Each upper left or
lower right end of the curve indicates the upper or lower plateau,
respectively. Values represent mean±SEM of observations made
in seven to nine rats.
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Comparison of HR-MAP Relation in
10-, 28-, and 36-Week-Old
Untreated SHR
The operating point of the curve was shifted to the
right
(ie, upward resetting) in 28- and 36-week-old compared with
10-week-old SHR (Fig 1
, bottom). Twenty-eight– and
36-week-old SHR had a decreased HR gain, HR range
(P<.05), upper plateau (P<.01), and lower
plateau (P<.05) and an unaltered range of reflex
tachycardia and bradycardia compared with 10-week-old
SHR. The BP50 was increased in 28- and
36-week-old compared with 10-week-old SHR
(P<.01) (Table 3).
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Experiment 2
MAP was lower in the four groups of treated
compared with
untreated SHR (P<.05). HR was also lower in atenolol-,
nicardipine-, and enalapril-treated compared with
untreated SHR (P<.05) (Table 4).
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Effects of Early-Start Antihypertensive Treatment on RSNA-MAP
Relation
The operating point of the curve was shifted to the left
(ie, downward resetting) in each group of treated compared with
untreated SHR (Fig 2). RSNA gain was greater in
trichlormethiazide- and atenolol-treated SHR (P<.05) as
well as nicardipine- and enalapril-treated SHR
(P<.01) compared with untreated SHR. RSNA range was
increased in all treated compared with untreated groups of SHR
(P<.01). The upper plateau was increased in
trichlormethiazide-, atenolol-, and enalapril-treated SHR
(P<.01) as well as nicardipine-treated SHR
(P<.05) compared with untreated SHR. The lower plateau was
decreased in atenolol-, nicardipine-, and
enalapril-treated compared with untreated SHR
(P<.05). The range of reflex sympathetic excitation was
increased in trichlormethiazide-, atenolol-, and enalapril-treated
SHR (P<.01) as well as nicardipine-treated
SHR (P<.05) compared with untreated SHR. The range of
reflex sympathetic inhibition was not increased in any of the treated
SHR. BP50 was decreased in trichlormethiazide- and
enalapril-treated SHR (P<.01) as well as atenolol- and
nicardipine-treated SHR (P<.05) compared with
untreated SHR (Table 5).
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Effects of
Early-Start Antihypertensive Treatment on HR-MAP
Relation
The operating point of the curve was shifted to the left
(ie, downward resetting) in each group of treated compared with
untreated SHR (Fig 3). The HR gain was greater in
trichlormethiazide- and nicardipine-treated SHR
(P<.05) as well as atenolol- and enalapril-treated SHR
(P<.01) compared with untreated SHR. The HR range was
increased in trichlormethiazide-treated SHR (P<.05) as
well as atenolol-, nicardipine-, and
enalapril-treated SHR (P<.01) compared with untreated
SHR. The upper plateau was decreased in atenolol-treated SHR
(P<.05), as was the lower plateau (P<.01)
compared with untreated SHR. The lower plateau was also decreased in
nicardipine- and enalapril-treated compared with
untreated SHR (P<.05). The range of reflex
tachycardia was increased in trichlormethiazide-treated
SHR (P<.05) as well as nicardipine- and
enalapril-treated SHR (P<.01) compared with untreated
SHR. The range of reflex bradycardia was increased in
atenolol-treated compared with untreated SHR (P<.05).
BP50 was decreased in trichlormethiazide-,
nicardipine-, and enalapril-treated SHR
(P<.01) as well as in atenolol-treated SHR
(P<.05) compared with untreated SHR (Table 6).
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Experiment 3
MAP was lower in the four groups of treated
compared with
untreated SHR (P<.05). HR was also lower in atenolol- and
nicardipine-treated compared with untreated SHR
(P<.01 and P<.05, respectively) (Table
7).
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Effects of Late-Start Antihypertensive
Treatment on RSNA-MAP
Relation
The operating point of the curve was shifted to the left
(ie, downward resetting) in each group of treated compared with
untreated SHR (Fig 4). The RSNA gain was greater in
nicardipine- and enalapril-treated compared with
untreated SHR (P<.01 and P<.05, respectively).
The RSNA range, upper plateau, lower plateau, and range of reflex
sympathetic excitation and inhibition were not altered in treated
compared with untreated SHR. BP50 was decreased in
atenolol-, nicardipine-, and enalapril-treated
compared with untreated SHR (P<.05) (Table 8).
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Effects of Late-Start Antihypertensive Treatment on HR-MAP
Relation
The operating point of the curve was shifted to the left (ie,
downward resetting) in each group of treated compared with untreated
SHR (Fig 5). The HR gain was slightly increased and HR
range was increased only in nicardipine-treated compared
with untreated SHR (both P<.05). The upper plateau was
decreased in nicardipine-treated compared with untreated
SHR (P<.05), as was the lower plateau in
trichlormethiazide-, atenolol-, and enalapril-treated SHR
(P<.05) as well as nicardipine-treated SHR
(P<.01) compared with untreated SHR. The range of reflex
tachycardia was increased in atenolol-treated compared
with untreated SHR (P<.05). The range of reflex bradycardia
was decreased in atenolol-treated SHR (P<.05) but
increased in nicardipine-treated SHR (P<.01)
compared with untreated SHR. BP50 was decreased in
atenolol- and enalapril-treated compared with untreated SHR
(P<.01 and P<.05, respectively) (Table
9).
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Discussion |
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The major findings of the present study in SHR are as follows: (1) The early start of antihypertensive treatment with four currently used agents markedly improved the RSNA gain, HR gain, and range of reflex sympathetic excitation compared with the late start of treatment; (2) the late start of treatment with nicardipine or enalapril but not trichlormethiazide or atenolol moderately improved the RSNA gain, whereas only nicardipine slightly improved the HR gain; and (3) none of the four agents with a late start of treatment improved the range of reflex sympathetic excitation.
With early-start treatment, the four agents improved both RSNA and HR gains. This finding is in good agreement with our previous study, in which short-term (2-week) treatment with four antihypertensive agents restored the impaired RSNA and HR gains in the early hypertensive stage of SHR.2 In the present study our notion is expanded, in that early-start and long-term antihypertensive treatment improved RSNA and HR gains from the early to established hypertensive stage in SHR. The finding that enalapril markedly improved the RSNA gain could have resulted from inhibition of an overactivated central renin-angiotensin system7 8 or cardiovascular tissue remodeling3 9 in addition to reduction in arterial pressure. Furthermore, an important finding in the present study is that the early start of atenolol or enalapril improved the HR gain markedly compared with trichlormethiazide or nicardipine, whereas late-start treatment with atenolol or enalapril failed to improve it. Our present data support findings in clinical studies. A discrepancy has been shown between normotensive subjects10 and borderline hypertensive11 and essential hypertensive12 13 patients; HR gain was improved in the former but not in the latter. Watson et al14 have also shown that a ß-blocker improved the HR gain in essential hypertensive patients younger than 40 years of age, whereas it failed to do so in patients older than 40 years. It has been widely accepted that ß-adrenergic activity in the early stage of hypertension is dominant compared with that in the chronic stage of hypertension.15 16 17 Accordingly, treatment with atenolol or enalapril from the early stage of hypertension could prevent the transitional changes in ß-adrenergic activity that occur during the course of hypertension and consequently lead to significant improvement of HR gain. Moreover, in SHR a synergistic action of the sympathetic nervous and renin-angiotensin systems is suggested.18 Angiotensin II is also suggested to play a facilitatory role in sympathetic nervous transmission and responses.19 20 21 22 It has been shown that the ß-blocker atenolol suppressed the sympathetic nervous system and increased vagal tone23 and that angiotensin II could inhibit the vagal activity to the heart.24 Therefore, the finding that early-start treatment with atenolol or enalapril markedly improved HR gain could have resulted from a long-term inhibition of the synergism, suppression of the sympathetic nervous system, and stimulation of vagal tone in addition to a reduction in arterial pressure.
The finding that early-start treatment with atenolol or enalapril markedly improved HR gain may be related to the recent notion from several large-scale, long-term intervention studies in which ß-blockers25 or angiotensin-converting enzyme inhibitors26 27 improved the prognosis of postmyocardial infarction and/or congestive heart failure. It has been recognized that neural and/or baroreceptor reflex mechanisms could initiate clinical complications in patients with cardiac disease.28 29 There is also evidence that HR gain is impaired in acute myocardial infarction30 and that the reflex control of HR is a predictive factor for sudden cardiac death.31 Therefore, it is suggested that HR gain could be added as a candidate for the factors affecting the prognosis of cardiac events.
The second important finding from the present study is that early-start treatment with the four antihypertensive agents improved the range of reflex sympathetic excitation. This finding also expands those from our previous study.2 We used the range of reflex sympathetic excitation as an index of baseline RSNA level. In other words, a large range of reflex sympathetic excitation indicates a low baseline RSNA level, and conversely, a small range of reflex sympathetic excitation indicates a high baseline RSNA level. On the basis of this concept, we evaluated the early- and late-start effects of antihypertensive agents on the baseline RSNA level. Whereas trichlormethiazide, atenolol, and enalapril markedly improved the range of reflex sympathetic excitation, nicardipine improved it only moderately, by a degree smaller than that of the other three agents. This finding suggests that the start of treatment with any of the four agents from the early hypertensive stage, even nicardipine, which may activate the sympathetic nervous system, could reduce blood pressure with little or no adverse activation of RSNA.
We found that late-start antihypertensive treatment failed to markedly improve the RSNA and HR gains. In particular, trichlormethiazide and atenolol did not induce any significant changes in RSNA and HR gains. However, nicardipine and enalapril moderately increased the RSNA gain, and nicardipine slightly increased the HR gain despite minor alterations achieved. Moreover, it has been shown that none of the four agents as late-start treatment increased the range of reflex sympathetic excitation. These findings would be supported by several lines of evidence that angiotensin-converting enzyme inhibitors and calcium channel antagonists are beneficial for structural changes in vessels.32 Also, it has been shown that structural changes in the vasculature usually begin around 24 weeks of age and continue to progress in SHR.33 34 Folkow35 36 has shown that dramatic attenuation in structural changes of the vasculature occurred only when treatment was started early in life. It is therefore conceivable that none of the four agents in late-start treatment could improve changes once they had been established, such as changes in vascular structure, inactivation of some fibers having lower threshold pressure, and impairment of adaptation of the baroreceptors for increased pressure.37 In contrast, Sumitani and Krieger38 demonstrated that complete reversal of resetting from hypertension is a very rapid process after 2 days of pressure normalization and that this process is independent of the duration of hypertension and the severity of morphological lesions. It is therefore suggested that the impairment of adaptation of the baroreceptors themselves for increased pressure would be less. The notion of Sumitani and Krieger is supported by recent evidence from our laboratory39 that the maximum value of whole aortic baroreceptor activity was similar in both 36-week-old SHR and their normotensive counterparts, indicating that degeneration of the baroreceptors, if it exists, may be minimal. In contrast to the pressure normalization intended by Sumitani and Krieger, we intended a mild to moderate reduction in arterial pressure. Both the 8- and 26-week treatment protocols in the present study are sufficiently long to elicit mild to moderate reduction in arterial pressure compared with our previous study.2 Moreover, the findings39 that the four agents used in the present study decreased baroreceptor threshold pressure to a similar extent in 36-week-old SHR, regardless of whether treatment was started early or late, clearly indicate that there are no remarkable differences in the effects on the downward resetting among these four antihypertensive agents. On the other hand, the decrease in saturation pressure in response to the lowering of blood pressure was larger in the early start of long-term (26-week) nicardipine- or enalapril-treated SHR than that in SHR treated with the other two agents. In addition, no significant differences in the decrease in saturation pressure among the four agents were found during late-start 8-week treatment.39 These findings indicate that baroreceptor sensitivity is improved with the early start of nicardipine and enalapril treatment, without normalization of arterial pressure. Accordingly, the results of baroreceptor threshold pressure and saturation pressure provide evidence that each agent exerts a different effect on resetting and sensitivity. This notion is in good agreement with our previous study.2 Again, we emphasize the notion that while downward resetting, evaluated as a decrease in BP50, could correlate with a reduction in arterial pressure, reflex sensitivity could be partly modulated by some specific actions of nicardipine and enalapril in addition to the reduction in arterial pressure. We therefore suggest that early-start treatment with nicardipine or enalapril could modify baroreceptor sensitivity, probably via actions on vascular components—ie, cardiovascular tissue remodeling or inhibition of the vascular renin-angiotensin system,3 9 40 vessel distensibility, and/or mechanical coupling of the baroreceptors to the vessel41 42 43 44 —rather than on the baroreceptors themselves. However, it is hard to decide whether there is a more significant difference in the effectiveness of the two types of treatment. Further study would be required to determine the mechanism by which calcium channel antagonists and angiotensin-converting enzyme inhibitors could exert beneficial actions on the vascular components, although the relative roles of the timing of the start of treatment versus treatment duration could not be ruled out completely.
In conclusion, the present study demonstrated that in SHR the start of antihypertensive therapy from the early hypertensive stage markedly improved RSNA gain, HR gain, and the range of reflex sympathetic excitation, whereas a late start of treatment did not. In particular, it was suggested that the early start of the four agents investigated could have exerted little or no adverse effects on RSNA, whereas the late start of the four agents could have activated RSNA. Accordingly, with regard to baroreceptor reflex function, the present study supports the hypothesis that a possible critical phase sensitive to intervention with antihypertensive treatment exists during the development of hypertension and indicates that early-start antihypertensive treatment would be required in clinical practice.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by a grant-in-aid (No. 05770480) from the Ministry of Education, Science, and Culture in Japan.
Received March 6, 1995; first decision May 19, 1995; accepted October 3, 1995.
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