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Introduction
Blood pressure (BP) is not constant and a spontaneous variation exists. This variation is defined as blood pressure
variability (BPV). The arterial baroreflex acts as an effective buffer of
short-term BP fluctuations and prevents excessive BP
swings[1]. The baroreflex arc may be interrupted by sinoaortic denervation (SAD) or complete lesion of the nucleus tractus
solitarus[2,3]. In these animals with baroreflex dysfunction, BPV is dramatically
high[4]. Recently, SAD animals have been
used as a high-BPV model for studying the physiology, pathology and pharmacology related to BPV.
It is reported that BPV is positively related to the severity of organ damage in hypertensive
patients[5,6]. In animal studies, we confirmed that BPV was related to the severity of
organ damage in spontaneously hypertensive rats
(SHR)[4,7]. Furthermore, a positive relationship was also reported to exist in SAD
rats[4,7]. This means that BPV alone without hypertension could
induce organ damage as the average BP level is normal in SAD rats. Recently, we found that the importance of BPV for
determining the organ damage was even greater than the BP
level[8,9]. Obviously, an antihypertensive drug with a
BP-stabilizing effect would benefit the hypertensives. Therefore, it is reasonable to take decreasing BPV into account in the
treatment of hypertension and it is proposed that BPV reduction may be a new strategy for the treatment of
hypertension[8]. Indeed, it has been found that BPV reduction has an important contribution to organ protection in the long-term treatment
of nitrendipine or ketanserin in
SHR[10,11].
Clinically, it will be important to know which antihypertensive drugs possess an effect on BPV reduction among more
than 50 agents available. Therefore, the present work was designed to observe the effects of some representative
antihypertensive drugs on BPV in SAD rats. Nine drugs were selected and included in this study: nifedipine, nitrendipine, amlodipine
(calcium antagonists), clonidine (centrally acting agent), prazosin
(a1 adrenoceptor blocker), atenolol
(b1 adrenoceptor blocker), telmisartan
(AT1 receptor blocker), captopril (angiotensin I converting enzyme inhibitor) and hydrochlorothiazide
(diuretic).
Materials and methods
Animals and drugs Male Sprague-Dawley rats were provided by Sino-British SIPPR/BK Lab Animals (Shanghai, China).
They were housed in controlled temperatures (22_25 ºC) and lighting (08:00 to 20:00 light; 20:00 to 08:00 dark), with free
access to tap water and rat chow. All procedures were in accordance with institutional animal care guidelines.
Nifedipine, hydrochlorothiazide, prazosin, clonidine, telmisartan and captopril were purchased from Sigma Chemical Co
(St Louis, MO, USA). Amlodipine was provided by Nanjing Pharmaceutical Co (Nanjing, China). Nitrendipine and atenolol
were provided by Shanghai Second Pharmaceutical Co (Shanghai, China). Nifedipine, nitrendipine, telmisartan and
hydrochlorothiazide were dissolved in the
0.5% carboxymethylcellulose sodium (CMC). Amlodipine, captopril, atenolol and clonidine were dissolved in distilled water.
Prazosin was suspended in polyethylene glycol (PEG) and diluted with distilled water for a final concentration of
0.2 mg/mL (PEG, 0.5%)[12]. The doses used were as
follows: nifedipine 3 mg/kg, nitrendipine 5 mg/kg, amlodipine 1 mg/kg,
clonidine 10 µg/kg, prazosin 0.5 mg/kg, atenolol 20 mg/kg, telmisartan 20 mg/kg, hydrochlorothiazide 40 mg/kg and captopril
50 mg/kg. Drugs were administered by intra-
gastric catheter implanted 3 days before the experiment.
Sinoaortic denervation At the age of 10_11 weeks, sinoaortic denervation was performed in Sprague-Dawley
rats according to the method described in a previous
study[13]. Rats were anesthetized with a mixture of ketamine (50 mg/kg) and
diazepam (5 mg/kg), intraperitoneally. Atropine sulfate (0.5 mg/kg) was then administered intraperitoneally. Each animal was
fixed in a supine position and a 2.5 cm midline incision was made in the neck. After bilateral isolation of the neck muscles,
aortic baroreceptor denervation was carried out bilaterally by cutting the superior laryngeal nerves near the vagi, removing
the sympathetic trunk, and sectioning aortic depressor nerves. The carotid sinus baroreceptors were denervated bilaterally
by stripping the carotid bifurcation and its branches, followed by the application of 10% phenol in 95% ethanol solution to
the external, internal, and common carotid arteries and the occipital artery. The incision was sutured closed and each rat was
injected intramuscularly with 60000 units of penicillin G.
Blood pressure measurement Four weeks after sinoaortic denervation, rats were anesthetized as mentioned. A
polyethylene catheter (PE-10 connected to PE-50) was chronically inserted into the lower abdominal aorta via the left femoral artery
for the measurements of BP and heart period (HP), and another catheter (PE-50) was inserted into the left femoral vein for the
examination of baroreflex function. The third catheter (PE-50) was inserted into the stomach for drug administration. These
catheters were tunneled subcuta-neously, exteriorized between the scapulae, and fixed on saddle. After 2 days of recovery,
BP was continuously recorded in conscious unrestrained rats with a computerized
technique (MPA 2000M, Alcott Biotech, Shanghai,
China)[13,14]. The BP signals, transmitted to the electric signals by a transducer, were digitized and processed on a
personal computer, which calculated online the BP and HP beat by beat. The average value was used as an index of BP, and
the standard deviation (SD) of beat-to-beat BP values as an index of BPV including systolic (SBPV) and diastolic BPV
(DBPV)[14]. The same method was used for the calculation of HP. In SAD rats, arterial baroreflex function for heart-rate
control was also assessed by intravenous injection of phenylephrine, 2 to 5 µg/kg. If SAD rats exhibit a bradycardia of less
than 20 beats/min, they were considered as successful baroreceptor denervation and included in the
study[13,14].
Protocol After approximately 4-h habituation to BP recording environment, the BP signal was recorded for half an hour
as the basal (pre-drug) value. The drug was then administered via the catheter of gastric fistula. One and a half hours after
administration of nifedipine, nitrendipine, clonidine, atenolol, hydrochlorothiazide and captopril, 2.5 h after administration of
prazosin and 3.5 h after administration of amlodipine and telmisartan, the BP signal was recorded for half an hour as
post-drug value.
Statistical analysis Data were expressed as mean±SEM. Comparisons between values obtained in the same group
before and after drug administration were made using the paired
t - test. P<0.05 was considered statistically significant.
Results
Effects of nine antihypertensive drugs on BP in SAD
rats The effects of nine antihypertensive drugs on BP in conscious
SAD rats are presented in Figure 1. It was found that SBP was significantly decreased after the administration of all of these
nine drugs. This decrease in SBP was approximately 20 mmHg (19_25 mmHg) for nifedipine, nitrendipine, amlodipine,
clonidine, prazosin, atenolol, and telmisartan; and was approximately 16 mmHg for hydrochlorothiazide and captopril. DBP
was also found to be significantly reduced by these nine drugs in SAD rats.
Effects of nine antihypertensive drugs on BPV in SAD
rats The effects of nine antihypertensive drugs on SBPV in SAD
rats are shown in Figure 2. It was found that nifedipine, nitrendipine, amlodipine, clonidine, prazosin and atenolol all
significantly decreased SBPV. Nifedipine decreased SBPV from 11.0±1.2 mmHg to 9.1±0.9 mmHg. Nitrendipine decreased
SBPV from 9.7±0.6 mmHg to 7.7±0.6 mmHg. Amlodi-pine decreased SBPV from 11.8±2.2 mmHg to 10.0±1.8 mmHg. Clonidine
decreased SBPV from 11.8±1.4 mmHg to 8.2±0.8 mmHg. Prazosin decreased SBPV from 12.4±1.4 mmHg to
8.9±0.6 mmHg. Atenolol decreased SBPV from 13.1±1.8 mmHg to 9.5±1.0 mmHg. Although telmisartan, hydrochlorothiazide
and captopril significantly decreased SBP to a similar extent with nifedipine and other drugs as shown in Figure 1, the values
of SBPV were unchanged (Figure 2).
Effects of nine antihypertensive drugs on DBPV in SAD
rats Figure 3 shows the results of 9 antihypertensive drugs on
DBPV in SAD rats. It was found that nifedipine, nitrendi-pine, amlodipine, clonidine, prazosin and atenolol all significantly
decreased DBPV, similar to SBPV. DBPV was decreased from 9.7±1.1 mmHg to 7.6±0.8 mmHg for nifedipine. DBPV was
decreased from 7.6±0.5 mmHg to 6.2±0.5 mmHg for nitrendipine. DBPV was decreased from 9.3±1.8 mmHg to 8.1±1.6 mmHg
for amlodipine. DBPV was decreased from
9.4±1.2 mmHg to 6.5±0.7 mmHg for clonidine. DBPV was decreased from 8.1±0.8 mmHg to 6.6±0.6 mmHg for prazosin. DBPV
was decreased from 12.8±2.0 mmHg to 10.1±1.2 mmHg for atenolol. Although telmisartan, hydrochlorothiazide and captopril
significantly decreased DBP to a similar extent with nifedipine and other drugs as shown in Figure 1, the values of DBPV were
unchanged (Figure 3).
Effects of nine antihypertensive drugs on HP and HPV after sinoaortic
denervation Among these nine antihypertensive
drugs, only clonidine and atenolol prolonged HP in SAD rats. There were no significant changes in HPV for any drugs
studied in SAD rats (Figure 4).
Discussion
During the past four decades, several classes of antihypertensive agents-calcium channel blockers, centrally acting
antihypertensive agents, a1-adrenoceptor antagonist,
b-blockers, AT1 receptor blockers, diuretics and
angiotensin-converting enzyme inhibitors have been shown to effectively reduce elevated blood pressure and associated cardiovascular
events[15_18]. The present work for the first time systematically studied and clearly demonstrated the effects of these representative
drugs on reducing BP and BPV in SAD rats. The main finding of the present work may be summarized as follows: (1) calcium
antagonists (nifedipine, nitrendipineand amlodipine) significantly decreased BPV in SAD rats; (2) antihypertensive drugs
inhibiting sympathetic nervous system (clonidine, prazosin and atenolol) significantly decreased BPV in SAD rats; (3) other
antihypertensive drugs, such as telmisartan, hydrochlorothiazide and captopril, did not significantly influence BPV in SAD
rats.
Dihydropyridine calcium antagonists are the most widely used antihypertensive drugs. According to their action
duration, they are divided into three subclasses. Nifedipine, nitrendipine and amlodipine are the representative drugs for the
short-, medium- and long- lasting drugs, respectively. In the present work, it was found that all three drugs significantly
decreased BPV in SAD rats. This means that the effects of calcium antagonists on BPV does not relate to the action duration
but relate to the intrinsic property of calcium antagonism. Generally speaking, the stability of BP is maintained by arterial
baroreflex in physiological conditions. Hemodynamic studies in conscious rats with neonatal chemical sympathectomy,
SAD, and acute neurohumoral blockade have revealed that one major source of hemodynamic
perturbations is the myogenic
©2006 CPS and SIMM response of vascular smooth muscle
cells[19_21]. Therefore, it is not surprising that all three calcium antagonists used
decreased BPV in SAD rats by preventing this myogenic
response[19].
Antihypertensive drugs inhibiting the sympathetic nervous system used in the present work were prazosin, atenolol and
clonidine. All of these three drugs significantly decreased BPV in SAD rats. These results suggest that activation of the
sympathetic nervous system is involved in the increased BPV after SAD. As prazosin and atenolol represent
a- and b-receptor antagonists, respectively, it seems that both
a- and b-receptors are involved in the SAD-induced high BPV. It is well
known that arterial baroreflex modulates sympathetic and parasympathetic nervous systems and keeps the balance between
these two autonomic nervous systems. The loss of this balance after SAD operation is often characterized by an
over-activation of sympathetic nervous systems and a deactivation of parasympathetic nervous systems probably contributing to
the eleva
tion of BPV.
The present work also revealed that captopril and telmisartan did not influence BPV in SAD rats. This means that the
activation of the renin-angiotensin system is not important in the
maintenance of high BPV induced by SAD in rats. In
addition, hydrochlorothiazide did not modify BPV in SAD rats. This suggests that elevated BPV may mainly be due
to the variation of peripheric resistance and not to the variation of blood volume.
These results may be helpful in the selection of antihypertensive drugs. For a hypertensive patient with high BPV, a
calcium antagonist, a drug inhibiting sympathetic nervous system, or the combination of two drugs from these classes
would be proposed. However, it should be noted that the mechanisms for increased BPV in SAD rats and in hypertensive
patients or rats may be different. In SAD rats, the increased BPV is induced purely by the loss of baroreflex control, while the
mechanism for increased BPV seen in hypertension is more complicated.
We conclude that calcium antagonists and drugs inhibiting the sympathetic nervous system significantly decreased BPV
in SAD rats. This suggests the involvement of the myogenic response of vascular smooth
muscle cells and activation of sympathetic nervous system in SAD-induced high BPV.
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