Just Started Amlodipine and Blood Pressure Increasing Again
J Prison cell Mol Med. 2009 April; 13(4): 726–734.
The combination of atenolol and amlodipine is better than their monotherapy for preventing end-organ harm in different types of hypertension in rats
Ping Han
aDepartment of Pharmacology, Second Military Medical Academy, Shanghai, Cathay
Fu-Ming Shen
aDepartment of Pharmacology, Second Armed forces Medical University, Shanghai, People's republic of china
He-Hui Xie
aDepartment of Pharmacology, Second Military Medical University, Shanghai, Prc
Yuan-Yuan Chen
aSection of Pharmacology, 2nd Armed services Medical University, Shanghai, Red china
Chao-Yu Miao
aDepartment of Pharmacology, Second Military Medical University, Shanghai, China
Jawahar L Mehta
bDepartment of Cardiovascular Medicine, University of Arkansas for Medical Sciences, Lilliputian Rock, AR, Usa
Jean Sassard
cDepartment of Physiology and Clinical Pharmacology, Faculty of Pharmacy, University Lyon-one, Lyon, France
Ding-Feng Su
aDepartment of Pharmacology, Second War machine Medical University, Shanghai, People's republic of china
Received 2008 Feb 20; Accepted 2008 Apr 18.
Abstruse
Combinations therapy is often used in hypertensive patients whether combination therapy is necessary for preventing end-organ damage is non known. The objective of this study was to make up one's mind in four dissimilar hypertensive animal models the necessity of adding the calcium channel blocker amlodipine to therapy with the ß-blocker atenolol to modulate end-organ impairment. Spontaneously hypertensive rats, DOCA-salt hypertensive rats, two-kidney, ane-clip renovascular hypertensive rats and Lyon genetically hypertensive rats were used to study this objective. These brute models have dissimilar sensitivities to atenolol and amlodipine. The dosages of therapy employed were x mg/kg atenolol alone, ane mg/kg amlodipine, 10 mg atenolol + ane mg/kg amlodipine and 5 mg/kg atenolol+0.5 mg/kg amlodipine. BP was continuously recorded in all animals. After conclusion of baroreflex sensitivity, rats were sacrificed for end-organ harm evaluation. The combination of amlodipine and atenolol had a synergistic inhibitory effect on blood pressure level and blood pressure variability, and end-organ harm as compared with monotherapy with atenolol or amlodipine in all animate being models. Baroreflex sensitivity besides improved with the combination therapy more with monotherapy. In determination, atenolol and amlodipine combination exerts a superior issue on claret pressure, blood pressure variability, baroreflex sensitivity and end-organ damage. The superior effect of the combination was observed in all four models of hypertension.
Keywords: amlodipine, atenolol, combination therapy, hypertension, hypertensive rats
Introduction
Randomized controlled trials have shown that single drug handling usually is non adequate to achieve claret pressure level goal in most hypertensive patients [one]. Initiating therapy with more than ane agent offers the potential advantages of achieving blood force per unit area control more than speedily and avoiding dose-related adverse furnishings of individual drugs by producing greater blood pressure reduction at lower doses of the component agents [2].
The sensitivity to an anti-hypertensive drug varies among hypertensive patients. For example, young people or those with high plas-ma renin activity are sensitive to ß-blockers, angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor blockers, while elderly or those with low plasma renin activity are sensitive to diuretics or calcium channel blockers [iii, four]. It is non clear if it is necessary to add a calcium channel blockers to patients with high plasma renin activity and treated with ß-blockers. Similarly, it is not articulate if addition of p-blockers confers advantage to monotherapy with a calcium aqueduct blocker. We hypothesized that a combination therapy would exist superior to therapy with either a β-blocker or a calcium channel blocker in well-nigh types of hypertension in terms of blood pressure reduction and prevention of end-organ damage. Therefore, the present work was designed to test this hypothesis in rats.
Atenolol and amlodipine, the representative drugs for ß-blockers and calcium channel blockers, respectively, were used equally anti-hypertensive drugs in this study. Spontaneously hypertensive rats (SHR), deoxycorticosterone acetate (DOCA)-induced hypertensive rats, ii-kidney, one-clip renovascular hypertensive rats (2K1C) and Lyon hypertensive rats (LH) were used as models for 4 different types of hypertension. SHR and LH are genetically hypertensive rats [5] and 2K1C and DOCA are models of experimentally induced hypertension. The 2K1C and SHR are models of angiotensin-dependent hypertension [vi, 7] while LH and DOCA are models of low-renin hypertension [eight].
Methods
Animals and chemicals
Amlodipine was provided past Beijing Shuanghe Pharmaceutical Co. Ltd. (Beijing, Red china) and atenolol past Shanghai Sanwei Pharmaceutical Co. Ltd. (Shanghai, China). DOCA was purchased from Sigma (St. Louis, MO, USA). Male person Spargue-Dawley rats (used for preparation of hypertensive models) were purchased from the Sino-British SIPPR/BK Lab Animal Ltd. (Shanghai, Communist china). Male SHR and LH rats with 16 weeks were provided by the animal eye of our university. The animals were housed with controlled temperature (23–25°C) and lighting (08:00–twenty:00 hrs light, 20:00–08:00 hrs dark) and with complimentary access to food and tap water. All the animals used in this work received humane intendance in compliance with institutional beast intendance guidelines.
Grooming of 2K1C hypertensive rats
Male person Sprague-Dawley rats weighing 180–200 yard were anaesthetized with a combination of ketamine (xl mg/kg) and diazepam (6 mg/kg). The right renal artery of each beast was isolated through a flank incision, every bit described previously [nine], and a silvery prune (0.ii-mm internal gap) was placed on the right renal artery. All animals were fed standard rat chow and tap water advert libitum. On twenty-four hours 21 later operation, blood pressures were measured by tail-gage plethysmography and the rats with systolic blood pressure >150 mmHg were used for this written report. V weeks subsequently placement of the clip, these rats received the handling with different drugs.
Preparation of DOCA hypertensive rats
DOCA hypertensive rats were prepared as previously described [10]. Male Sprague- Dawley rats weighing 110–130 k were anaesthetized with a combination of ketamine (twoscore mg/kg) and diazepam (vi mg/kg) and underwent a right nephrectomy viaa flank incision. Rats were given daily subcutaneous injections of DOCA (fifty mg/kg) and 0.nine% saline to drink for 5 weeks. Systolic blood force per unit area was measured by tail-cuff plethysmography before the anti-hypertensive drug administration and the rats with Systolic claret pressure >150 mmHg were used for this study.
Intra-arterial blood force per unit area measurements
Systolic claret pressure level, diastolic blood pressure and center period were continuously recorded using previously described technique [eleven]. Briefly, rats were anaesthetized past a combination of ketamine (40 mg/kg) and diazepam (6 mg/kg). A floating polyethylene catheter was inserted into the lower intestinal aorta viathe left femoral artery for blood pressure level measurement and some other catheter was inserted into left femoral vein for phenylephrine injection. The catheters were exteriorized through the inter-scapular skin. After a two-24-hour interval recovery menstruation, the animals were placed in private cages containing food and water. The aortic catheter was connected to a blood pressure transducer viaa rotating swivel that allowed the animals to move freely in the cage. Later about 4-hrs habituation, the blood pressure point was digitized by a microcomputer. Systolic blood pressure, diastolic blood pressure and middle menses values from every heartbeat were determined on line. The hateful values of these parameters during a period of 4 hrs for each rat were calculated. The standard deviation of the mean was calculated and defined as the quantitative parameter of variability; that is systolic blood pressure level variability, diastolic blood pressure level variability and heart menstruation variability.
Conclusion of baroreflex sensitivity
Later a 4-hrs claret pressure recording, baroreflex sensitivity was measured in the conscious rat by using our previously described method [12]. A bolus of phenylephrine was injected to induce a blood force per unit area elevation. The dose of phenylephrine (5–x mg/kg) was adjusted to heighten systolic blood pressure in the range of xx–40 mmHg. At that place exists a filibuster (about 1 sec.) between the elevation of blood pressure (stimulus) and the prolongation of HP (response) for arterial baroreflex. In rats, the eye catamenia is about v or 6/sec. So, centre menstruation was plotted confronting systolic blood pressure for linear regression analysis for ii–8 shifts (calculated by computer); the slope with the best close correlation coefficient of heart period/systolic blood pressure level was expressed equally baroreflex sensitivity (ms/mmHg). The mean of 2 measurements with proper dose served as the concluding result.
Morphological examination
The animals were weighted and euthanized with intraperitoneal sodium pentobarbital. The thoracic and peritoneal cavities were immediately opened. The right kidney, aorta and center were excised and rinsed in common cold physiological saline. The right kidney and the heart were gently blotted for gross detection, including kidney weight, renal cortical thickness, renal medullary thickness, eye weight, left ventricular weight and left ventricular wall thickness. At the same time, the aorta was cleaned of adhering fat and connective tissue. Simply below the branch of the left subclavicular artery, a 30-mm-long segment of thoracic aorta was harvested, blotted and weighted. Ratio of left ventricular weight to body weight (LVW/BW), left ventricular thickness (LVT), aortic weight to the length of aorta (AW/length) and right cortical thickness to correct medullar thickness (RCT/RMT) were calculated.
For semi-quantitative evaluation of glomerular damage, the glomerular sclerosis score (GSS) of the right kidney was adamant according to the previously published criteria [13]. Approximately fifty glomeruli from the outer cortex and the same number of glomeruli from the inner cortex for each kidney were graded based on the caste of sclerosis; form 0, if no mesangial expansion; grade 1, if mild mesangial expansion (less than 30% of a glomerular surface area); course 2, if moderate mesangial expansion (30–lx% of a glomerular area); grade three, if marked mesangial expansion (more than 60% of a glomerular expanse); and grade 4, if the sclerosis was global. A composite sclerosis score was then calculated for each kidney co-ordinate to the post-obit formula: GSS =[ane ten(number of grade 1 glomeruli) + 2x(number of class 2 glomeruli) + 3x(number of grade 3 glomeruli) + 4x(number of grade four glomeruli)]x100/(number of glomeruli observed).
Experimental protocols
At least l rats in each hypertension model were randomly divided into 5 groups. Amlodipine and atenolol were mixed in the chow. The content of drugs in the rat chow was calculated according to consumption. The daily-ingested doses were as follows: atenolol (x mg/kg/day), amlodipine (one mg/kg/day), combinations of atenolol and amlodipine (5 + 0.5, and ten + 1 mg/kg/day). Subsequently xvi weeks of drug administration, systolic blood pressure level, diastolic claret pressure and HP were continuously recorded in the witting country for 4 hrs. Then, the claret pressure variability was calculated and the baroreflex sensitivity was adamant in conscious freely moving rats.
Probability sum test
To decide if the drugs were interim synergistically, we used the probability sum test (qtest) [14]. Compared with the mean values in the control group of rats, treated rats with a decrease in blood pressure >twenty mmHg were defined every bit responders and rats with a decrease in claret pressure 20 mmHg were defined every bit not-responders. For blood pressure variability, the criterion was 2 mmHg. The formula used is as follows: q=Pa+b/(Pa+Pb-Pa×Pb). Hither, A and B signal drug A and drug B; P is the per centum of responders in each group. Pa+b is the real percentage of responders and (Pa+Pb–Pa×Pb) is the expected response rate. (Pa+Pb) is the sum of the probabilities when drug A and drug B are used alone. Pa×-Pb is the probability of rats responding to both drugs when they were used lone. When q was <0.85, the combination was thought to be antagonistic, when q > 1.fifteen, the combination was thought to exist synergistic, and when q was between 0.85 and i.15, the combination was thought to be condiment.
Statistical analysis
Data are expressed as mean ± Due south.D. The differences amid groups were evaluated using assay of variance followed by a two-tailed Student's unpaired t-test. The human relationship between morphological and haemody-namic parameters was assessed by univariate regression analysis. The correlation coefficients and their 95% confidence intervals were calculated for haemodynamic and morphological data.
Results
Effects of combination therapy on claret pressure level and heart period in 4 types of hypertensive rats
After 4 months of treatment, atenolol therapy lone was found to significantly reduce systolic blood pressure in SHR and 2K1C rats and had less effects in LH and DOCA rats. Compared to atenolol, amlodipine therapy decreased systolic blood pressure more effectively in LH and DOCA rats, but less effectively in SHR and 2K1C rats. The combination of atenolol and amlodipine (ten + 1 mg/kg) produced the largest effect on blood pressure reduction in all iv types of hypertensive rats. Systolic blood pressure fell (P< 0.001) in SHR (−37 mmHg), DOCA (−25 mmHg), 2K1C (−42 mmHg) and LH (−30 mmHg). Even in rats treated with half-dose of the combination (atenolol + amlodipine = 5 + 0.five mg/kg), the decrease in systolic claret pressure was greater than with monotherapy with either atenolol or amlodipine in SHR, DOCA and LH and like to that induced by atenolol in 2K1C rats. The effects of combination therapy on diastolic claret pressure level were similar to those on systolic blood force per unit area. Finally, we observed that atenolol when used lonely increased eye flow in all four types of hypertensive rats. No meaning alter in center menstruation was found in rats treated with amlodipine or with combination therapy (Fig. i).
Effects of long-term handling with combination of amlodipine and atenolol on blood pressure (BP) and eye period (HP) in spontaneously hypertensive rats (SHR), Deoxycorticosterone Acetate-Salt rats (DOCA), 2-kidney, 1-clip rats (2K1C) and Lyon genetically hypertensive rats (LH). n= x, mean ± S.D. *P < 0.05, **P < 0.01, ***P < 0.001 versus command.
Effects of combination therapy on blood pressure variability and baroreflex sensitivity
As shown in Figure two, monotherapy had little consequence on systolic blood pressure variability. Atenolol significantly (P < 0.05) decreased systolic blood pressure variability in 2K1C rats and diastolic claret pressure level variability in SHR; amlodipine significantly (P< 0.05) decreased systolic blood force per unit area variability and dias-tolic blood pressure variability in LH. Both systolic blood pressure variability and diastolic blood force per unit area variability decreased significantly in all four types of hypertension models, with total dose combination therapy. The reduction in systolic blood pressure level variability was 33% in SHR (P < 0.001), 43% in DOCA (P< 0.001), 25% in 2K1C (P< 0.01) and 32% in LH (P< 0.01). One-half-dose combination therapy (0.5 + 5 mg/kg/d) as well significantly reduced systolic blood pressure level variability in SHR, DOCA and LH rats and diastolic claret pressure variability in SHR. No meaning changes in heart period variability was observed in whatsoever group of animals (Fig. 2), with the exception of LH rats treated with full dose of combination in which the heart period variability was significantly decreased (P< 0.05). In this report, baroreflex sensitivity fell in all animals groups, particularly in SHR (0.204 ms/mmHg) and 2K1C (0.281 ms/mmHg) groups of rats in the conscious state.
Effects of long-term treatment with combination of amlodipine and atenolol on blood force per unit area variability (BPV), heart period variability (HPV) and Baroreflex sensitivity (BRS) in SHR, DOCA, 2K1C and LH. n= x, mean ± S.D. See Figure 1 for abbreviations. *P < 0.05, **P < 0.01, ***P < 0.001 versus command.
Importantly, long-term handling with the combination improved baroreflex sensitivity significantly in all iv types of hypertensive rats (Fig. two).
Effects of combination therapy on organ damage in four types of hypertensive rats
Some representative parameters of end-organ damage are shown in Figure iii. The parameters shown are LVW/BW (reflecting left ventricular hypertrophy), AW/length (reflecting aortic hypertrophy) and RCT/RMT and GSS (reflecting glomerular damage). We observed that atenolol alone reduced left ventricular hypertrophy, aortic hypertrophy and glomerular damage in SHR and 2K1C rats.
Effects of long-term treatment with atenolol, amlodipine lone and in combination on pathological changes in ventricles, kidneys and aorta in SHR, DOCA, 2K1C and LH. north= 10, mean ± S.D. Run across Tabular array 2 and Figure 1 for abbreviations. *P < 0.05, **P < 0.01, ***P < 0.001 versus control.
Amlodipine solitary reduced aortic hypertrophy and glomerular damage in SHR and DOCA rats. When animals were treated with full dose combination, all iv parameters of end-organ impairment were markedly less (P< 0.01 or P< 0.001 versus monotherapy) in all 4 types of hypertension models. Most of the end-organ damage parameters were less pronounced when half dose of the combination was used (Fig. 3).
Synergism between amlodipine and atenolol
Table 1 shows the results of the probability sum examination for haemo-dynamic data from SHR, DOCA, 2K1C and LH treated with amlodipine (i mg/kg/d), atenolol (10 mg/kg/d) and a combination of these two agents (one + 10 mg/kg/d). All q values were larger than 1.15, implying that the combination of amlodipine and atenolol exerted a significant synergistic outcome on claret pressure and blood pressure variability reduction and baroreflex sensitivity enhancement in SHR, DOCA, 2K1C and LH. Table 2 shows the results of the probability sum test for cease-organ damage data in all four hypertension models. All qvalues were larger than 1.15, once again implying that the combination of amlodipine and atenolol exerted a synergism protective consequence confronting end-organ damage in all 4 hypertension models.
one
The effect of probability sum exam on haemodynamics in 4 hypertensive rat models treated with long-term atenolol and amlodipine
| Drug (mg/kg/d) | SHR | DOCA | 2K1C | LH | ||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| SBP | Ate (x) | PAte | 4/x | 2/10 | four/x | 1/10 | ||||||||||||||||||||
| Aml (1) | PAml | 3/x | 3/x | ii/ten | 3/x | |||||||||||||||||||||
| Rummage (10 + 1) | PAte+Aml | 8/ten | eight/ten | 8/10 | 6/10 | |||||||||||||||||||||
| q | one.38 | 1.81 | 1.54 | 1.62 | ||||||||||||||||||||||
| DBP | Ate (10) | PAte | 2/10 | ane/x | 3/10 | two/ten | ||||||||||||||||||||
| Aml (1) | PAml | 3/x | 3/10 | 2/x | 2/10 | |||||||||||||||||||||
| Comb (10 + one) | PAte+Aml | seven/ten | 6/10 | 6/10 | v/10 | |||||||||||||||||||||
| q | 1.59 | 1.62 | one.36 | 1.39 | ||||||||||||||||||||||
| SBPV | Ate (x) | PAte | 3/10 | 3/10 | iii/10 | ii/x | ||||||||||||||||||||
| Aml (ane) | PAml | 3/10 | iii/10 | ii/ten | 2/10 | |||||||||||||||||||||
| Rummage (10 + i) | PAte+Aml | 9/10 | vii/10 | 7/x | 6/10 | |||||||||||||||||||||
| q | 1.76 | 1.37 | 1.59 | 1.67 | ||||||||||||||||||||||
| DBPV | Ate (10) | PAte | 2/ten | 2/10 | 2/10 | 2/10 | ||||||||||||||||||||
| Aml (1) | PAml | 2/10 | three/x | 2/10 | 4/10 | |||||||||||||||||||||
| Rummage (10 + 1) | PAte+Aml | vi/ten | 6/ten | 5/10 | viii/ten | |||||||||||||||||||||
| q | 1.67 | one.36 | i.38 | 1.54 | ||||||||||||||||||||||
| BRS | Ate (10) | PAte | 2/10 | 2/ten | iii/10 | 1/x | ||||||||||||||||||||
| Aml (ane) | PAml | 3/10 | 3/x | 0 | 2/x | |||||||||||||||||||||
| Rummage (x + 1) | PAte+Aml | seven/10 | vi/10 | six/10 | 4/10 | |||||||||||||||||||||
| q | one.25 | 1.36 | ii | 1.43 | ||||||||||||||||||||||
2
The event of probability sum exam on pathological changes in four different hypertensive rat models treated with long-term atenolol and amlodipine
| Drug (mg/kg/d) | P or q | SHR | DOCA | 2K1C | LH | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| VW/BW | Ate (10) | PAte | 3/10 | 0 | five/10 | ii/x | ||||||||||||||||||||
| Aml (1) | PAml | 1/x | 3/ten | 2/x | 3/x | |||||||||||||||||||||
| Rummage (10 + ane) | PAte+Aml | half dozen/10 | 5/x | ix/10 | 7/10 | |||||||||||||||||||||
| q | ane.62 | 1.67 | 1.five | i.59 | ||||||||||||||||||||||
| W/length | Ate (10) | PAte | 4/10 | 1/x | four/10 | 0 | ||||||||||||||||||||
| Aml (1) | PAml | two/10 | 4/10 | three/ten | three/ten | |||||||||||||||||||||
| Rummage (ten + 1) | PAte+Aml | 8/10 | 7/10 | viii/10 | v/ten | |||||||||||||||||||||
| q | i.54 | 1.52 | 1.38 | ane.67 | ||||||||||||||||||||||
| RCT/RMT | Ate (10) | PAte | 2/ten | 3/x | v/10 | 2/ten | ||||||||||||||||||||
| Aml (1) | PAml | one/x | 3/10 | ii/x | 2/ten | |||||||||||||||||||||
| Rummage (x + 1) | PAte+Aml | 5/x | 8/10 | ix/x | half-dozen/10 | |||||||||||||||||||||
| q | i.79 | 1.57 | 1.5 | 1.67 | ||||||||||||||||||||||
| GSS | Ate (10) | PAte | 2/x | 0 | 3/10 | i/ten | ||||||||||||||||||||
| Aml (i) | PAml | 3/10 | 3/x | ane/10 | 2/10 | |||||||||||||||||||||
| Rummage (10 + 1) | PAte+Aml | 8/10 | six/10 | eight/10 | v/ten | |||||||||||||||||||||
| q | ane.82 | 2.0 | 2.16 | i.79 | ||||||||||||||||||||||
Relationships betwixt blood pressure level, blood force per unit area variability, baroreflex sensitivity and end-organ harm
The relative dependence of end-organ impairment on haemodynamic improvement was assessed by linear regression analysis (Table three).
3
Linear regression coefficient (r) between BP, BPV, BRS values and organ damages in treated and untreated four different hypertensive rat models (northward= 50)
| SHR | LVW/BW | AW/length | RCT/RMT | GSS |
|---|---|---|---|---|
| SBP | 0.621* * | 0.536* * | −0.601* * | 0.677* * |
| DBP | 0.514* * | 0.477* * | −0.422* * | 0.399* |
| SBPV | 0.503* | 0.671* * | −0.401* | 0.439* |
| DBPV | 0.375* | 0.451* | −0.269 | 0.286 |
| BRS | −0.546* * | −0.483* * | 0.467* | −0.413* |
| DOCA | ||||
| LVW/BW | AW/length | RCT/RMT | GSS | |
| SBP | 0.532* * | 0.504* * | −0.647* * | 0.521* * |
| DBP | 0.423* * | 0.379* | −0.467* * | 0.367* |
| SBPV | 0.511* * | 0.595* * | −0.421* | 0.368* |
| DBPV | 0.342* | 0.497* * | −0.306* | 0.272 |
| BRS | −0.583* * | −0.574* * | 0.592* * | −0.477* |
| 2K1C | ||||
| LVW/BW | AW/length | RCT/RMT | GSS | |
| SBP | 0.645* * | 0.547* * | −0.572* * | 0.702* * |
| DBP | 0.425* | 0.377* | −0.423* * | 0.543* * |
| SBPV | 0.589* * | 0.544* * | −0.462* * | 0.518* * |
| DBPV | 0.379* | 0.476* * | −0.331* | 0.432* |
| BRS | −0.523* * | −0.422* | 0.425* | −0.574* * |
| LH | ||||
| LVW/BW | AW/length | RCT/RMT | GSS | |
| SBP | 0.557* * | 0.513* * | −0.572* * | 0.543* * |
| DBP | 0.312* | 0.378* | −0.413* | 0.376* |
| SBPV | 0.549* * | 0.417* * | −0.532* * | 0.499* * |
| DBPV | 0.287 | 0.354 | −0.402* | 0.231 |
| BRS | −0.502* * | −0.544* * | 0.485* | −0.532* * |
In all iv different hypertension models, end-organ impairment correlated systolic claret pressure, diastolic blood pressure level and systolic blood pressure variability and lower baroreflex sensitivity. The function of diastolic blood force per unit area variability in determination of terminate-organ damage parameters seemed less important than that of systolic claret pressure variability.
Give-and-take
The chief findings of the nowadays work are that: (ane) in that location is a syn-ergistic interaction betwixt atenolol and amlodipine on blood pressure level reduction, blood pressure variability reduction, barore-flex sensitivity enhancement and protection of terminate-organs. Even half-dose of the combination produces a greater effect than either single drug; (2) the synergism interaction between atenolol and amlodipine is seen in all four types of hypertension models.
A number of medications are available for the treatment of hypertension, and all tin can reduce blood force per unit area to normal or near-normal level [xv, 16]. The present work showed that the combination of two commonly used drugs atenolol and amlodipine produced issue on blood pressure that was superior to that of either amanuensis given alone. A major aim of anti-hypertensive therapy is to reduce cardiovascular events such as stroke, middle failure, renal failure and astute myocardial infarction that are often lethal. In this report, the synergistic interaction betwixt the 2 drugs extended to a reduction in end-organ damage. The parameters of end-organ damage in this work included those reflecting left ventricular hypertrophy, aortic hypertrophy and renal injury. Both aortic hypertrophy and left ventricular hypertrophy are the typical pathological changes following hypertension. Regression of hypertrophy has been a major goal of clinical trials and of hypertension research [17]. Left ventricular weight/torso weight (LVW/BW) and aortic weight/length (AW/Length) can reverberate distinguished left ventricular hypertrophy and aortic hypertrophy directly. Kidney is one of the most important target organs in hypertension. Glomerulosclerosis and tubulointer-stitial fibrosis lead to renal dysfunction. Right cortical thickness/right medullar thickness (RCT/RMT) and glomerulosclerosis score (GSS) reverberate the degree of glomerulosclerosis and tubuloint-erstitial fibrosis [eighteen]. In addition, blood pressure variability and baroreflex sensitivity were also studied and both were improved considerably by the combination therapy. There is increasing evidence showing that high blood pressure variability and depression baroreflex sensitivity contribute to terminate-organ damage in hypertension [19–26]. Interestingly, the present work clearly demonstrates a synergism between atenolol and amlodipine not only with regard to reduction in claret pressure, only also with regard to reduction in blood pressure level variability, enhancement of baroreflex sensitivity and protection against cease-organ damage.
The decision of synergistic interaction between drugs is not easy in exercise. Recently, the probability sum exam (q test) was successfully introduced to written report the phenomenon of synergism of two anti-hypertensive drugs [27]. Using this examination, we observed that the synergism between atenolol and amlodipine was highly meaning. It is to be noted that the minimal q value was 1.38 for the furnishings on AW/length in 2K1C rats; the synergism begins when q exceeds one.15. The probability sum test was calculated based on the results obtained from the treatment with total doses of the drugs. We also examined the effects of half-dose combination, and observed potentially salutary effects of half-dose combination. We institute that one-half-dose combination produced a greater effect than either single drug or a similar upshot to the 'sensitive' drug used alone. The latter finding likewise implies that it is not necessary to use large dose of an agent to which the animal is 'sensitive'. Among the synergistic interaction between different anti-hypertensive drugs, the synergism between atenolol and amlodipine seems to be nigh pronounced (unpublished data).
The rapid availability of SHR has made it possible not only to place numerous cardiovascular abnormalities in this model but also to evaluate their role in the pathogenesis of hypertension by ways of various interventions. It is well accepted that SHR is the best animal model for human essential hypertension. 2K1C model of hypertension shows high renin activity [28]. DOCA model of hypertension is associated with markedly depressed plasma renin action [29]. LH rats exhibit low renin; and it is possible that the enhanced renal sensitivity to angiotensin II plays a primary role in the pathogenesis of hypertension in this model [30]. Our study showed that compared with amlodipine, atenolol was more constructive in SHR and 2K1C rats, just less effective in LH and DOCA rats. Interestingly, a very significant synergism between atenolol and amlodipine was seen on all the parameters studied in all iv types of hypertension models. Theoretically, this combination volition be suitable for almost all hypertensive patients as information technology has a large coverage. The hypertensive patients with coronary avenue diseases and/or with over-activity of sympathetic nervous system may do good the well-nigh from this combination.
Individualization is another principle in the handling of hypertension; however, identifying the all-time agent may take fourth dimension. With combination therapy, it is obviously easier and quicker to control hypertension. Combination therapy may too lead to fewer side effects equally larger doses of a unmarried amanuensis are avoided. This stance is also supported by meta-analysis of data from randomized, controlled clinical trials that showed no pregnant difference in total major cardiovascular events between regimens based on major first-line anti-hypertensive medication used lonely versus combination therapy although there were some differences in cause-specific outcomes [1]. So, the selection of drug may be decided past tolerability rather than long-term safety or efficacy [31]. In our contempo unpublished data, nosotros have observed a synergism on blood pressure and blood force per unit area variability reduction and terminate-organ protection non just with the combination of atenolol and amlodip-ine, but also with the combination of atenolol and nitrendipine [32]; hydrochlorothiazide and enalapril; amlodipine and candesar-tan; and amlodipine and irbesartan. Amidst these combinations we studied, information technology was found that the synergism of the combination between atenolol and amlodipine was the largest.
In conclusion, we have demonstrated a synergistic interaction between atenolol and amlodipine with regard as not simply claret pressure reduction, but besides blood pressure variability reduction, baroreflex sensitivity enhancement and stop-organ protection. The synergism of atenolol and amlodipine was found in all models of hypertension.
Acknowledgments
This study was supported past grants from the National Natural Scientific discipline Foundation of China (30730106), the National How-do-you-do-Engineering science Research & Evolution Programme (project 863, 2006AA02Z4C1) and the Science and Applied science Evolution Foundation of Shanghai (07JC14065).
References
1. Franco Five, Oparil S, Carretero OA. Hypertensive therapy: Part Two. Circulation. 2004;109:3081–viii. [PubMed] [Google Scholar]
2. Chobanian AV, Bakris GL, Blackness 60 minutes, Cushman WC, Green LA, Izzo JL, Jr, Jones DW, Materson BJ, Oparil S, Wright JT, Jr, Roccella EJ. 7th written report of the Articulation National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC seven (Express) Report. JAMA. 2003;289:2560–72. [PubMed] [Google Scholar]
3. Cruickshank JM. New guidelines on hypertension. Lancet. 2006;368:641. [PubMed] [Google Scholar]
4. Staessen JA, Fagard R, Thijs L, Celis H, Arabidze GG, Birkenhager WH, Bulpitt CJ, De Leeuw Pow, Dollery CT, Fletcher AE, Forette F, Leonetti G, Nachev C, O'Brien ET, Rosenfeld J, Rodicio JL, Tuomilehto J, Zanchetti A. Randomised double-bullheaded comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet. 1997;350:757–64. [PubMed] [Google Scholar]
5. Zicha J, Kunes J. Ontogenetic aspects of hypertension development: analysis in the rat. Physiol Rev. 1999;79:227–82. [PubMed] [Google Scholar]
6. Goldblatt H, Lynch J, Hanzal RF, Summerville WW. Studies on experimental hypertension Part I: product of persistent elevation of systolic blood pressure level by means of renal ischemia. J Exp Med. 1934;59:347–9. [PMC free article] [PubMed] [Google Scholar]
7. Grollman A. A simplified process for inducing chronic renal hypertension in the mammal. Proc Soc Exp Biol Med. 1947;57:102–4. [Google Scholar]
8. Gavras H, Brunner Hr, Laragh JH, Vaughan ED, Jr, Koss M, Cote LJ, Gavras I. Cancerous hypertension resulting from deoxycorticosterone acetate and table salt backlog: role of renin and sodium in vascular changes. Circ Res. 1975;36:300–9. [PubMed] [Google Scholar]
9. Guan Southward, Fox J, Mitchell KD, Navar LG. Angiotensin and angiontensin-covering enzyme tissue level in two-kindney, one-clip hypertensive rats. Hypertension. 1992;20:763–7. [PubMed] [Google Scholar]
10. Hirata Y, Matsuoka H, Suzuki E, Hayakawa H, Sugimoto T, Matsuda Y, Morishita Y, Kangawa K, Minamino North, Matsuo H. Role of endogenous ANP in DOCA-salt hypertensive rats: effects of a novel not-peptide antagonist for ANP receptor. Circulation. 1993;87:554–61. [PubMed] [Google Scholar]
11. Norman RA, Jr, Coleman TG, Paring AC. Continuous monitoring of arterial pressure indicates sinoaortic denervated rats are non hypertensive. Hypertension. 1981;3:119–25. [PubMed] [Google Scholar]
12. Su DF, Chen L, Kong XB, Cheng Y. Determination of arterial baroreflexblood pressure command in conscious rats. Acta Pharmacol Sin. 2002;23:103–ix. [PubMed] [Google Scholar]
thirteen. Kimula Thousand, Tojo A, Matsuoka H, Sugimoto T. Renal arteriolar diameters in spontaneously hypertensive rats: vascular cast study. Hypertension. 1991;18:101–10. [PubMed] [Google Scholar]
14. Xu LP, Miao CY, Shen FM, Jiang YY, Su DF. Synergism of atenolo and amlodipine on lowering and stabilizing blood pressure in spontaneously hypertensive rats. Fundam Clin Pharmacol. 2004;18:33–8. [PubMed] [Google Scholar]
fifteen. Moser M, Setaro JF. Resistant or difficult-to-control hypertension. N Engl J Med. 2006;355:385–92. [PubMed] [Google Scholar]
16. Turnbull F. Effects of different claret force per unit area-lowering regimens on major cardiovascular events: results of prospectively designed overviews of randomized trials. Lancet. 2003;362:1527–35. [PubMed] [Google Scholar]
17. Eichhorn EJ, Bristow MR. Medical therapy can amend the biological properties of the chronically declining heart: a new era in the treatment of heart failure. Circulation. 1996;94:2285–96. [PubMed] [Google Scholar]
xviii. Garovic VD, Textor SC. Renovascular hypertension and ischemic nephropathy. Circulation. 2005;112:1362–74. [PubMed] [Google Scholar]
19. Su DF, Miao CY. Reduction of claret pressure variability: a new strategy for the treatment of hypertension. Trends Pharmacol Sci. 2005;26:388–90. [PubMed] [Google Scholar]
twenty. Miao CY, Xie HH, Zhan LS, Su DF. Blood force per unit area variability is more than of import than claret pressure level level in conclusion of end-organ damage in rats. J Hypertens. 2006;24:1125–35. [PubMed] [Google Scholar]
21. Gu XW, Xie HH, Wang J, Shen FM, Su DF. Arterial baroreflex is not involved in salt preference in rats. Clin Exp Pharmacol Physiol. 2006;33:607–11. [PubMed] [Google Scholar]
22. Parati G, Mancia One thousand. Blood pressure level variability every bit a risk factor. Blood Press Monit. 2001;6:341–seven. [PubMed] [Google Scholar]
23. Sander D, Kukla C, Klingelhofer J, Winbeck K, Gontrd B. Human relationship between circadian blood pressure level patterns and progression of early carotid atherosclerosis: a 3-year fallow-up study. Apportionment. 2000;102:1536–41. [PubMed] [Google Scholar]
24. Zhang C, Chen H, Xie HH, Shu H, Yuan WJ, Su DF. Inflammation is involved in the organ damages induced by sinoaortic denervation in rats. J Hypertens. 2003;21:2141–viii. [PubMed] [Google Scholar]
25. Shen FM, Zhang SH, Xie HH, Jing Q, Wang DS, Su DF. Early structural changes of aortic wall in sinoaortic-denervated rats. Clin Exp Pharmacol Physiol. 2006;33:358–63. [PubMed] [Google Scholar]
26. Kikuya M, Hozawa A, Ohokubo T, Tsuji I, Michimata M, Maysubara M, Ota One thousand, Nagai Chiliad, Araki T, Satoh T, Ito Due south, Hisamichi S, Imai Y. Prognostic significance of blood pressure and eye period variabilities: the Ohasama study. Hypertension. 2000;36:901–6. [PubMed] [Google Scholar]
27. Su DF, Xu LP, Miao CY, Xie HH, Shen FM, Jiang YY. 2 useful methods for evaluating antihypertensive drugs in witting freely moving rats. Acta Pharmacol Sin. 2004;25:148–51. [PubMed] [Google Scholar]
28. Phillips MI, Saavedra JM. Angiotensin II AT1A receptor antisense lowers claret pressure in astute 2-kidney, 1-clip hypertension. Hypertension. 2001;38:674–8. [PubMed] [Google Scholar]
29. Guyton AC. Long-term arterial pressure command: an assay from fauna experiments and computer and graphic models. Am J Physiol. 1990;259:865–77. [PubMed] [Google Scholar]
30. Aguilar F, Lo M, Claustrat B, Saez JM, Sassard J, Li JY. Hypersensitivity of the adrenal cortex to trophic and secretory effects of angiotensin II in Lyon genetically-hypertensive rats. Hypertension. 2004;43:87–93. [PubMed] [Google Scholar]
31. Chocolate-brown MJ, Palmer CR, Castaigne A, De Leeuw Pw, Mancia G, Rosenthal T, Ruilope LM. Morbidity and bloodshed in patients randomized to double-bullheaded treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention every bit a Goal in Hypertension Treatment (INSIGHT) Lancet. 2000;356:366–72. [PubMed] [Google Scholar]
32. Xie HH, Miao CY, Jiang YY, Su DF. Synergism of atenolol and nitrendipine on hemodynamic amelioration and organ protection in hypertensive rats. J Hypertens. 2005;23:193–201. [PubMed] [Google Scholar]
Manufactures from Journal of Cellular and Molecular Medicine are provided here courtesy of Blackwell Publishing
Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3822879/
0 Response to "Just Started Amlodipine and Blood Pressure Increasing Again"
Post a Comment