He-hui Xie

Blood pressure variability is more important than blood pressure level in determination of end-organ damage in rats.

Objective This study was designed to determine how important a novel risk factor of elevated blood pressure variability (BPV) is in the determination of end-organ damage by comparison with the classic risk factor of a high blood pressure (BP) level. Methods and results The effects of haemodynamics on cardiovascular morphology were evaluated by univariate and multivariate regression analysis in two different rat models with an enlarged distribution of haemodynamics. In male sham-operated and sinoaortic-denervated Wistar–Kyoto rats and spontaneously hypertensive rats (n = 34), BPV was more important than BP in cardiac and renal damage and aortic hypertrophy. BPV and BP had independent effects, explaining 59.4% of the variation in damage to these organs. In male (n = 44) and female (n = 46) F1 hybrids of Sprague–Dawley rats and spontaneously hypertensive rats, the greater importance of BPV than BP was further demonstrated in left ventricular hypertrophy, glomerular damage and aortic hypertrophy. The phenomenon was more evident in females than males for cardiovascular hypertrophy. BPV and BP or BPV alone had independent effects, explaining 46.9% (male) or 37.5% (female) of the variation in damage to these organs. Conclusion BPV is a more critical determinant than BP level for cardiac damage, renal lesions and aortic hypertrophy in rats, strongly suggesting the significance of BPV control for the protection of these organs.

Arterial Baroreflex Function Determines The Survival Time In Lipopolysaccharide-induced Shock In Rats

Lipopolysaccharide (LPS) mimics many of the effects of septic shock. LPS-induced death has been attributed to systemic hypotension, hyporeactiveness to vasoconstrictors, metabolic acidosis, and organ damage. However, there is no research directed to the involvement of the baroreflex sensitivity (BRS) in LPS-induced death. The purpose of this study was to evaluate the effect of BRS on the survival time after lethal LPS challenge. Four groups of rats were used. Each rat received an equivalent dose of intravenous LPS (50 mg/kg). It was found that the anesthetized sinoaortic-denervated (SAD) rats (representative of the lowest BRS, BRS = 0.022 ± 0.015 ms/mmHg) survived the shortest time (36 ± 11.1 min). The conscious SAD rats (BRS = 0.198 ± 0.035 ms/mmHg) and the anesthetized sham-operated rats (BRS = 0.304 ± 0.072 ms/mmHg) were alive a relatively long time (101 ± 11.5 min and 110 ± 12.4 min, respectively). The conscious sham-operated rats (BRS = 0.943 ± 0.097 ms/mmHg) survived the longest time (148 ± 6.5 min). These results demonstrated that arterial baroreflex function determined the survival time in the LPS-induced lethal shock.

Synergism of atenolol and nitrendipine on hemodynamic amelioration and organ protection in hypertensive rats

Objective This study was designed to investigate the possible synergism of atenolol and nitrendipine on blood pressure (BP) and blood pressure variability (BPV) reductions, baroreflex sensitivity (BRS) amelioration, and organ protection in hypertensive rats. Method The dose was 20 mg/kg for atenolol, 10 mg/kg for nitrendipine and 20 + 10 mg/kg for the combination of these two drugs. In an acute study, a single dose was given via a catheter previously inserted into the stomach in spontaneously hypertensive rats (SHR). In a subacute study, SHR, deoxycorticosterone acetate (DOCA)-salt rats, and two-kidney, one-clip (2K1C) rats were used. They received the same dose by gavage daily for 10 days. BP was measured 24 h after drug administration. In chronic studies, these drugs at the aforementioned dose were mixed into rat chow. SHR were treated for 4 months. BP was then continuously recorded for 24 h. After the determination of BRS, rats were killed for organ-damage evaluation. Results In the acute study, it was found that the combination of atenolol and nitrendipine had an obviously greater and longer BP reduction than treatment with each of these two drugs separately. In the subacute study, an effective decrease in BP 24 h after administration was found only in the rats treated with the combination. In chronic studies, it was found that the combination possessed the obvious synergism on BP and BPV reduction, BRS amelioration and organ protection in SHR. Multiple-regression analysis showed that the decrease in left ventricular hypertrophy was most significantly related to the decrease in systolic BPV and BP, the decrease in aortic hypertrophy was most significantly related to the increase in BRS and the decrease in systolic BPV, and amelioration in the renal lesion was most significantly associated with the restoration of BRS. Conclusion Treatment with a combination of atenolol and nitrendipine exhibited a rapid and persistent antihypertensive effect and possessed an obvious synergism on BP and BPV reduction, BRS restoration and organ protection in hypertensive rats. The decrease in BPV and the restoration of BRS may importantly contribute to organ protection in SHR with chronic treatment.

Blood pressure variability, cardiac baroreflex sensitivity and organ damage in experimentally hypertensive rats.

1. The present study was designed to investigate the haemodynamic features and morphological changes in experimentally hypertensive rat models.

Ketanserin stabilizes blood pressure in conscious spontaneously hypertensive rats.

1. It has been demonstrated that blood pressure variability (BPV) is increased in hypertension and related to organ damage. It will be important to lower BPV in the treatment of hypertension. The present study was designed to investigate the effect of ketanserin, a 5‐HT2A receptor antagonist with a weak α1‐adrenoceptor blocking effect, on BPV in conscious spontaneously hypertensive rats (SHR).

EARLY STRUCTURAL CHANGES OF AORTIC WALL IN SINOAORTIC‐DENERVATED RATS

1 The present work was designed to observe the early structural changes in the aortic wall in Sprague‐Dawley rats 1, 2 and 4 weeks after sinoaortic denervation (SAD). 2 Rats were examined 1, 2 and 4 weeks after SAD. Blood pressure (BP) was recorded in the conscious state. The thoracic aortas were taken for investigations, including: light microscopy, electron microscopy, immunohistochemistry and terminal deoxynucleotidyl transferase (TdT)‐mediated dUTP nick‐end labelling (TUNEL). 3 Blood pressure variability (BPV) was significantly increased in the SAD groups 1, 2 and 4 after the operation when compared with the sham‐operated ones. 4 Two weeks after SAD the percentage proportion of smooth muscle cell density (SMC%) was obviously increased. 5 Four weeks after SAD: the SMC%, percentage proportion of collagen density (CD%) and aortic wall thickness (WT) were obviously increased with vascular smooth muscle cells blebbing concomitantly. Endothelial cells showed degenerative changes and swelling with blebbing of the cell membrane and increased condensation of peripheral nuclear chromatin and cytoplasmic vacuolization. It was also found that the number of apoptotic endothelial cells was increased and expression of eNOS was reduced. 6 This is the first study that shows the time‐course of aortic wall and endothelial cell changes induced by SAD. Increased BPV might be the priming factor in the development of organ damage induced by SAD.

Reduction of blood pressure variability by combination therapy in spontaneously hypertensive rats.

Objective To test the hypothesis that combination therapy might be a powerful tool to reduce blood pressure variability (BPV) in the treatment of hypertension. Methods In chronic studies, male spontaneously hypertensive rats were given drugs in their rat chow for 18 weeks (n = 9 or 10 for each group of rats). Doses were as follows: atenolol (10 mg/kg per day), amlodipine (1 mg/kg per day), a combination of atenolol and amlodipine (2.5 + 0.25, 5 + 0.5, and 10 + 1 mg/kg per day), hydrochlorothiazide (8 mg/kg per day), enalapril (3.2 mg/kg per day), and a combination of hydrochlorothiazide and enalapril (2 + 0.8, 4 + 1.6, and 8 + 3.2 mg/kg per day). In acute studies, drugs were perfused through the left femoral vein in conscious rats. Results In chronic studies, compared with monotherapy, the combinations of two antihypertensive drugs were more effective in reducing the blood pressure (BP), BPV, and organ damage. The indexes of organ damage were all positively related to BP and/or BPV. In acute studies, the constant infusion of phenylephrine (6.25 μg/kg per min) markedly increased the BP, but showed no significant effects on BPV. The infusion of a combination of atenolol and amlodipine (62.5 + 6.25 μg/kg per min) or a combination of hydrochlorothiazide and enalapril (500 + 200 μg/kg per min) significantly reduced the BP and BPV; moreover, a significant reduction in BPV was still found when the rats BP was restored to control levels by a concomitant infusion of phenylephrine. Conclusions Combination therapy may be a powerful and useful tool for BPV reduction in the treatment of hypertension. In addition to the BP reduction, the decrease in BPV may contribute significantly to the prevention of organ damage in hypertension.

Restoration of arterial baroreflex function contributes to organ protection in spontaneously hypertensive rats treated with long-term hydrochlorothiazide mixture

1. Hydrochlorothiazide mixture (HCTM) is widely used in China for the treatment of hypertension. This mixture consists of hydrochlorothiazide, triamterene, reserpine, hydralazine and chlordiazpoxide, with small (one‐third to one‐fifth of normal) doses of each drug. The present study was designed to investigate the effects of this mixture on blood pressure, blood pressure variability (BPV), baroreflex sensitivity (BRS) and end‐organ damage in spontaneously hypertensive rats (SHR).

Synergistic effects of atenolol and amlodipine for lowering and stabilizing blood pressure in 2K1C renovascular hypertensive rats

AbstractAim:To test the synergistic effects of atenolol and amlodipine on lowering blood pressure (BP) and reducing blood pressure variability (BPV) in 2-kidney, one-clip (2K1C) renovascular hypertensive rats.Methods:Forty-eight 2K1C renovascular hypertensive rats were randomly divided into 6 groups. They were respectively given 0.8% carboxymethylcellulose sodium (control), atenolol (10.0 mg/kg), amlodipine (1.0 mg/kg), and combined atenolol and amlodipine (low dose: 5.0+0.5 mg/kg; intermediate dose: 10.0+1.0 mg/kg; high dose: 20.0+2.0 mg/kg). The drugs were given via a catheter in a gastric fistula. BP was recorded for 25 h from 1 h before drug administration to 24 h after administration.Results:Compared with BP before medication, all 3 doses of combined atenolol and amlodipine significantly decreased the BP at 24 h after administration, except for the low dose on diastolic BP. Compared with the control group, all 3 doses of combined atenolol and amlodipine significantly reduced the average BP levels for the 24 h period after administration; furthermore, the high and intermediate doses also significantly decreased the BPV levels for the same period. The q values calculated by probability sum analysis for systolic and diastolic BP for the 24 h period after administration were 2.29 and 1.45, respectively, and for systolic and diastolic BPV for the same period they were 1.41 and 1.60, respectively.Conclusion:There is significant synergism between atenolol and amlodipine in lowering and stabilizing BP in 2K1C renovascular hypertensive rats.

The combination of atenolol and amlodipine is better than their monotherapy for preventing end‐organ damage in different types of hypertension in rats

Combinations therapy is often used in hypertensive patients whether combination therapy is necessary for preventing end‐organ damage is not known. The objective of this study was to determine in four different hypertensive animal models the necessity of adding the calcium channel blocker amlodipine to therapy with the ß‐blocker atenolol to modulate end‐organ damage. Spontaneously hypertensive rats, DOCA‐salt hypertensive rats, two‐kidney, one‐clip renovascular hypertensive rats and Lyon genetically hypertensive rats were used to study this objective. These animal models have different sensitivities to atenolol and amlodipine. The dosages of therapy employed were 10 mg/kg atenolol alone, 1 mg/kg amlodipine, 10 mg atenolol + 1 mg/kg amlodipine and 5 mg/kg atenolol+0.5 mg/kg amlodipine. BP was continuously recorded in all animals. After determination of baroreflex sensitivity, rats were sacrificed for end‐organ damage evaluation. The combination of amlodipine and atenolol had a synergistic inhibitory effect on blood pressure and blood pressure variability, and end‐organ damage as compared with monotherapy with atenolol or amlodipine in all animal models. Baroreflex sensitivity also improved with the combination therapy more than with monotherapy. In conclusion, atenolol and amlodipine combination exerts a superior effect on blood pressure, blood pressure variability, baroreflex sensitivity and end‐organ damage. The superior effect of the combination was observed in all four models of hypertension.