Ai-jun Liu

Sodium tanshinone IIA sulfonate protects cardiomyocytes against oxidative stress-mediated apoptosis through inhibiting JNK activation.

Sodium tanshinone IIA sulfonate (STS) is a water-soluble derivative of tanshinone IIA, a well-known Chinese medicine for treating cardiovascular disorders. Cardiomyocyte apoptosis plays a major role in the development of cardiovascular diseases. The present study was designed to investigate the effects of STS on cardiomyocyte apoptosis induced by in vivo acute myocardial infarction (MI) in adult rats and by in vitro H2O2-treated neonatal rat ventricular myocytes. In MI rats, STS significantly reduced the infarct sizes, the blood lactate dehydrogenase (LDH) level, and the number of apoptotic cardiomyocytes in the infarcted hearts. In the in vitro study, STS reversed the decreased effect of cell viability induced by H2O2. In addition, STS also markedly inhibited H2O2-induced cardiomyocyte apoptosis. C-Jun N-terminal kinases/stress-activated protein kinases (JNKs/SAPKs) and p38 MAPK are classic oxidative stress-activated protein kinases. Our further mechanistic study revealed that increased JNK phosphorylation stimulated by H2O2 was abolished by STS treatment. In conclusion, inhibition of JNK activation plays a significant role in cardioprotective effects of STS.

Protective effects of scutellarin and breviscapine on brain and heart ischemia in rats.

Scutellarin is an active molecule existing in Erigeron breviscapus (vant.) Hand-Mazz. The present work was designed to study the antiischemic effects of scutellarin and its mixture with another substance, breviscapine, in male Sprague-Dawley (SD) rats. Ligature of left anterior descending arteries was performed to induce acute myocardial infarction (MI), and the middle cerebral artery occlusion was created to induce focal cerebral ischemia. The MI size was significantly reduced by scutellarin (15 and 50 mg/kg) but not by breviscapine (5 to 50 mg/kg); the effect of scutellarin on the anti-MI was dose-dependent. Compared with control group, scutellarin (50 mg/kg) reduced the myocardium cell apoptosis in MI rats. The two drugs together (5 to 50 mg/kg) significantly reduced infarction size in focal brain ischemic rats (P < 0.05). There were no significant differences among the 3 dosages in breviscapine-treated rats, and the effect of scutellarin on the anticerebral ischemia was dose-dependent. The results demonstrate that the protective effects of scutellarin on cardiovascular and cerebrovascular ischemia were better than its mixture, breviscapine, in rats.

PRESSOR AND NON-PRESSOR EFFECTS OF SODIUM LOADING ON STROKE IN STROKE-PRONE SPONTANEOUSLY HYPERTENSIVE RATS

1 Aetiological studies have shown that sodium loading increases both blood pressure and death from stroke. The present study was designed to investigate the pressor and non‐pressor effects of sodium loading on stroke in stroke‐prone spontaneously hypertensive rats (SHRSP). 2 Eighty‐five female SHRSP were used. Forty‐nine SHRSP, aged 5 months, were randomly divided into two groups with or without sodium loading and their survival times were recorded. Thirty‐six SHRSP, aged 3 months, were randomly divided into two groups and were instrumented to determine blood pressure, heart period and baroreflex sensitivity (BRS) after 4 months of sodium loading or normal rat chow. After determination of BRS, blood samples were collected for the measurement of tumour necrosis factor (TNF), interleukin (IL)‐1β, IL‐6 and angiotensin (Ang) II and brains were dissected for light microscopic examination. 3 Over the 15 month period, the mortality of control SHRSP was 37.5%, which reached 80.0% in the sodium loading group. Compared with the control group, blood pressure was increased but BRS was significantly decreased (P < 0.001) in sodium‐loaded rats. Levels of IL‐1β, IL‐6 and AngII were all significantly increased (P < 0.05) in the sodium‐loaded rats. Sodium loading also markedly increased the number of cerebral aneurysms. Multivariate regression analysis showed that IL‐6 was the most significant factor related to aneurysm formation. 4 Sodium loading increases death from stroke in SHRSP. The increased blood pressure, impaired BRS, inflammatory reaction and the formation of cerebral aneurysms may contribute to the development of stroke.

A novel animal model for motion sickness and its first application in rodents.

The present work was designed to establish a novel animal model for motion sickness (MS) in rodents and to evaluate the effects of a combination of scopolamine and modafinil on MS with this novel method. It was found that the rats and mice presented several symptoms induced by rotation such as, piloerection, tremble, urinal and fecal incontinence. As the rats and mice are lack of emesis response to rotation, we used a score based on abovementioned symptoms as an index for the severity of MS in rodents. MS index was determined in 260 mice with this novel method. It was found that the distribution of MS index was normal (W=0.99; P=0.23. P>0.05 considered values normal distribution). The effects of scopolamine on MS were studied in mice and rats. It was found that scopolamine significantly decreased MS index at the dose of 0.3 mg/kg in mice and 1.0 mg/kg in rats. Finally, the effects of a combination of scopolamine and modafinil were observed with this novel method in rats. It was found that the efficacy of the combination (5.0+5.0 mg/kg) was greater than the single drugs (10 mg/kg). Even the smallest dose of the combination (0.5+0.5 mg/kg) had a similar effect to large dose of scopolamine or modafinile when they were used alone. In conclusion, this animal model is suitable for MS study in rats and mice and the combination of scopolamine and modafinil might be a new method to treat or prevent MS.

Effects of combination therapy with atenolol and amlodipine on blood pressure control and stroke prevention in stroke-prone spontaneously hypertensive rats

AbstractAim:To test the effects of atenolol and amlodipine, either alone or in combination, on blood pressure, blood pressure variability (BPV), baroreflex sensitivity (BRS), and the prevalence of stroke in stroke-prone spontaneously hypertensive rats (SHR-SP).Methods:In the first set of the study, 24 8-month-old, female SHR-SP rats were randomly divided into 3 groups. Blood pressure, heart period, and BRS were determined before and after the intragastric administration of atenolol (10 mg/kg) and amlodipine (1.0 mg/kg), either alone or in combination. In the second set of the study, 40 male and 40 female rats were randomly assigned to 1 of the following 4 groups: control, atenolol (10 mg·kg−1·d−1), amlodipine (1.0 mg·kg−1·d−1), and both (10 male and 10 female in each group). The stroke incident and survival time were recorded.Results:Atenolol and amlodipine, either alone or in combination, significantly decreased blood pressure, with the exception of the amlodipine-induced effect on diastolic blood pressure. Meanwhile, only the combination treatment significantly decreased the BPV levels for the same period. The q-values calculated by the probability sum analysis were 1.17 and 2.67 for systolic and diastolic blood pressure, respectively, and were 2.48 and 2.10 for systolic and diastolic BPV, respectively, following administration. Neither drug exhibited any significant effect on BRS. Atenolol and amlodipine, either alone or in combination, significantly increased the lifespan of SHR-SP, with the best effect elicited by the combination therapy.Conclusion:A significant synergism exists between atenolol and amlodipine in lowering and stabilizing blood pressure in SHR-SP. Combination therapy may be an optimal strategy for the prevention of stroke in hypertension.

Clonidine, moxonidine, folic acid, and mecobalamin improve baroreflex function in stroke-prone, spontaneously hypertensive rats

AbstractAim:To investigate the effect of clonidine, moxonidine, folic acid, and mecobalamin on arterial baroreflex (ABR) function in stroke-prone spontaneously hypertensive rats (SHR-SP) and the possible mechanisms involved.Methods:Eighty-one SHR-SP were divided into 7 groups. Four groups were designated for the intragastric (ig) administration of clonidine (1.0 and 10.0 μg/kg), moxonidine (0.1 and 1.0 mg/kg), folic acid (1.0 mg/kg), and mecobalamin (1.0 mg/kg). Three groups were for the intracerebroventricular (icv) injection of clonidine (4 μg/4 μL), moxonidine (5 μg/4 μL), and mecobalamin (20 μg/4 μL). Blood pressure (BP) was recorded in the conscious state for 30 min and baroreflex sensitivity (BRS) was determined respectively before and after drug administration.Results:Clonidine and moxonidine significantly decreased BP, prolonged the heart period (HP), and increased BRS when administered as either ig or icv injections. Both BP and HP were unchanged by ig folic acid or mecobalamin injection. However, BRS was significantly increased by both.Conclusion:Clonidine, moxonidine, folic acid, and mecobalamin improved impaired ABR function in SHR-SP. The central mechanism was involved in this effect of either clonidine or moxonidine. Mecobalamin improved ABR function through the peripheral mechanism.

Effects of allisartan, a new AT1 receptor blocker, on blood pressure and end-organ damage in hypertensive animals

AbstractAim:To investigate the effects of allisartan, a new angiotensin II type 1 (AT1) receptor antagonist, on blood pressure (BP) and end-organ damage (EOD) in hypertensive rats and dogs.Methods:First, a single dose of allisartan was given intragastrically to evaluate the BP reduction in spontaneously hypertensive rats (SHRs), two kidney-one clip (2K1C) renovascular hypertensive rats and dogs, and Beagle dogs with angiotensin II-induced hypertension. Second, allisartan was mixed in rat chow for long-term treatment. After 4 months of drug administration, rats were instrumented to determine BP and baroreflex sensitivity (BRS). Observation of morphologic changes was used to estimate EOD. Third, the acute toxicity of allisartan was compared with that of losartan in mice.Results:BP was significantly decreased after intragastric administration of allisartan in SHRs, 2K1C rats, 2K1C dogs and Beagle dogs with angiotensin II-induced hypertension. Compared with the control, SHRs that received long-term treatment with allisartan exhibited an improved BRS and organ protective effects. Mice who were administered allisartan experienced less acute toxicity than those treated with losartan.Conclusion:Allisartan is highly effective for BP reduction and organ protection with low toxicity.

The survival time post-cecal ligation and puncture in sinoaortic denervated rats.

Arterial baroreflex (ABR) function is an important determinant factor in prognosis of many cardiovascular diseases. The present work was designed to study the relationship between ABR function and the survival time of septic shock in a cecal ligation and puncture (CLP) rat model. The dysfunction of ABR was introduced by sinoaortic denervation (SAD). It was found that the survival time after CLP was significantly reduced in SAD rats compared with sham-operated rats (12.7 ± 2.92 hours versus 15.0 ± 4.01 hours; P < 0.05). Furthermore, significant differences were also seen when the results were expressed by Kaplan-Meier survival curves. Compared with the baseline values, both noradrenaline and adrenaline significantly increased in both SAD and Sham groups after CLP, but we found the baseline of noradrenaline was significantly elevated in SAD rats. In addition, the TNF-α, noradrenaline, and adrenaline levels of the SAD group were significantly higher than those of the Sham group at 5 hours post-CLP. In conclusion, the present work demonstrates that ABR function was related to the survival time in CLP-induced lethal shock model. The loss of inhibition in the sympathetic activity and in the release of some inflammatory cytokines during CLP-induced septic shock related to baroreflex and/or chemoreflex dysfunction may be the mechanisms involved in the poorer prognosis in septic shock.

Circadian expression of clock genes and angiotensin II type 1 receptors in suprachiasmatic nuclei of sinoaortic-denervated rats

AbstractAim:To investigate whether the circadian expression of central clock genes and angiotensin II type 1 (AT1) receptors was altered in sinoaortic-denervated (SAD) rats.Methods:Male Sprague-Dawley rats underwent sinoaortic denervation or a sham operation at the age of 12 weeks. Four weeks after the operation, blood pressure and heart period were measured in the conscious state in a group of sham-operated (n=10) and SAD rats (n=9). Rest SAD and sham-operated rats were divided into 6 groups (n=6 in each group). The suprachiasmatic nuclei (SCN) tissues were taken every 4 h throughout the day from each group for the determination of the mRNA expression of clock genes (Per2 and Bmal1) and the AT1 receptor by RT-PCR; the protein expression of Per2 and Bmal1 was determined by Western blotting.Results:Blood pressure levels in the SAD rats were similar to those of the sham-operated rats. However, blood pressure variabilities significantly increased in the SAD rats compared with the sham-operated rats. The circadian variation of clock genes in the SCN of the sham-operated rats was characterized by a marked increase in the mRNA and protein expression during dark periods. Per2 and Bmal1 mRNA levels were significantly lower in the SAD rats, especially during dark periods. Western blot analysis confirmed an attenuation of the circadian rhythm of the 2 clock proteins in the SCN of the SAD rats. AT1 receptor mRNA expressions in the SCN were abnormally upregulated in the light phase, changed to a 12-h cycle in the SAD rats.Conclusion:The circadian variation of the 2 central clock genes was attenuated in the SAD rats. Arterial baroreflex dysfunction also induced a disturbance in the expression of AT1 receptors in the SCN.

Synergism of telmisartan and amlodipine on blood pressure reduction and cardiorenal protection in hypertensive rats.

Aim: This study was designed to investigate the effects of telmisartan and amlodipine on reduction of blood pressure (BP), myocardial hypertrophy, and renal injury in hypertensive rats. Method: In acute experiments, the BP was measured in conscious freely moving rats. Spontaneously hypertensive rats were treated with intragastric administration of amlodipine (1, 2, 4 mg/kg), telmisartan (4, 8, 12, 16, 20 mg/kg), and their different combinations (4 + 4, 2 + 4, 4 + 8, 4 + 12, 1 + 4, 2 + 8, 4 + 16, 2 + 12, 1 + 8, 2 + 16, 2 + 20, 1 + 12, 1 + 16, 1 + 20 mg/kg). The probability sum test (q test) was used to evaluate the synergistic action on BP reduction. In two-kidney, one-clip rats, the effects of amlodipine (1 mg/kg), telmisartan (6 mg/kg) and their combination on BP reduction were observed. In the chronic study, spontaneously hypertensive rats were treated with amlodipine (1 mg/kg), telmisartan (6 mg/kg), and their combination for 4 months. Histopathologic examinations were performed after the determination of BP and BP variability. Results: There is a synergistic interaction between amlodipine and telmisartan on BP reduction. The optimal dose ratio was found at 1:6. The synergistic effect of this dose ratio (1:6) was also seen in two-kidney, one-clip rats. Long-term treatment with this combination results in a beneficial effect on the reduction of BP and BP variability. The end-organ damage, including myocardial hypertrophy, glomerular atrophy, and fibrosis, was significantly attenuated by this combination. Conclusion: The optimal dose ratio of amlodipine and telmisartan on BP was 1:6. This combination is beneficial for the BP and BP variability reduction and end-organ damage prevention.