| Background:Atherosclerosis is one primary diseases threating human health, but the occurrence of the mechanism has not been completely expounded. Endothelial injury response theory indicates that it is mainly a series of inflammatory reaction on the basis of the damage to endothelium cell. Endothelial cells can release a large number of active substances in which NO is the major diastolic factor and endothelin is the major systolic factor. The two types of active substances keep the balance of blood vessel and pressure. Endothelial dysfunction is closely related to the occurrence and development of Atherosclerosis.A number of studies have suggested that Calcium Channel Blockers (CCB) have the effect of Anti-Atherosclerosis, but the efficacy is not considered to relate to hypotensive effect. Many studies reported that Amlodipine could increase NO production, and increased production of NO play a role against atherosclerosis in a dose-dependent. AAA study showed that Amlodipine reduces intimal thickness, inhibiting the progress of early AS. Amlodipine can increase NO production in a dose dependent manner after incubation with porcine endothelial cells, increasing its bioavailability. It also present dose-dependent manner interfering caveolin and endothelial nitric oxide synthase (eNOS) interaction with caveolin to promote separation, triggering the activation of eNOS caveolin-dependent, thus promoting the formation of NO, which may and improving endothelial function.Osteoporosis (osteoprosis, OP) is a common disease of the elderly. The relationship between the bone metabolism and cardiovascular diseases more and more attention by the medical profession. On one hand, osteoblasts formate new bone and osteoclasts absorb the formed bone on the other hand, both in relative steady state, to maintain the bone shape, the overall bone mass and bone strength. Clinical studies have indicated that there are also calcium channels in osteoclasts and osteoblasts. And different from the calcium channels of myocardial cells and smooth muscle on the cardiovascular system, the channel is slow. CCB can inhibit osteoclast L-type calcium channel, so that lacunae decreased, bone resorption decreased, intracellular calcium increased. It can be inferred that CCB can affect bone metabolism, so that bone mineral density changes.It can be seen that the current study shows that the role of CCB with anti-AS, but the anti-AS mechanisms are not yet clear. There are also effects on bone density, but the studies have reported the impact of CCB on bone mineral density have a positive impact, but also have a negative impact, so there is no unified opinion. Amlodipine is a long-acting dihydropyridine CCB, the compounds have the type of L-and D-isomers, and the activity of L-body is nearly 1,000 times of D-body, 2 times of the racemic. Levamlodipine besylate (Shi Hui Da) is the L-amlodipine besylate counterpart. This research taking the current new calcium antagonist amlodipine L-acid drugs for the study to explore its effects on SD rats with AS. We use balloon injuring aortic combined with high fat diet and high dose of calcium load to copy a SD rat model of AS and observe the impact of levamlodipine besylate on serum lipid metabolism and indices of endothelial function of AS rats. Take aortic of the rats for morphological observations to research levamlodipine besylate of preventive interventions AS rats, preliminary study Levamlodipine besylate role of anti-AS. On the other hand,by using the levamlodipine besylate, to compare bone mineral density and serum of rats free calcium, phosphorus and alkaline phosphatase concentration , studying on bone metabolism, providing new ideas for prevention and theoretical basis for the OP. Chapter One Levamlodipine Besylate On Endothelial Function Of Atherosclerosis RatsPurpose: Observe impact of the calcium antagonist , Levamlodipine besylate on atherosclerosis of SD rats, and to explore its possible mechanism.Methods: Use balloon injuring aortic combined with high fat diet and high dose of calcium load ( Single intraperitoneal injection of vitamin D3 60,000U/Kg) to copy a SD rat model of AS. 54 SPF male SD rats, randomly divided into 4 groups: (1).Control group (Group A): normal diet, sham (2).Model group (Group B): high fat diet, aortic balloon injury, intraperitoneal injection of vitamin D3 (3). Levamlodipine besylate group (Group C): Levamlodipine besylate(Ig 2.5mg/Kg.d) on model group 4.Simvastatin group (Group D): Simvastatin(Ig 20mg/kg.d) on model group. Levamlodipine besylate group and Simvastatin group of drugs were taken oral administration from the first day of the modeling , and the control group and model group were given the same amount of normal saline. The model group and drugs group were taken artery balloon injury operation after first week , and the control group was taken the sham operation at the same time.After modeling 8 weeks, invasive blood pressure and heart rate were measured, and then blood samples were drawn and centrifuged, and placed -80℃refrigerator after centrifugation. Took thoracic aorta and abdominal aorta obtained by HE staining, Masson staining for morphology observation and ultrastructure of blood vessels were observed under transmission electron microscopy. Determined and compared among the SD groups of serum TC, TG, LDL-c, HDL-c and NO, NOS, ET-1 levels.Results:1. AS model group reduced food intake and weight loss began to appear after 4 weeks of modeled,weight gain was significantly decreased.2. Model group and the drugs groups were abnormal lipid metabolism, expressed as serum TC, TG and LDL-c levels were significantly increased, but there are no significant differences between the Levamlodipine besylate group and model group in blood lipid levels.3. Model group and the drugs groups' serum nitric oxide (NO) and nitric oxide synthase (NOS) were significantly lower than control group (P <0.05), endothelin -1 (ET-1) was significantly higher than control group (P <0.05). Comparing drugs groups with model group, NO and NOS levels decreased (P <0.05), but ET-1 levels were not significantly different (P> 0.05).Levamlodipine besylate group compared with the Simvastatin group, NO, NOS and ET-1 levels were not significantly different (P> 0.05).4. Model group and the treatment group significantly increased serum LDL-c, and serum NO, NOS levels negatively correlated (P <0.05), and ET-1 has positive correlation (P <0.05).5. Morphological results of aortic rat model successfully replicated AS. Levamlodipine besylate significantly improved SD model of atherosclerotic changes in rat aorta morphology. HE staining: less damage to vascular endothelial cells, intimal thickening was significantly less than the model group, less plaque than the model group. Masson staining showed that amlodipine besylate group of aortic collagen fibers was significantly less than the model. Transmission electron microscopy shows that Levamlodipine besylate group can reduce aortic plaque area, the reduction of intimal damage.6. Levamlodipine besylate group's systolic blood pressure, diastolic and mean arterial pressure were lower than other groups, but remained within the normal range.Rats in each group no significant difference in heart rate.Conclusion:1. Using balloon injuring aortic combined with high fat diet and high dose of calcium load can copy AS model successfully.2. Levamlodipine besylate can inhibit the progress of AS without affecting blood lipid and blood pressure levels. Its anti-atherosclerosis may be associated with lower serum levels of ET-1, increased NO, NOS levels related,then improve endothelial function.3. AS SD's serum LDL-c and NO, NOS levels negatively correlated with the level of ET-1 positive correlation.. Levamlodipine besylate can inhibit LDL oxidation as ox - LDL maybe one of the mechanism to improe endothelial function Chapter Two Levamlodipine Beaylate Influence On The Bone Mineral Density(BMD) Of Atherosclerosis RatsPurpose: To observe the influence of Calcium antagonists as levamlodipine besylate on bone mineral density(BMD) and bone metabolism of SD-rats,and to discuss the effect of Levamlodipine besylate on OP preliminary.Methods:To establish AS animal model of rats, measure and compare the concentration of blood serumionized calcium, phosphorus and ALP of each group. And to measure the lumbar spine and femoral BMD by small animals CB- DXA software, analysis the images acquired. And compared respectively in bilateral femoral BMD and lumbar BMC of each groups.Results:1. The level of serum calcium in group B (model group), group D (simvastatin group) are lower than group A's(blank group) (P < 0.05),with Significant difference. Compared with C group (levamlodipine besylate group) and group A (blank group),there is no significant difference (P > 0.05).2. Compared with the level of serum phosphorus in each groups, there is no significant difference (P > 0.05).3. The concentration of serum ALP in Group B is significantly higher than group A, C group and group D greup (p < 0.05). Group C's is higher than group A's ,with Significant difference (p < 0.05),while compared with group D,there is no significant difference (p > 0.05).4. Compared with the level of BMD and BMC in each groups , there is no significant difference (p > 0.05).The left femoral BMD value of Model group rats is lower than other groups, with Significant difference (P < 0.05), though compared between the two groups, there are no significant difference (P > 0.05),The left femur BMC value of model group is lower than group C,D, with Significant difference (P < 0.05). the right femoral BMD and BMC values of each groups have no significant difference (p > 0.05).5. The bilateral femoral BMD value of Group B is significantly lower than group A, C, with Significant difference (P < 0.05).While compared Group A with group C, Group B and D, there are no significant difference (p > 0.05). the bilateral femoral BMC value of Group B is lower than group A, C, with Significant difference (P < 0.05). The bilateral femoral BMC value of Group B is lower than group D ,with no significant difference (p > 0.05).when compared with each other among groupA,C,D, there are no significant difference (p > 0.05).6. Compared with the bilateral femoral and lumbar BMD value of each two groups,there are no significant difference (p > 0.05).But the BMC value of model group is lower than other groups,compared with group A, D, with Significant difference (P < 0.05), while compared with group C, there are no significant difference (P > 0.05); when compared with each other among groupA,C,D, there are no significant difference (p > 0.05).Conclusion:1. AS rat model appears lower level of serum Ca+, Levamlodipine besylate can improve the level of serum Ca+.2. Levamlodipine besylate had no significant effect on the level of serum P increase in AS rats.3. AS rat model appears serum ALP leveling up, Levamlodipine besylate can reduce serum ALP levels. It indicates that Levamlodipine besylate changing bone formation may play a role in inhibition of OP.4. Levamlodipine besylate can improve BMD of femur in rats of AS, on the lumbar spine bone mineral density had no such significant effect. |
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