| Hypertension is an important modifiable risk factor for cardiovascular disease, its prevention and treatment all the time represents major health concerns around the world, especially in western countries.It was reported that only 40-60% of patients achieved optimal blood pressure (BP) control with single-drug therapy in the management of hypertension according to the clinical practices. This indicates that there exists great variation across individuals in drug responses. In addition, Schwartz GL et al reported that the BP response to any single antihypertensive drug is characterized by marked interindividual variation. Such a variation may be attributed to the differences in race, age, sex, genes and genetic polymorphisms; the method of administration, and environmental factors can also influence drug responses. In animal study, the following factors may be well controlled: race, age, sex, drug administration, and the environmental factors. Accordingly, we speculated that the variation in the effect of a given antihypertensive drug in hypertensive animal, such as spontaneously hypertensive rat (SHR), might be mainly related to the functional and structural status of the cardiovascular system.In the treatment of hypertension, the four classes of antihypertensive drugs commonly used as the first-line drugs are as follows: diuretics, beta-blockers, angiotensin converting enzyme inhibitors and angiotensin-II receptor antagonists, and calcium channel blockers. Calcium channel blockers (CCBs) have long been recognized as potent agents for hypertension therapy, either alone or in combination with other drugs. Nifedipine, the first generation of dihydropyridines, with the properties of a rapid onset and short duration of action, has been used as a powerful antihypertensive agent in clinical therapeutics since 1970s, it acutely lowers bloodpressure mainly by inhibiting voltage-dependent L-type calcium channels, which leads to vascular smooth muscle relaxation.Therefore, the present work was designed to study the relationships between the responsiveness to nifedipine and some parameters reflecting the functional and structural status of the cardiovascular system in SHR. A single dose of nifedipine was given intravenously in conscious rats. The parameters studied included the baseline blood pressure (BP), baroreflex sensitivity (BRS), the blood contents of angiotensin II and endothelin-1, the cardiovascular hypertrophy variables. And this study was aimed to confirm the hypothesis that the functional and structural status of the cardiovascular system may be responsible for variations across individuals in drug responses.METHODS AND RESULTS1. Determination of hemodynamic parameters and BRS( baroreflex sensitivity)With computerize blood pressure monitoring systems, 21 male conscious freely moving spontaneously hypertensive rats (SHRs), aged 50-52 weeks, were instrumented to determine BP for 1 hour including systolic and diastolic blood pressure(SBP,DBP) and BRS was determined before nifedipine administration . BRS was determined by the Smyth method. Nifedipine was intravenously administered at a dose of 1mg/kg. Immediately after nifedipine adminstration, another 3-hour blood pressure signals were recorded ,and SBP and DBP were computed. The blood pressure changes(â–³BP) including systolic and diastolic blood pressure changes (â–³ SBP, â–³DBP), induced by nifedipine administration was regarded as the significant measuring indicator of antihypertensive effect of drugs.2. Morphological evaluation and plasma humoral determinationTwo days after blood pressure(BP) recording, rats were killed for organ-damage evaluation and blood samples were taken for plasma angiotensin II and endothelin-1 concentrations assay. Plasma angiotensin II and endothelin-1 contents were determined by radioimmunoassay. End organ damage scoring was performed semiquantitatively according to both gross observation and light microscopicevaluation.3. Statistical analysis and resultsThe relationships between BP changes induced by nifedipine administration and hemodynamic parameters or plasma angiotensin II and angiotensin-1 levels or organ damage indices were analyzed by classic univariate correlation analysis, univariate correlation analysis showed that (1) ASBP were negatively conelated with EOD score (r=-0.706, P<0.01) and ADBP were negatively conelated with EOD score (r=-0.782, P<0.01);(2) ASBP was negatively correlated with aortic weight/length (r=-0.615, P<0.01), and ADBP was negatively correlated with aortic weight/length (r=-0.444, P<0.05); (3) ASBP was positively conelated with left kidney weight/body weight (r=0.434, P<0.05) and ADBP was positively correlated with left kidney weight/body weight (r=0.471, P<0.05); (4) ASBP was positively correlated with basal SBP (r=0.554, P<0.01) , and ADBP was positively correlated with basal DBP (r=0.618, P<0.01)o No statistically significant correlations were found between BP changes and plasma angiotensin II or endothelin-1 levels. The relative dependencies of hypotensive effect of nifedipine on BRS, basal BP, AW/length, LKW/BW and EOD score were assessed by step-wise multiple regression analysis. It was demonstrated that ASBP was independently associated with lower AW/length(6= -0.462,P<0.01), lower EOD score(B= -0.467, P<0.01) and higher basal SBP(8=0.313, P<0.05). Meanwhile, ADBP were associated with lower EOD score(6= -0.539, P<0.01) , lower AW/length (B= -0.314, P<0.05) and higher Basal DBP (8=0.394, P<0.01). By comparing the standardized partial regression coefficient ( 6 ), it was found that the contribution of EOD score to BP changes seems the greaterest, the initial blood pressure levels was also of importance, it also appears that aortic hypertrophy significantly reduced systolic blood pressure changes after drug administration just next to EOD score.CONCLUSION1. it was confirmed that the functional and structural status of cardiovascular systems such as baseline blood pressure levels and the severity of end organ damage in...
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