Study Of Antihypertensive Therapy From Pre-hypertension: Drug Selection And Best Administration Time

BackgroundPre-hypertension, a transitional phase from normal blood pressure (BP)to hypertension，is defined by a systolic BP (SBP) of120to139mmHg ora diastolic BP of80to89mmHg (1). Many studies have found that a highprevalence of pre-hypertension was accompanied with increasedcardiovascular risk factors, and partly with target organs damages (2,3).In addition， pre-hypertension is also a signal of adverse cardiovascularevents for healthy adults (4). The cohort study of MONICA found that theprogression of BP is related with cardiovascular events，and the risk ofcardiovascular and cerebrovascular events is equivalent between theprogression of BP from normal BP or pre-hypertension to hypertension andthe maintenance of BP in pre-hypertension or hypertension (5). Therefore，treatment of pre-hypertension can prevent or delay the occurrence ofhypertension and protect target organs，and reduce the morbidity andmortality of cardiovascular and cerebrovascular diseases.Therapeutic lifestyle changes are still the prerequisite and basisof pre-hypertension treatment, but it is difficult to implement it,especially in the young and middle-aged patients with pre-hypertension(6). Furthermore，treatment of pre-hypertension is in line with theconcept of primary prevention and the respect for a healthy life (7).Previous studies suggested that treatment of pre-hypertension isbeneficial (8-12). However，there are still many questions about treatmentof pre-hypertension that need to be addressed，such as treatment timing，administration dose and time，comparative efficacy of anti-hypertensive drugs，cost-benefit ratio and the effects of early treatment to long-termBP and target organs，and so on. In this study，stroke-prone spontaneouslyhypertensive rat (SHRSP）was used as experimental model to study effectsof anti-hypertensive therapy from pre-hypertension to long-term BP andtarget organs，especially for stroke.Objective1. To investigate the optimal timing and the appropriate drug forantihypertensive therapy from pre-hypertension.2. To illustrate the effects of anti-hypertensive therapy frompre-hypertension to long-term BP and protection againstcardiovascular and cerebrovascular events.MethodsA total of120male,4-week-old SHRSP were randomly divided into thefollowing5groups (n=24rats in each group)：(1)SHRSP-Veh: SHRSP treatedwith saline,2ml/kg；(2)SHRSP-Los6：SHRSP treated with20mg/kg/d losartanfor6weeks；(3)SHRSP-Los16: SHRSP treated with20mg/kg/d losartan for16weeks；(4)SHRSP-Aml6：SHRSP treated with10mg/kg/d amlodipine for6weeks；and (5)SHRSP-Aml16：SHRSP treated with10mg/kg/d amlodipine for16weeks. Twenty-four untreated Wistar Kyoto rats were used as a controlgroup. All rats were followed up until to40weeks of age. SBP was measuredby tail-cuff method. At10，20and40weeks of age，the left ventricularmass index (LVMI) was determined. Cardiac structure and function weremeasured by echocardiography and left ventricular cannulation. Collagenvolume fraction was analyzed with picrosirius red staining. Expressionof mRNA of left ventricular brain natriuretic peptide（BNP）was measuredby RT-PCR. Stroke was observed by clinical performance score andmicroscope. Apoptosis was analyzed by TdT-mediated dUTP-biotin nick endlabeling, and the levels of angiotensin Ⅱ and aldosterone were measured by radioimmunoassay. Protein expressions of BNP，angiotensin Ⅱ type1and type2receptor (AT1R and AT2R)，gp91phox, superoxide dismutase (SOD)were determined by western blot.Results1. Both losartan and amlodipine treatments delayed the progression of BPin SHRSP in the intervening period（P＞0.05）. At20weeks of age，longer administration，slowered the progression of BP（P＜0.05）. Afterdrug administration was stopped, the progression of BP were slower inSHRSP-Los6and SHRSP-Los16. At40weeks of age, level of SBP in theSHRSP-Los16was lower than that in other groups of SHRSP（P＜0.05）.2. Losartan and amlodipine decreased LVMI，left ventricular end-diastolicinterventricular septum thickness, left ventricular end-systolicpressure and expressions of mRNA and protein of left ventricular BNP，but increased left ventricular end-diastolic diameter, leftventricular ejection fraction （LVEF）and left ventricular pressuremaximum rate of change（The difference in LVEF was statisticallysignificant only at40weeks of age）(P＜0.05). Longer administrationdelivered more benefits（P＜0.05），especially for losartan（P＜0.05）.After drug administration was stopped, those effects lasted longer inSHRSP-Los6and SHRSP-Los16（P＜0.05）.3. Losartan and amlodipine reduced left ventricular myocardialinterstitial collagen volume fraction under the same administrationtime（P＜0.05）. Longer administration，less fibrosis（P＜0.05）. Afterdrug administration was stopped, losartan showed advantage ininhibiting myocardial fibrosis（P＜0.05）.4. Compared with amlodipine, losartan showed superior in improvinglong-term structure of cerebral cortex and reducing stroke（P＜0.05）.Longer administration delivered more benefits（P＜0.05）. Those effects lasted longer in losartan after drug administration was stopped（P＜0.05）.5. Amlodipine showed advantage in delaying apoptosis peak in cerebralcortex and reducing apoptosis of cerebral cortex and myocardium underthe same administration time （P＜0.05）.Longer administrationdelivered more benefits（P＜0.05）. Those effects lasted longer inamlodipine after drug administration was stopped（P＜0.05）.6. Amlodipine had no effect on the levels of angiotensin Ⅱ andaldosterone in the serum and cerebral cortex，but decreased those inthe left ventricular myocardium（especially for SHRSP-Aml16）（P＜0.05）.Losartan had no effect on the level of angiotensin Ⅱ in the cerebralcortex，but increased the level of angiotensin Ⅱin the serum and leftventricular myocardium and decreased the level of aldosterone inserum， cerebral cortex and left ventricular myocardium（especiallyfor SHRSP-Los16）（P＜0.05）. Those effects lasted longer in for losartanafter drug administration was stopped（P＜0.05）.7. Amlodipine had no effect on the protein expressions of AT1R and AT2Rin left ventricular myocardium, while losartan down-regulated formerand up-regulated latter（especially for SHRSP-Los16）（P＜0.05）. Incerebral cortex，losartan and amlodipine down-regulated the proteinexpression of AT1R（P＜0.05）. Those effects lasted until40weeks ofage for losartan after drug administration was stopped（P＜0.05）.Losartan significantly up-regulated the protein expression of AT2R incerebral cortex，while amlodipine showed weak in it（P＜0.05）.8. Losartan and amlodipine（especially amlodipine）down-regulated theprotein expression of gp91phoxand up-regulated the protein expressionof SOD in left ventricular myocardium and cerebral cortex（P＜0.05）.Longer administration had greater impacts（P＜0.05）. Those effects lasted longer for amlodipine after drug administration was stopped（P＜0.05）.Conclusions1. Losartan and amlodipine treatments delay the progression of BP frompre-hypertension. Longer administration，slower the progression of BP.After drugs withdraw, losartan shows advantage in delaying theprogression of BP.2. Losartan and amlodipine treatments starting from pre-hypertension caninhibit myocardial remodeling and improve the functions of heart andbrain tissue, and delay the peak of apoptosis and/or reduce cellapoptosis. Longer administration delivered more benefits. After drugadministration was stopped, losartan shows superior in inhibitingmyocardial remodeling，improving cardiac function and brain tissue（especially in reducing stroke）within a certain time. This may berelated with its stronger inhibition of renin-angiotensin-aldosteronesystem. While amlodipine shows superior in delaying the peak ofapoptosis and/or reducing cell apoptosis，this may be related with itsstronger anti-oxidative stress.