| Objective Few studies compared the relative efficacy and tolerability of antihypertensive drug classes as initial treatment for hypertensive patients in rural area in developing countries.The study "An antihypertensive intervention trial to lower blood pressure in untreated hypertensive patients based on the gene polymorphisms in the pathway of the drug-metabolism and biological effects"was a randomized, double-blind,active-controlled,community based clinical trial in rural area in China aiming to determine antihypertensive effects and side effects of atenolol,captopril,nifidipine sustained release and hydrochlorothiazide relative to the gene polymorphisms in untreated hypertensive patients in countryside.The present study is the preliminary results of the study to investigate the different efficacy of mono-therapy with different antihypertensive drugs in Chinese patients with isolated systolic hypertension,isolated diastolic hypertension,and combined systolic and diastolic hypertension after 4-week' s treatment.Design and methods We recruited 442 patients with isolated systolic hypertension,104 patients with isolated diastolic hypertension and 1352 patients with combined systolic and diastolic hypertension patients aged 40 to 75 years from 7 communities in XinYang county,HeNan province.They were randomly divided into four groups:One hundred and thirty-three patients with isolated systolic hypertension,37 patients with isolated diastolic hypertension and 313 patients with combined systolic and diastolic hypertension received hydrochlorothiazide(12.5mg/d or 25mg/d);Sixty-six patients with isolated systolic hypertension,19 patients with isolated diastolic hypertension and 220 patients with combined systolic and diastolic hypertension received atenolol(12.5mg/d or 25mg/d);One hundred and thirty patients with isolated systolic hypertension,27 patients with isolated diastolic hypertension and 439 with combined systolic and diastolic hypertension patients received nifedipine sustained release(20mg/d or 40mg/d);One hundred and thirty-three patients with isolated systolic hypertension,21 patients with isolated diastolic hypertension and 380 patients with combined systolic and diastolic hypertension received captopril(25mg/d or 50mg/d) respectively for 4 weeks.The systolic and diastolic blood pressures were measured before and after treatment to determine the efficacy of drugs.Results:Both mean systolic and diastolic blood pressure were reduced significantly after the treatment of antihypertensive drugs(P＜0.001). The incidence of side effect was the lowest in hydrochlorothiazide group, and the highest in atenolol group.Up to now,hydrochlorothiazide was the cheapest in all anti-hypertensive drugs.After adjustment for age,sex,pretreatment corresponding blood pressure, body mass index,waist -hip ratio,waist,high-density lipoprotein cholesterol,low-density lipoprotein cholesterol,total cholesterol, triglyceride,fasting blood glucose,creatinine,smoking,and drinking:In patients with isolated systolic hypertension,the reduction in systolic blood pressure was significantly lower in atenolol group than in hydrochlorothiazide(P=0.0339) and nifedipine sustained release(P=0.005) groups;The reduction in diastolic blood pressure was lower significantly in hydrochlorothiazide group than in nifedipine sustained release group(P=0.015);The reduction in pulse pressure was significant]y greater in hydrochlorothiazide group than in atenolol(P=0.006) and captopril(P=0.019) groups.In patients with isolated diastolic hypertension,the reduction in systolic blood pressure was significantly greater in hydrochlorothiazide group than in atenolol(P=0.040) and captopril(P=0.016) groups;The reduction in diastolic blood pressure had no significant difference in four groups;The increase in pulse pressure was lower in hydrochlorothiazide group than in atenolol(P=0.029) and captopril(P=0.031)groups.In patients with combined systolic and diastolic hypertension,the reduction in systolic blood pressure was significantly greater in nifedipine sustained release group than in hydrochlorothiazide group(P=0.001),that in hydrochlorothiazide group than that in atenolol(P＜0.001) and captopril (P＜0.001) groups;Nifedipine sustained release decreased diastolic blood pressure to a greater extent than hydrochlorothiazide and atenolol groups(P＜0.001),and hydroehlorothiazide decreased diastolic blood pressure to a greater extent than captopril(P＜0.001).The reduction in pulse pressure was significantly greater in hydrochlorothiazide and nifedipine sustained release groups than that in atenolol and captopril groups (P＜0.001).Conclusions In patients with isolated systolic hypertension or combined systolic and diastolic hypertension,our results support that hydrochlorothiazide is suitable as the first line antihypertensive drug in developing countries due to its significantly higher efficacy, better tolerability,and lower cost.In reducing blood pressure,Atenolol and captopril seem to be more effective antihypertensive drug for patients with isolated diastolic hypertension compared with hydrochlorothiazide and nifedipine sustained release;Nifedipine sustained release seems to be more effective antihypertensive drugs for patients with combined systolic and diastolic hypertension compared with atenolol and captopril. Background and Objectives A total of 95%of hydrochlorothiazide is excreted unchanged by organic anion transporter 1 from the blood into the tubular lumen by inhibiting thiazide-sensitive Na,Cl-cotransporter of the distal tubule.Both WNK1 and WNK4 proteins are localized to distal nephrons,WNK1 under physiological condition inactivates WNK4 and WNK4 is an inactivator for thiazide-sensitive Na,Cl-cotransporter.It has been reported that the mutations in TSC cause Gentleman's syndrome characterized by hypotension.On the contrary,the mutations in WNK1 or WNK4 cause familial hypertension known as pseudohypoaldosteronism typeⅡ.However,the association of common polymorphisms in these genes with hypertension and antihypertensive effects of hydrochlorothiazide remains unclear. This study investigated whether the common polymorphisms in OAT1, TSC,WNK1,and WNK4 were associated with risk of essential hypertension and antihypertensive response to hydrochlorothiazide.Methods We selected 8 single-nucleotide polymorphisms in these 4 genes.The association of these polymorphisms with risk of essential hypertension was determined in 2 independent studies with 820 hypertensive patients and 772 controls recruited from HeNan province,and 286 patients and 316 controls from ShanDong province.We then conducted 2 clinical trials to confirm the association of these polymorphisms with the effect of hydrochlorothiazide in patients treated with hydrochlorothiazide(12.5-25mg/day) for 4 weeks(545 patients from HeNan province) and for 8 weeks(245 patients from ShanDong province),respectively.Results The polymorphisms of WKN1 rs1468326 conferred high risk of essential hypertension(OR 1.55,95%CI 1.22-1.95,P＜0.001) and so did WNK4 rs9916754(OR 1.88,95%CI 1.32-2.66,P＜0.001) in first study after adjustment for conventional risk factors. These results were replicated in the second population(OR 1.55 for WKN1 rs1468326 and OR 1.82 for WNK4 rs9916754).The carrier of OAT1 rs10792367 C allele had 2.6mmHg(P=0.010) lower reduction in mean blood pressure and 4.1mmHg(P=0.014) lower in systolic blood pressure response to hydrochlorothiazide than did the carriers of GG genotype in the first clinical trial.The results were replicated in the second clinical trial:The mean blood pressure was 3.5 mmHg(P=0.010) lower and systolic blood pressure response to hydrochlorothiazide was 5.9mmHg(P=0.002) lower in C allele carriers than in carriers of GG genotype.Conclusions The polymorphisms in WNK1 and WNK4 may increase susceptibility to essential hypertension.The OAT1 polymorphisms predict the antihypertensive effect to hydrochlorothiazide in Chinese hypertensive patients.
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