Adrenoceptors, L-type Calcium Channel Blokers Antihypertensive Efficacy, And A New Strategy On Improving Lower Urinary Tract Symptoms

It is widely recognized that essential hypertension is a complex trait resulting from the interaction of environmental and genetic factors.It affects about 0.2 billion individuals in China and in 2008,a total of 0.266 billion Renmingbi were expended on the treatment of hypertension.Previous clinical trials have demonstrated that an average reduction of 10 mm Hg in systolic blood pressure or 5 mm Hg in diastolic blood pressure is associated with a 40-50%reduction in stroke,15-20%in coronary artery disease,and 50%in congestive heart failure.Thus,the effective reduction in blood pressure plays an important role to prevent it's related complications.However, considerable inter-individual variation was observed in the treatment of hypertension. MATH trial showed that responsive rate of nifedipine GITS on hypertension is 76%. The mechanisms underlying such inter-individual variation are yet unclear.One of the possible explanation is the individuals have different genetic background. Besides those encoding the target proteins and the key metabolic enzymes,genes involving in the regulation of blood pressure may also contribute to such inter-individual variation in antihypertensive treatment.The sympathetic nervous system plays an important role in the pathogenesis of essential hypertension,mainly through the catecholamines acting on G protein-coupledαandβadrenoceptors.A chronic increase in the sympathetic functions as well as the alterations in the balance of adrenoceptors in cardiovascular tissues is found in many hypertensive patients.In old population,hypertension and lower urinary tract symptoms are the common comorbid conditions,both of which may be caused by increased overactivity of the sympathetic system.This makes it more difficult to treat these patients properly and efficiently.Furthermore,it will reduce the quality of life of those patients and increase the economical burden individually and socially.In Chinese male population aged more than 65 years,42.7%suffer from hypertension and lower urinary tract symptoms simultaneously.Hypertension may increase the risk of developing lower urinary tract symptoms.Given the high comorbidity of hypertension and LUTS,it is important to consider and investigate therapeutic regiment that can effectively and safely manage both conditions in a certain patient, rather than treating the two conditions separately.Based on these evidences,it is valuable to study the genetic factors underlying the antihypertensive treatment and to find more ways and personalized medications for effectively treating hypertension and the co-existing lower urinary tract symptoms.This study aimed to 1) evaluate whether the polymorphisms in theα1A andβ2 adrenoceptor genes were associated with the antihypertensive effects of nifedipine in Chinese population;2) investigate the efficiacy of the L-type calcium channel blocker amlodipine combined withα1 adrenergic antagonist terazosin on the simultaneous treatment of hypertension and lower urinary tract disorder in model rats;3) by applying a randomized,double-blind clinical trial,evaluate the efficacy and safety of those two drugs used in combination on the treatment of hypertension and lower urinary tract symptoms.1.Association between Arg347Cys polymorphism ofα1A-adrenoceptor gene, Arg16Giy and Gln27Glu polymorphisms of Beta 2 adrenoceptor gene and blood pressure lowering effect of nifedipine[Aims]:To investigate whether polymorphisms in theα1A andβ2 adrenoceptor genes influence antihypertensive effect of nifedipine GITS.[Methods]:Hypertensive patients,aged 35-60 years old,not taking antihypertensive medications for 4 weeks prior to this study,received daily treatment with an oral dosage of 30 mg nifedipine GITS for 16 days.Genotypes of the Arg347Cys polymorphism in theα1A-adrenoceptor gene,Arg16Gly and Gln27Glu polymorphisms in theβ2-adrenoceptor gene were determined by TaqMan SNP genotyping assay.The 16^th day steady state plasma concentration of nifedipine was measured using high performance liquid chromatography with ultraviolet detection.Multivariate linear regression was performed in a total of 447 patients to evaluate the impacts of these polymorphisms on the blood pressure response to nifedipine GITS.[Results]:1) Patients carrying the 347Cys allele of theα1A-adrenoceptor gene had a greater systolic blood pressure reduction than those carrying two Arg347 alleles of theα1A-adrenoceptor gene(27.3±15.5mmHg versus 32.5±14.0mmHg,P=0.006).2) Diastolic blood pressure reduction was not associated with the Arg347Cys polymorphism in theα1A-adrenoceptor gene;3) No significant associations were observed between blood pressure reduction and two polymorphisms in theβ2-adrenoceptor gene.[Conclusion]:The Arg347Cys polymorphism in theα1A-adrenoceptor gene may predict the blood pressure response to nifedipine GITS in Chinese hypertensive patients. 2.Effects of L-type calcium channel blocker amlodipine or combined withα1 adrenergic antagonist terazosin on hypertension and lower urinary tract disorder in rat models[Aims]:To investigate the blood pressure lowering effects of amlodipine combined with terazosin in hypertension rat model and to investigate the effects of amlodipine, alone or combined with terazosin on urodynamics in rats with benign prostatic hyperplasia(BPH) and in female rats with detrusor instability(DI).[Method]:Two kidney 1 clip operation was conducted to induce hypertensive rat model.Model rats were semi-randomly assigned to four groups according to their body weight and blood pressure level:Model control group,amlodipine group(0.5 mg/kg),terazosin group(0.4 mg/kg) and amlodipine plus terazosin group(0.5 + 0.4 mg/kg).All the rats were intragastrically administered with assigned drugs for 28 days. Non-invasive blood pressure measurement was conducted in week 1,2,3 and 4. Rat models of BPH were induced by subcutaneous injection of testosterone(0.5 mg per rat for 21 days).Female rat models of DI were induced by partial bladder outlet ligation for 6 weeks.Model rats were intragastrically administered with assigned drugs(amlodipine,terazosin or combination of these two drugs) for 14 days in the three experiments.Continuous cystometry was performed under urethane anesthesia. [Results]:1) Systolic blood pressure(SBP) and diastolic blood pressure(DBP) in model rats were significantly increased at each timepoint.SBP and DBP in amlodipine and terazosin group were all significantly decreased.Compared with the two monotherapy group,the amlodipine plus terazosin group reached the greatest reduction on SBP and DBP.2) Amlodipine 0.5,1 and 3 mg/kg significantly decreased bladder index(BI),threshold pressure(TP),micturition pressure(MP) and significantly increased inter-micturition duration(IMD) in BPH rats.Moreover, amlodipine 0.5 mg/kg plus terazosin 0.4 mg/kg obtained the greatest improvements in all urodynamic parameters and reported greater decreased BI,TP,MP and greater increased IMD compared to either of the two drugs used alone in BPH and DI rats and showed similar efficacy compared to terazosin 1 mg/kg.The combination treatment also reached greater decreased nonvoiding bladder contraction(NVC) in DI rats.[Conclusions]:1) Amlodipine plus terazosin could efficiently decrease blood pressure in model rats,which showed more advantage on blood pressure lowering effects than amlodipine alone or terazosin alone.2) Amlodipine or combined with terazosin may have a potential for alleviating lower urinary tract symptoms(LUTS). Meanwhile,the combination therapy appears to be more suitable for LUTS with predominant irritative symptoms.3.Efficacy of combined amlodipine and terazosin therapy in male hypertensive patients with lower urinary tract symptoms:a randomized,double-blind clinical trial[Aims]:Based on the findings in the second part of the study,this trial was to investigate the therapeutic efficacy and safety of amlodipine alone or in combination with terazosin for the presence of hypertension.[Methods]:A total of 355 patients with Stage 1 or 2 hypertension and LUTS(as defined by an International Prostate Symptom Score of≥10) were randomly assigned to receive 2 mg of terazosin(n=117),5 mg of amlodipine(n=119),or 5 mg of amlodipine plus 2 mg of terazosin(n=119) once daily for a total of 28 days.The primary outcomes were a reduction in the total and subscores of the International Prostate Symptom Score and blood pressure.Analyses were performed by intention to treat.This trial is registered with ClinicalTrials.gov(No.NCT00693199).[Results]:At day 28 of the trial,the amlodipine plus terazosin group achieved the greatest blood pressure control compared with either the terazosin group(P＜0.01) or amlodipine group(P＜0.05).The amlodipine plus terazosin group also demonstrated comparable efficacy in lowering the total International Prostate Symptom Score and significant improvement in the presence of overactive bladder compared with the terazosin group(P＜0.05) and significant improvement in quality of life compared with the amlodipine group(P＜0.05).All 3 treatment regimens were well tolerated by the study patients.[Conclusions]:The results of this 4-week,double-blind,randomized trial have demonstrated that in Chinese male hypertensive patients with LUTS,low-dose amlodipine plus terazosin therapy appears to be a safe and effective combination therapy to control both conditions,especially for those with predominant overactive bladder symptoms.