Effect Of GRK4 Variation On Blood Pressure Fluctuations And The Efficacy Of Long-term Treatment With Candesartan

Background:Essential hypertension and its complications have become the first major disease to human health, prevention and treatment for hypertension can significantly reduce the incidence ofcardiovascular and cerebrovascular disease. However, the current control rate of hypertension in china is far lower than the western developed countries. Previous studies found that the patients with similar clinical symptoms will get different antihypertensive effect when given same dose of the antihypertensive drug, it may be associated with that drug metabolism associated genes and target genes appear to variant. Our previous study found that GRK4 variants will lead to its own activity increased, thus increase the function of AT1 R and affect the kidneys urinary sodium excretion and vasomotor function, eventually leading to hypertension. Previous studies have found that calcium channel gene variants increase the antihypertensive effect of calcium channel blockers; β-receptor variants also increased β-blockers metoprolol antihypertensive effect; the patients with AT1 receptor variants A1166 C will get better ACEI antihypotensive effect.Some studies have found that there is very large difference of efficacy between patients in the course of clinical treatment of candesartan. The candesartan targets is AT1 R, and the mutation of GRK4 will affect AT1 R function, Therefore, we conjecture that GRK4 variants may affect the antihypertensive efficacy of candesartan,and the variants may lead to patient’s blood pressure variability and morning peak phenomenon vary by influence renin-angiotensin system. This study will focus on effect on the fluctuation of blood pressure change and on the Candesartan antihypertensive of GRK4 variation.Methods:Outpatient and inpatient 651 people were interviewed in department of cardiology Daping Hospital from 2012 September to 2015 March, and 303 cases agreed to participate in the study, 187 cases met the criteria, 63 cases leaved for various reasons;so finally we get 124 cases.65 cases of male patients, female patients 59 cases of which. Eligible patients were systolic ≥140mm Hg and(or) diastolic blood pressure ≥90 mm Hg,and their age greater than 40 years old but less than 70 years old, no tumors, kidney disease and other secondary hypertension. By PCR direct sequencing method, we get patients GRK4 gene variation,and then we grouped patients.We 24 h get patients 24 h mean systolic and diastolic blood pressure changes in each group by ambulatory blood pressure monitor after give patients Candesartan 4mg / times / day 4 weeks. Results: GRK4 mutation will affect circadian blood pressure fluctuation, blood pressure fluctuations of patients with A142 V, A486 V mutation were mainly non-dipper, but R65 L mutation and wild type patients were mainly dipper. After giving a patient Candesartan 4 mg / times / day for 4 weeks, the decrease in blood pressure, drop of morning peak, increase of T/P ratio, elevation of blood pressure smoothness index of GRK4 mutation patiens is more significantly than GRK4 wild type patients, which shows that GRK4 variation will affect the antihypertensive effect of candesartan, and the mutation patiens will get better antihypertensive effect.Results:1. The influence of GRK4 mutation on fluctuation of blood pressure : fluctuations of blood pressure in patients with GRK4 A142 V, GRK4 A486 V mutation was major non-dippers(percentage of non-dippers in GRK4 A142 V patients is 68.4%, and percentage of GRK4 A486 V is 72.7%),but GRK4 R65 L mutation has no influence on mode of blood pressure(percentage of non-dippers in R65 L patients is 55.6%,);2. The influence of GRK4 mutation on candesartan antihypertensive effect:After given candesartan for 4 weeks, decrease in blood pressure, decline in morning peak, increased rate of T/P ratio, increase of blood pressure smoothness index of GRK4 mutation patients are more obvious than wild type patients,which suggests that GRK4 mutation may influence candesartan antihypertensive effect, patients with GRK4 mutation may get better antihypertensive effect.Conclusions:1.GRK4 A142 V, A486 V mutation in patients is associated with blood pressure spoon and non-spoon distribution;2. The drug reactions of candesartan in patients with GRK4 mutation may be better than GRK4 wild-type patients.