Transplantation. Jul 27;66(2) Uricosuric effect of the angiotensin II receptor antagonist losartan in heart transplant recipients. Minghelli G(1). This agent promotes uric acid excretion via effects on the organic anion transport The AIIA losartan also produces a uricosuric effect in healthy volunteers. Uricosuric medications (drugs) are substances that increase the excretion of uric acid in the urine, thus reducing the concentration of uric acid in blood plasma. In general, this effect is achieved by action on the proximal tubule of the the uricosurics benzbromarone and losartan had no effect, suggesting these drugs act.
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The angiotensin receptor blocker losartan inhibited urate transporter 1 URAT1 according to in vitro experiments.
However, it is still unknown whether the inhibitory effect of losartan on URAT1 contributes to its uricosuric action in humans. Thirty-two patients with hypertension and nine patients with idiopathic renal hypouricemia five with and four without hypertension were enrolled for this study. Before and after 1-month treatment, the serum concentration of urate Sur and creatinine Scrand the clearance value of urate Cur and creatinine Ccr were determined.
Blood pressure BP significantly decreased in the patients treated with either losartan or candesartan.
The effect of angiotensin II receptor blockers on hyperuricemia
The lack of effect of URAT1 urkcosuric on renal excretion of urate was independent uricisuric the renal function of hypouricemic patients. These findings suggested that losartan inhibited URAT1 and thereby it lowered Sur levels in hypertensive patients. The angiotensin II receptor blocker losartan lowers serum concentration of urate Kosartan in hypertensive subjects through a significant uricosuric action. Loss-of-function mutations of URAT1 cause idiopathic renal hypouricemia due to high urinary urate excretion.
Exercise-induced acute renal failure and nephrolithiasis have been reported as complications of hypouricemia. In this study, we first confirmed the uricosuric action of losartan in hypertensive patients in comparison with candesartan.
Second, we examined the effect of losartan and benzbromarone on urinary urate excretion in hypertensive patients with idiopathic hypouricemia with homozygote and compound heterozygote of loss-of-function mutations of URAT1.
Patients and clearance study in hypertensive patients. Thirty-two untreated hypertensive outpatients 66 years old on average, 24 males attending Tottori University Hospital, Shinsei Hospital, and Nosaka Clinic Yonago, Japan were enrolled for this study. None of them had gout or urinary calculi, or were they under uicosuric with oral antidiabetic agents, nonsteroidal anti-inflammatory drugs or fibrates. All the procedures carried out in this study were in accordance with the Helsinki Declaration of as revised in All patients provided written informed consent for their participation in the study whose protocol had been authorized by the ethical committee of Tottori University.
Clinic BP was measured using a mercury sphygmomanometer and a cuff of appropriate size in accordance with the American Heart Association Committee on Blood Pressure Determination. After the patient sat for 5 min, BP was measured three times at 1—2- min intervals, and the mean value was taken as the average BP for that visit. The two treatment groups were comparable in terms of age, BMI, weight, height, baseline sitting BP, fasting plasma glucose levels, serum levels of total cholesterol, and triglycerides.
Urine samples were collected from 8: Renal clearance for urate Cur and creatinine Ccr was determined as described elsewhere.
Mutation analysis of URAT1 and clearance study of hypertensive patients with idiopathic renal hypouricemia. Five hypertensive outpatients with idiopathic renal hypouricemia 49 years old on average, effwct men and four normotensive outpatients with idiopathic renal hypouricemia all women whose average age was 56 were enrolled for this study.
These patients were unrelated and provided written informed consent for the study. Renal clearance study to determine Cur and Ccr was performed as described elsewhere. A month after the benzbromarone test, the patients received 50 mg oral losartan and the same measurements were taken. Eight hypertensive subjects carrying the wild URAT1 gene matched for age and gender with five hypertensive hypouricemia patients were subjected to the benzbromarone and losartan tests.
To estimate the validity of a single period for the clearance test, we conducted probenecid and losartan loading tests in hypertensive case no.
The phase before the administration of the drug consisted of a single-clearance period of 30 min. A venous blood sample was drawn halfway through each uricosurric phase. Two-way analysis lsoartan variance with repeated measures was performed to analyze the effects of losartan and candesartan. Wilcoxon’s test was used to assess the effect effsct losartan on hypouricemic patients.
There were no statistical differences in the pre- and postadministration values between the two groups. All patients carried the wild-type SLC22A12 gene.
There were no statistical differences in the baseline values of Scr 0. Losartan induced a significant reduction in Sur 6. Losartan induced a significant increase in Oosartan 4. However, candesartan did not influence Cur 5. Because changes in renal excretion of urate induced by angiotensin receptor blockers might be influenced by renal adaptation rffect their administration, we reexamined the acute effects of candesartan before and 2 h after its administration on renal excretion of urate.
Candesartan did not influence Sur 5. Table 1 summarizes the SLC22A12 genes and clinical characteristics of five hypertensive patients and four normotensive patients with idiopathic renal hypouricemia. These findings were compatible with the diagnosis of idiopathic renal hypouricemia.
Except for CA, all other mutations were previously reported to be loss-of-function mutations. Clinical data and SLC22A12 genes of renal hypouricemic patients with or without hypertension. Table 2 shows the effect of benzbromarone and losartan on the renal excretion of urate in four hypouricemic hypertensive patients harboring URAT1 mutations hypertensive case nos.
On the other hand, in hypouricemic hypertensive patients with URAT1 mutations hypertensive case no. In hypertensive case no. In a hypertensive patient with idiopathic renal hypouricemia who harbored the wild-type URAT1 gene hypertensive case no. Effect of losartan on renal excretion of urate in a hypouricemic hypertensive uriicosuric no.
Effect of losartan and benzbromarone on renal excretion of urate in hypouricemic hypertensive patients carrying the mutant URAT1 gene. As shown in Table 4benzbromarone did not change renal excretion of urate in these two groups. Effect of benzbromarone on renal excretion of urate in URAT1-deficient hypouricemic patients distributed into those with normal Ccr and those with impaired Ccr. In this study, we found that in hypertensive patients the effects of losartan on renal excretion of urate differed significantly from those of candesartan.
We demonstrated that candesartan did not increase urate excretion 2 h after its administration, or after 1 month of treatment. In this regard, we had previously reported that losartan significantly increased urate excretion 2 h after its administration, 4 uricoosuric that the increase was similar after 1 month of treatment.
Taken together, these findings show that the effects of these angiotensin receptor blockers on urate excretion are not influenced by renal adaptation. Urate transport in the kidney involves glomerular lozartan, reabsorption, llosartan, and postsecretory reabsorption.
Moreover, renal excretion of urate has not been investigated in URAT1-deficient hypertensive patients given losartan. Idiopathic renal hypouricemia urkcosuric an inherited and heterogeneous disorder characterized by impaired tubular urate transport.
Uricosuric – Wikipedia
We could enroll only four hypouricemic patients without hypertension and five hypouricemic patients with hypertension for this study, because renal hypouricemia itself is a rare disease with an incidence of 0.
We demonstrated that losartan at a clinical dose level failed to induce uricosuria in URAT1-deficient hypouricemia patients. This is the first evidence that loss-of-function of URAT1 abolished the urate-lowering effect induced by losartan in humans. This effect of losartan was comparable with the effect of benzbromarone on the renal excretion of urate in hypertensive patients. The results of the multiple-clearance test of urate were comparable to those of the single-clearance test, demonstrating the validity of the single-clearance test.
The URAT1 inhibitor did not modify urate excretion in the URAT1-deficient patients with or without impaired renal function, indicating impaired renal function associated with idiopathic renal hypouricemia did not affect the results of the URAT1 inhibitor loading test. Urate-induced hypertension has been investigated in both experimental and clinical studies.
Thus, we postulate that losartan induces a particularly brisk response of BP regardless of Sur values. Although serum urate levels are also controlled by the production of uric acid in the liver, losartan and its active metabolite E have been reported to exert no inhibitory effects on the xanthine oxidase activity egfect an in vitro experiment.
The effect of angiotensin II receptor blockers on hyperuricemia
It has been implied that uric acid would play a role in vascular smooth muscle cell proliferation, nitric oxide synthesis, inflammation, local activation of the renin—angiotensin system, and endothelial dysfunction. In conclusion, we demonstrated that the uricosuric action of losartan was abolished in hypertensive patients who carried loss-of-function mutations in the URAT1 gene, while in hypertensive patients harboring the wild-type URAT1 gene losartan induced uricosuria, indicating that URAT1 is responsible for the uricosuric action of losartan in humans.
Oxford University Press is a department of the University of Oxford. It furthers the University’s objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account. Close mobile search navigation Article navigation. View large Download slide. Pilot study of the uricosuric effect of DuP, a new angiotensin II receptor antagonist, in healthy subjects. Interaction of nonpeptide angiotensin II receptor antagonists with the urate transport in rat renal brush-border membranes.
Effect of eposartan and losartan on uric acid metabolism in patients with essential hypertension. Effect of the angiotensin II receptor antagonist losartan on uric acid and oxypurine metabolism in healthy subjects. Renal effects of angiotensin II receptor blockade in normotensive subjects. Effects of uricosuric and antiuricosuric agents on urate transport in human brush-border membrane vesicles. Concentration-dependent mode of interaction of angiotensin II receptor blockers with uric acid transporter.
Identification of a novel voltage-driven organic anion transporter present at apical membrane of renal proximal tubule. Clinical and molecular analysis of patients with renal hypouricemia in Japan—influence of URAT1 gene on urinary urate excretion.
Renal hypouricemia with both drug-insensitive secretion and defective reabsorption of urate: A novel type of renal hypouricemia. Effect of losartan versus candesartan on uric acid, renal function, and fibrinogen in patients with hypertension and hyperuricemia associated with diuretics. Renal handling of uric acid in normal and gouty subject: The renal-specific transporter mediates facilitative transport of organic anions at the brush border membrane of mouse renal tubules.
Mutations in human urate transporter 1 gene in presecretory reabsorption defect type of familial renal hypouricemia. Excess urate excretion correlates with severely acidic urine in patients with renal hypouricemia. Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism. The impact of serum uric acid on cardiovascular outcomes in the LIFE study. Status of endothelial dependent vasodilation in patients with hyperuricemia.
Uric acid stimulates vascular smooth muscle cell proliferation and oxidative stress via the vascular renin-angiotensin system.
Uricosuric effect of losartan in patients with renal transplants.
Email alerts New issue alert. Receive exclusive offers and updates from Oxford Academic. More on this topic A comparison of the efficacy and duration of action of candesartan cilexetil and losartan as assessed by clinic and ambulatory blood pressure after a missed dose, in truly hypertensive patients: