Probenecid

About: Probenecid is a research topic. Over the lifetime, 1511 publications have been published within this topic receiving 41290 citations. The topic is also known as: Probalan® & p-(Dipropylsulfamoyl)benzoic acid.

High-dose allopurinol improves endothelial function by profoundly reducing vascular oxidative stress and not by lowering uric acid

Abstract: Background— Allopurinol has been shown to improve endothelial function in chronic heart failure. This study aimed to establish its mechanism of action and to construct a dose–response curve for the effect of allopurinol. Methods and Results— Two randomized, placebo-controlled, double-blind, crossover studies were performed for 1 month on patients with New York Heart Association Class II–III chronic heart failure, comparing 300 mg allopurinol, 600 mg allopurinol, and placebo for the first study and 1000 mg probenecid versus placebo in the second study. Endothelial function was assessed by standard forearm venous occlusion plethysmography. Allopurinol 600 mg/d significantly increased forearm blood flow response to acetylcholine compared with both allopurinol 300 mg/d and placebo (% change in forearm blood flow [mean±SEM]: 240.31±38.19% versus 152.10±18.21% versus 73.96±10.29%, P<0.001). For similar levels of urate lowering, the uricosuric agent probenecid had no effect on endothelial function. Sodium nitrop...

The MRP4/ABCC4 Gene Encodes a Novel Apical Organic Anion Transporter in Human Kidney Proximal Tubules: Putative Efflux Pump for Urinary cAMP and cGMP

Abstract: The cyclic nucleotides cAMP and cGMP play key roles in cellular signaling and the extracellular regulation of fluid balance. In the kidney, cAMP is excreted across the apical proximal tubular membrane into urine, where it reduces phosphate reabsorption through a dipyridamole-sensitive mechanism that is not fully understood. It has long been known that this cAMP efflux pathway is dependent on ATP and is inhibited by probenecid. However, its identity and whether cGMP shares the same transporter have not been established. Here the expression, localization, and functional properties of human multidrug resistance protein 4 (MRP4) are reported. MRP4 is localized to the proximal tubule apical membrane of human kidney, and membrane vesicles from Sf9 cells expressing human MRP4 exhibit ATP-dependent transport of [(3)H]cAMP and [(3)H]cGMP. Both probenecid and dipyridamole are potent MRP4 inhibitors. ATP-dependent [(3)H]methotrexate and [(3)H]estradiol-17beta-D-glucuronide transport by MRP4 and interactions with the anionic conjugates S-(2,4-dinitrophenyl)-glutathione, N-acetyl-(2,4-dinitrophenyl)-cysteine, alpha-naphthyl-beta-D-glucuronide, and p-nitrophenyl-beta-D-glucuronide are also demonstrated. In kidneys of rats deficient in the apical anionic conjugate efflux pump Mrp2, Mrp4 expression is maintained at the same level. It is concluded that MRP4 is a novel apical organic anion transporter and the putative efflux pump for cAMP and cGMP in human kidney proximal tubules.

Oxidative stress with an activation of the renin-angiotensin system in human vascular endothelial cells as a novel mechanism of uric acid-induced endothelial dysfunction

Abstract: Aims Oxidative stress is known to be a major mechanism of endothelial dysfunction, which plays a key role in the development of cardiovascular disease. Although uric acid is one of the most important antioxidants, recent studies have suggested that uric acid may have a causal role in endothelial dysfunction. In order to understand the paradoxical association of uric acid with oxidative stress and vascular disease, we investigated whether uric acid induced oxidative stress in human vascular endothelial cells. We also examined whether uric acid-induced changes in redox status were related to aging and death of endothelial cells or an activation of local renin-angiotensin system, another mediator of endothelial dysfunction. Methods Endothelial senescence and apoptosis were evaluated by senescence-associated beta-galactosidase staining and annexin V-propidium iodide staining in primary isolated human umbilical vein endothelial cells (HUVECs). Production of reactive oxygen species was assessed by dichlorofluorescein diacetate staining. mRNA expression of angiotensinogen, angiotensin-converting enzyme and the receptors of angiotensin II was evaluated by real-time PCR, and angiotensin II levels were measured in uric acid-stimulated HUVECs. Results Uric acid-induced senescence and apoptosis in HUVECs at concentrations more than 6 and 9 mg/dl, respectively. Uric acid-induced alterations in cell proliferation, senescence and apoptosis were blocked by probenecid, enalaprilat or telmisartan. Uric acid significantly increased production of reactive oxygen species beginning at 5 min, and uric acid-induced senescence and apoptosis of HUVECs were ameliorated by N-acetylcysteine or tempol. Uric acid also upregulated the expression of angiotensinogen, angiotensin-converting enzyme and angiotensin II receptors and increased angiotensin II levels, which was ameliorated with tempol. Conclusion Uric acid-induced aging and death of human endothelial cells are medicated by local activation of oxidative stress and the renin-angiotensin system, which provides a novel mechanism of uric acid-induced endothelial dysfunction. Therapies targeting uric acid maybe beneficial in cardiovascular disease.

Probenecid, a gout remedy, inhibits pannexin 1 channels.

Abstract: Probenecid is a well-established drug for the treatment of gout and is thought to act on an organic anion transporter, thereby affecting uric acid excretion in the kidney by blocking urate reuptake. Probenecid also has been shown to affect ATP release, leading to the suggestion that ATP release involves an organic anion transporter. Other pharmacological evidence and the observation of dye uptake, however, suggest that the nonvesicular release of ATP is mediated by large membrane channels, with pannexin 1 being a prominent candidate. In the present study we show that probenecid inhibited currents mediated by pannexin 1 channels in the same concentration range as observed for inhibition of transport processes. Probenecid did not affect channels formed by connexins. Thus probenecid allows for discrimination between channels formed by connexins and pannexins.

Application of steady-state kinetics to studies of the transfer of 5-hydroxyindoleacetic acid from brain to plasma

Abstract: Probenecid, a drug that competitively inhibits the renal tubular secretion of a number of acidic substances, also blocks the efflux of 5-hy-droxyindoleacetic acid (5-HIAA) from rat brain. The rate at which 5-HIAA is accumulated after probenecid administration almost exactly equals the rate of formation of this acid from serotonin (5-HT). These results imply that 5-HIAA and perhaps other acidic products of brain metabolism are transferred directly from brain to plasma by a specialized process.