title: Anti-hypertensive effects of probenecid via inhibition of the α-adrenergic receptor.
abstract: Probenecid has long been used in the treatment of gout. Its anti-gout mechanisms consist of uric acid reuptake inhibition and the consequent facilitation of uric acid excretion. In the present study, we investigated whether probenecid could exert an anti-hypertensive effect in spontaneously hypertensive rats (SHR). The noninvasive indirect tail cuff method was employed to measure blood pressure and heart rate. The administration of probenecid (50 mg/kg, ip) induced a significant systolic blood pressure (SBP) decrease, from 167 mmHg to 141 mmHg, within 120 min. In contrast, probenecid had little effect on normotensive control Wistar Kyoto rats (WKY). The anti-hypertensive effects of probenecid are almost as potent as those of atenolol. In a further exploration of the anti-hypertensive mechanisms of probenecid, its effects on phenylephrine-induced blood vessel contraction were tested. Our results suggest that probenecid significantly inhibited the contractions of rat aorta. This effect was also observed with endothelium-removed rat aorta, suggesting that probenecid can directly interact with the α-adrenergic receptor. Moreover, probenecid inhibited the α-adrenergic-receptor-mediated activation of ERK I/II in MC3TC-E1 cells. Therefore, our results indicate that probenecid might alleviate high blood pressure in SHR via inhibition of the α-adrenergic receptor and ERK I/II.
authors.affiliation: Department of Pharmacology and Toxicology, Metabolic Diseases Research Laboratory, School of Dentistry, Kyung Hee University, Seoul, Korea.
authors.forename: Jin Baek
authors.initials: JB
authors.lastname: Park
authors.forename: Sung-Jin
authors.initials: SJ
authors.lastname: Kim
mesh_terms: D041721:3T3-L1 Cells; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D001262:Atenolol / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002460:Cell Line; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000187:drug effects; D048052:Mitogen-Activated Protein Kinase 3 / Q000187:drug effects / Q000378:metabolism; D011339:Probenecid / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000317:Adrenergic alpha-Antagonists; D000959:Antihypertensive Agents; D011942:Receptors, Adrenergic, alpha; D001262:Atenolol; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D011339:Probenecid