M C Kammerl1, R M Nüsing, W Richthammer, B K Krämer, A Kurtz. 1. Institut für Physiologie I, Universität Regensburg, Universitätstrasse 31, 93053 Regensburg, Germany. martin.kammerl@klinik.uni-regensburg.de
Abstract
BACKGROUND: It is well established that the diuretic- and renin-stimulated effects of loop diuretics can be attenuated by nonselective cyclooxygenase inhibitors. Since it is yet unclear which of the isoforms of cyclooxygenases, COX-1 and COX-2, is relevant in this context, our study aimed to determine the effects of selective COX-2 inhibition on the renal effects of the loop diuretic furosemide, as well as the diuretic hydrochlorothiazide, which acts on the distal tubule. METHOD: Male Sprague-Dawley rats were treated with furosemide (12 mg/day subcutaneously by osmotic pump) or hydrochlorothiazide (30 mg/kg body weight/day orally by gavage). In addition, parallel groups received rofecoxib (1 to 10 mg/kg body weight/day) for selective inhibition of COX-2. Controls were treated with vehicle. RESULTS: Induction of COX-2 mRNA expression due to furosemide was paralleled by increased renal excretion of prostanoids. Also, hydrochlorothiazide led to a rise in prostanoid excretion. Rofecoxib blunted the diuretic-induced increase in prostanoid excretion, thus confirming an effective blockade of COX-2. Moreover, the COX-2 inhibitor rofecoxib dose-dependently attenuated diuresis and saluresis, as well as the stimulation of the renin system induced by furosemide. Furthermore, rofecoxib completely reversed diuresis and saluresis and prevented the increase of plasma renin activity induced by hydrochlorothiazide. CONCLUSIONS: These findings suggest that COX-2-derived prostanoids are of major relevance in modulating the renal effects of diuretics. COX-2 inhibitors might be valuable drugs to treat salt and water wasting during Bartter and Gitelman diseases.
BACKGROUND: It is well established that the diuretic- and renin-stimulated effects of loop diuretics can be attenuated by nonselective cyclooxygenase inhibitors. Since it is yet unclear which of the isoforms of cyclooxygenases, COX-1 and COX-2, is relevant in this context, our study aimed to determine the effects of selective COX-2 inhibition on the renal effects of the loop diuretic furosemide, as well as the diuretic hydrochlorothiazide, which acts on the distal tubule. METHOD: Male Sprague-Dawley rats were treated with furosemide (12 mg/day subcutaneously by osmotic pump) or hydrochlorothiazide (30 mg/kg body weight/day orally by gavage). In addition, parallel groups received rofecoxib (1 to 10 mg/kg body weight/day) for selective inhibition of COX-2. Controls were treated with vehicle. RESULTS: Induction of COX-2 mRNA expression due to furosemide was paralleled by increased renal excretion of prostanoids. Also, hydrochlorothiazide led to a rise in prostanoid excretion. Rofecoxib blunted the diuretic-induced increase in prostanoid excretion, thus confirming an effective blockade of COX-2. Moreover, the COX-2 inhibitor rofecoxib dose-dependently attenuated diuresis and saluresis, as well as the stimulation of the renin system induced by furosemide. Furthermore, rofecoxib completely reversed diuresis and saluresis and prevented the increase of plasma renin activity induced by hydrochlorothiazide. CONCLUSIONS: These findings suggest that COX-2-derived prostanoids are of major relevance in modulating the renal effects of diuretics. COX-2 inhibitors might be valuable drugs to treat salt and water wasting during Bartter and Gitelman diseases.
Authors: Carlos P Vio; Mariana Quiroz-Munoz; Catherina A Cuevas; Carlos Cespedes; Nicholas R Ferreri Journal: Am J Physiol Renal Physiol Date: 2012-05-23
Authors: Anne Blanchard; Rosa Vargas-Poussou; Marion Vallet; Aurore Caumont-Prim; Julien Allard; Estelle Desport; Laurence Dubourg; Matthieu Monge; Damien Bergerot; Stéphanie Baron; Marie Essig; Frank Bridoux; Ivan Tack; Michel Azizi Journal: J Am Soc Nephrol Date: 2014-07-10 Impact factor: 10.121