The loop diuretic torasemide interferes with endothelin-1 actions in the aorta of hypertensive rats

Abstract

Background. The direct effects of torasemide and furosemide on vasoconstriction and increases in intracellular free calcium concentration ([Ca2+]i) induced by endothelin-1 (ET-1) were investigated in the aorta of spontaneously hypertensive rats (SHR). Methods. Vascular responses were assessed in endothelium-denuded aortic rings using an organ bath system. Changes of [Ca2+]i in cultured vascular smooth muscle cells (VSMCs) were assessed using fura-2 methodology. Results. ET-1-induced vasoconstriction was reduced in a dose-dependent way by torasemide and furosemide (IC50 values: 4.3 ± 1.4 × 10-5 and 9.8 ± 5.6 × 10-5 M, respectively). The ET-1-induced biphasic [Ca2+]i increase was blocked by torasemide (IC50=2.0 ± 0.2 × 10-8 and 2.7 ± 0.6 × 10-6 M, respectively). Furosemide inhibited the initial rise in [Ca2+]i induced by ET-1, with no effect on the second rise. The specific chloride (Cl-) channel blocker diphenylamine-2-carboxylate inhibits both ET-1-induced responses in VSMCs (IC50 = 8.0 ± 0.3 × 10-9 and 2.5 ± 0.7 × 10-7 M, respectively). Conclusions. These results suggest that the ability of loop diuretics to interfere with the vascular actions of ET-1 may involve different molecular mechanisms. The ability of torasemide to block the vasoconstrictive action of ET-1 could include an inhibitory action on C1- channels.