Na+,2Cl−,K+ cotransport system as a marker of antihypertensive activity of new torasemide derivatives

Abstract

A series of compounds related to torasemide, a loop diuretic, were synthesized and examined for their diuretic potency and inhibitory activity on the erythrocyte and renal medullary thick ascending limb vesicle Na+,2Cl−,K+ cotransport in Milan hypertensive (MHS) and normotensive (MNS) rat strains, where previous studies had demonstrated an alteration of the cotransport system genetically related to hypertension. From the results of the screening, structure-activity relationships were drawn and two compounds, JDL 961 and C 2921 were selected. Their IC50 on renal vesicle cotransport were similar in the two strains (JDL 961: MHS = 1.8 μM; MNS = 1.2 μM; C 2921: MHS = 4 μM; MNS = 3.8 μM), and were 4–8 times lower than those of torasemide (MHS = 13 μM; MNS = 31 μM, P < 0.01) and 50–60 times lower than those of bumetanide (MHS = 145 μM; MNS = 206 μM, P < 0.05) taken as reference compounds. Their ability to reduce the development rate of hypertension was tested both in MHS and in Okamoto spontaneously hypertensive rats (SHR) strain, in which cotransport alterations are opposite to those of MHS. Both torasemide derivatives (7.5 mg·kg−1 os per day) prevented development of hypertension in the two strains. The time course of this hypotensive activity was faster and the percentage of blood pressure fall greater in MHS (20–25%) than in SHR rats (12–15%), even though the absolute value of blood pressure fall was similar in MHS (JDL 961 = −17 mm Hg; C 2921 = −30 mm Hg) and SHR (JDL 961 = −25 mm Hg; C 2921 = −20 mm Hg). A superimposable effect of bumentanide was observed in the two strains, but at 8 times higher daily dose (60 mg·kg−1). These results suggest that new loop diuretics can be selected for their antihypertensive activity on the basis of their in vitro potency in inhibiting the Na+,2Cl−,K+.