Furosemide enhances the release of endothelial kinins, nitric oxide and prostacyclin.
Despite a wealth of data, the mechanism of the direct dilator effect of furosemide on the systemic arterial and venous systems is far from being satisfactorily understood. Therefore, we investigated whether furosemide is capable of stimulating the production of the endogenous vasodilators nitric oxide and prostacyclin in primary cultured bovine aortic endothelial cells by an enhanced synthesis and release of endothelium-derived kinins. Nitric oxide production was assessed in terms of intracellular guanosine cyclic-3',5' monophosphate accumulation; kinin and prostacyclin release were determined by specific radioimmunoassays. Furosemide concentration- and time-dependently increased the formation of nitric oxide and prostacyclin. Maximal increases of both autacoids were already obtained after a 5-min incubation with 3 x 10(-7) to 10(-6) mol/l of furosemide. In the same concentration range, furosemide led to an enhanced release of kinins into the supernatant of the cells. This observation was supported by the inhibitory effect of the specific B2 kinin receptor antagonist icatibant (Hoe 140) on the furosemide-induced increase of nitric oxide and prostacyclin. Thus the hemodynamic effects, and in particular the direct early dilator effect, of furosemide may be explained in part by an enhanced endothelial synthesis and release of bradykinin and related kinins, which in turn stimulates endothelial autacoid formation via B2 kinin receptor activation.
Wiemer
G
G
Hoechst AG, SBU Cardiovascular Agents, Frankfurt/Main, Germany.
Fink
E
E
Linz
W
W
Hropot
M
M
Schölkens
B E
BE
Wohlfart
P
P
D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000378:metabolism; D011464:Epoprostenol / Q000096:biosynthesis*; D005665:Furosemide / Q000494:pharmacology*; D007705:Kinins / Q000096:biosynthesis*; D009569:Nitric Oxide / Q000096:biosynthesis*
D007705:Kinins; D009569:Nitric Oxide; D005665:Furosemide; D011464:Epoprostenol; D006152:Cyclic GMP