Furosemide Enhances the Release of Endothelial Kinsis, 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.