Hypertension, Vol 18, 558-563, Copyright © 1991 by American Heart Association
G Wiemer, BA Scholkens, RH Becker and R Busse
We studied whether inhibition of angiotensin converting enzyme stimulates
the formation of nitric oxide and prostacyclin in cultured human and bovine
endothelial cells by an enhanced accumulation of endothelium-derived
bradykinin. Nitric oxide formation was assessed in terms of intracellular
cyclic GMP accumulation, prostacyclin release by a specific
radioimmunoassay. Inhibition of angiotensin converting enzyme by ramiprilat
dose- and time-dependently increased the formation of nitric oxide and
prostacyclin. These increases, peaking within 10 minutes, were maintained
for at least 60 minutes. The ramiprilat- induced cyclic GMP increase was
completely abolished by the stereospecific inhibitor of nitric oxide
synthase, NG-nitro-L-arginine. The B2-kinin receptor antagonist, Hoe 140
(0.1 microM), markedly attenuated the cyclic GMP accumulation and abolished
the increase in prostacyclin release. The supernatant of endothelial cells,
incubated with ramiprilat (0.3 microM) for 15 minutes, elicited a
significant nitric oxide release (as assessed by a guanylyl cyclase assay)
in untreated endothelial cells used as detector tissue. Preincubation of
the detector cells with Hoe 140 completely abolished this nitric oxide
release. These data indicate that cultured endothelial cells from different
species are capable of producing and releasing bradykinin into the
extracellular space in amounts that lead to a sustained stimulation of
nitric oxide and prostacyclin formation, provided that bradykinin
degradation is prevented by angiotensin converting enzyme inhibition. Thus,
the protective effect of angiotensin converting enzyme inhibitors observed
on endothelial vasomotor function in hypertension may be explained by the
local accumulation of endothelium- derived bradykinin that acts in an
autocrine and paracrine manner as potent stimulus for endothelial autacoid
formation.
ARTICLES
Ramiprilat enhances endothelial autacoid formation by inhibiting breakdown of endothelium-derived bradykinin
Hoechst AG, Frankfurt/Main, FRG.
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