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(Hypertension. 1997;30:1183-1190.)
© 1997 American Heart Association, Inc.
Articles |
Angiotensin-Converting Enzyme Inhibition Alters Nitric Oxide and Superoxide Release in Normotensive and Hypertensive Rats
From Hoechst Marion Roussel, DG Research Cardiovascular, Frankfurt/Main, Germany (G.W., W.L., B.A.S.); and the Department of Chemistry, Institute of Biotechnology, Oakland University, Rochester, Mich (S.H., T.M.).
Correspondence to Prof Tadeusz Malinski, Department of Chemistry, Institute of Biotechnology, Oakland University, Rochester, MI 48309-4401.
Abstract Young (
1 month old) male normotensive
Wistar-Kyoto rats (n=26) and spontaneously hypertensive rats (n=38)
were randomized into three groups treated via drinking water for 2
years with, respectively, placebo, low doses, or high doses of an
angiotensin-converting enzyme inhibitor,
ramipril (10 µg · kg-1 ·
d-1, non–blood pressure–lowering dose, or 1
mg · kg-1 ·
d-1, blood pressure–lowering dose). Relative
to placebo treatment in each respective rat strain, both ramipril
dosages increased endothelial constitutive nitric oxide
synthase expression (Western blot) and resultant synthesis of nitric
oxide (porphyrinic sensor) in freshly excised carotids and thoracic
aortas, respectively. Paradoxically, this activity was associated with
an increased/decreased superoxide accumulation (chemiluminescence) in
freshly excised aortas from 24-/22-month-old
normotensive/hypertensive rats. In normotensive rats, relative to
placebo treatment, the threefold increase in superoxide accumulation
with antihypertensive ramipril treatment is most likely from the
>300% increase in endothelial constitutive nitric
oxide synthase expression (some of which may be disarranged by local
insufficiencies in L-arginine or tetrahydrobiopterin). In
hypertensive rats, relative to placebo treatment, the 35% increase in
nitric oxide availability by long-term antihypertensive ramipril
treatment may contribute to the preservation of the
endothelium and prevent its dysfunction by inhibiting
superoxide production. Increased nitric oxide
production with concomitant decreased superoxide accumulation
(approximately one third of placebo levels) correlates positively with
the previously reported +40% life span extension for rats with genetic
hypertension that were treated with antihypertensive doses of ramipril.
Key Words: ramipril • nitric oxide • nitric oxide synthase-III • hypertension • aging • endothelium • superoxide
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