Angiotensin-converting enzyme inhibition alters nitric oxide and superoxide release in normotensive and hypertensive rats.
Young (approximately 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 approximately 2 years with, respectively, placebo, low doses, or high doses of an angiotensin-converting enzyme inhibitor, ramipril (10 microg x kg[-1] x d[-1], non-blood pressure-lowering dose, or 1 mg x kg[-1] x 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.
Wiemer
G
G
Hoechst Marion Roussel, DG Research Cardiovascular, Frankfurt/Main, Germany.
Linz
W
W
Hatrik
S
S
Schölkens
B A
BA
Malinski
T
T
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D000001:Calcimycin / Q000494:pharmacology; D002339:Carotid Arteries / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006973:Hypertension / Q000378:metabolism*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D017257:Ramipril / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012016:Reference Values; D013481:Superoxides / Q000378:metabolism*
D000806:Angiotensin-Converting Enzyme Inhibitors; D013481:Superoxides; D009569:Nitric Oxide; D000001:Calcimycin; D019001:Nitric Oxide Synthase; D017257:Ramipril