Tonic levels of angiotensin II reduce tonic levels of vascular nitric oxide even in salt-replete man.
BACKGROUND
Losartan improves stimulated endothelial function in patients with cardiovascular disease, but there are no data to establish whether losartan has this effect in normal man. Furthermore, whether losartan improves basal nitric oxide (NO) activity is controversial. We therefore examined whether treatment with losartan improved basal NO activity in normal, salt-replete man. If so, this would imply that tonic levels of angiotensin II (Ang II) reduce tonic basal levels of NO, even in salt-replete normal man.


METHODS
We performed a randomised, placebo-controlled, double-blind crossover study in 24 healthy volunteers, comparing losartan 50 mg daily for one month versus placebo. Brachial artery endothelial function was assessed by bilateral venous occlusion plethysmography, measuring the response to intra-arterial infusions of the endothelial-dependent and endothelial-independent vasodilators, acetylcholine and sodium nitroprusside respectively and the endothelial-dependent vasoconstrictor NG-monomethyl-L-arginine. Results were analysed by multiple analysis of variance and statistical significance was taken as a p value of <or= 0.05.


RESULTS
Losartan significantly increased the vasoconstriction in response to NG-monomethyl-L-arginine (-37+2% vs. -32+2%, losartan vs. placebo; p=0.05). Losartan improved the vasodilatation response to acetylcholine; however, this result did not reach significance (214+20% vs. 174+20%, losartan vs. placebo; p=0.15). Losartan did not affect the response to nitroprusside (172+15% vs. 176+16%, losartan vs. placebo; p=0.84). There was no significant difference in blood pressure between the two study days.


CONCLUSIONS
Losartan improves basal NO bioactivity in healthy salt-replete volunteers. Even in salt-replete man, basal Ang II levels exert a tonic effect, which reduces basal NO.
Division of Medicine & Therapeutics, Ninewells Hospital & Medical School, Dundee, UK.
Justein S N
JS
Sim
Colin
C
Farquharson
Allan D
AD
Struthers
D000109:Acetylcholine / Q000008:administration & dosage; D000328:Adult; D000804:Angiotensin II / Q000502:physiology*; D000959:Antihypertensive Agents / Q000008:administration & dosage*; D001794:Blood Pressure / Q000187:drug effects; D001916:Brachial Artery / Q000187:drug effects / Q000502:physiology; D018592:Cross-Over Studies; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D006801:Humans; D019808:Losartan / Q000008:administration & dosage*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D009599:Nitroprusside / Q000008:administration & dosage; D012039:Regional Blood Flow / Q000187:drug effects; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000502:physiology; D017673:Sodium Chloride, Dietary; D014665:Vasodilator Agents / Q000008:administration & dosage; D019323:omega-N-Methylarginine / Q000008:administration & dosage
D000959:Antihypertensive Agents; D004791:Enzyme Inhibitors; D017673:Sodium Chloride, Dietary; D014665:Vasodilator Agents; D000804:Angiotensin II; D009599:Nitroprusside; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D019808:Losartan; D000109:Acetylcholine