Impaired nitric oxide-mediated vasodilatation and total body nitric oxide production in healthy old age.
1. Basal release of nitric oxide from the vascular endothelium maintains a constant vasodilating tone. Impaired nitric oxide-mediated vasodilatation has been described in hypertension and atheromatous disease. Circulatory diseases account for considerable morbidity and almost half of all deaths in people over the age of 75 years. 2. We have therefore compared nitric oxide-dependent vasorelaxation in 12 healthy elderly subjects with 12 young volunteers matched for blood pressure, cholesterol and glucose, using forearm occlusion venous plethysmography combined with brachial artery infusions of the nitric oxide synthase inhibitor, NG-monomethyl-L-arginine (L-NMMA; 1, 2 and 4 mumol/min) with noradrenaline (60, 120 and 240 pmol/min) as a control vasoconstrictor. We also measured urinary nitrate excretion after a controlled 48 h low nitrate diet as an index of total body nitric oxide production and correlated these changes with forearm blood flow responses to L-NMMA and noradrenaline in both groups. 3. The mean age and blood pressure of the elderly subjects was 76 (range 66-82) years and 132/76 (SEM 4/3) mmHg respectively, while in the young these were 27 (20-35) years and 131/72 (4/3) mmHg respectively. L-NMMA and noradrenaline produced dose-dependent reductions in forearm blood flow in both groups. L-NMMA (4 mumol/min) produced less vasoconstriction in the elderly than in the young (-37.7 +/- 2.6 versus -48.3 +/- 4.2%; P = 0.017). The mean slope of the L-NMMA dose-response curves in the elderly was significantly less than the younger group (-35.2 +/- 3.1 versus -63.7 +/- 10.6; P = 0.041). Noradrenaline, 240 pmol/min, also produced less vasoconstriction in the elderly compared with the young (-22.8 +/- 2.9 versus -35.3 +/- 5.0%; P = 0.029) although the slopes of the dose-response curves did not differ significantly. 4. Urinary nitrate adjusted for creatinine clearance was also significantly higher in the younger group (460.6 +/- 97.7 versus 205.9 +/- 64.8 mumol/day; P = 0.042) and showed a significant correlation with the percentage change in forearm blood flow in response to the maximum dose of L-NMMA (r = 0.5, P = 0.046). 5. We conclude that nitric oxide-mediated vasodilatation in the forearm vascular bed is diminished in old age and this reflects a more generalized reduction in nitric oxide production (as measured by urinary nitrate) in the circulation of older people. The blunted response to noradrenaline points to a more generalized reduction in vascular reactivity in the elderly.
Lyons
D
D
Clinical Age Research Unit, King's College School of Medicine and Dentistry, London, U.K.
Roy
S
S
Patel
M
M
Benjamin
N
N
Swift
C G
CG
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003430:Cross-Sectional Studies; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005542:Forearm / Q000098:blood supply; D006801:Humans; D008297:Male; D009566:Nitrates / Q000652:urine; D009569:Nitric Oxide / Q000096:biosynthesis / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009638:Norepinephrine / Q000494:pharmacology; D010991:Plethysmography; D012039:Regional Blood Flow / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000502:physiology*; D019323:omega-N-Methylarginine / Q000494:pharmacology
D009566:Nitrates; D014662:Vasoconstrictor Agents; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D009638:Norepinephrine