Endothelium-dependent vasodilatation and exercise hyperaemia in ageing humans: impact of acute ascorbic acid administration

Abstract

Age-related increases in oxidative stress impair endothelium-dependent vasodilatation in humans, leading to the speculation that endothelial dysfunction contributes to impaired muscle blood flow and vascular control during exercise in older adults. We directly tested this hypothesis in 14 young (22 +/- 1 years) and 14 healthy older men and women (65 +/- 2 years). We measured forearm blood flow (FBF; Doppler ultrasound) and calculated vascular conductance (FVC) responses to single muscle contractions at 10, 20 and 40% maximum voluntary contraction (MVC) before and during ascorbic acid (AA) infusion, and we also determined the effects of AA on muscle blood flow during mild (10% MVC) continuous rhythmic handgrip exercise. For single contractions, the peak rapid hyperaemic responses to all contraction intensities were impaired approximately 45% in the older adults (all P < 0.05), and AA infusion did not impact the responses in either age group. For the rhythmic exercise trial, FBF (approximately 28%) and FVC (approximately 31%) were lower (P = 0.06 and 0.05) in older versus young adults after 5 min of steady-state exercise with saline. Subsequently, AA was infused via brachial artery catheter for 10 min during continued exercise. AA administration did not significantly influence FBF or FVC in young adults (1-3%; P = 0.24-0.59), whereas FBF increased 34 +/- 7% in older adults at end-exercise, and this was due to an increase in FVC (32 +/- 7%; both P < 0.05). This increase in FBF and FVC during exercise in older adults was associated with improvements in vasodilator responses to acetylcholine (ACh; endothelium dependent) but not sodium nitroprusside (SNP; endothelium independent). AA had no effect on ACh or SNP responses in the young. We conclude that acute AA administration does not impact the observed age-related impairment in the rapid hyperaemic response to brief muscle contractions in humans; however, it does significantly increase muscle blood flow during continuous dynamic exercise in older adults, and this is probably due (in part) to an improvement in endothelium-dependent vasodilatation.

Figure 1. Experimental time line

Following placement of the brachial artery catheter and general setup, subjects received a 5 min intra-arterial infusion of either acetylcholine (ACh) or sodium nitroprusside (SNP) to assess endothelium-dependent or endothelium-independent vasodilatation, respectively. Next, single 1 s dynamic forearm muscle contractions were performed at 10, 20 and 40% MVC in triplicate and in random order. Noted as Trial 1, rhythmic handgrip (HG) exercise was performed at 10% MVC for 5 min with saline to achieve ‘steady-state’ haemodynamics, and the next 10 min consisted of continued exercise with concurrent ascorbic acid infusion to give a total of 15 min. The dose of ascorbic acid was then reduced to 40% of the original dose and infused for the remainder of the experiment. During maintenance ascorbic acid administration, endothelium-dependent and -independent vasodilatation was again tested, followed by single contractions, and then a second 5 min rhythmic handgrip exercise trial (Trial 2). See text for further details.

Figure 2. Dynamic rapid hyperaemic responses to single forearm muscle contractions at 10, 20 and 40% MVC

The peak hyperaemic response occurred at 3–4 cardiac cycles post-contraction for all exercise intensities regardless of age or ascorbic acid administration. There were significant age group differences in contraction-induced rapid vasodilatation for all intensities, and ascorbic acid did not impact this response in either young or older adults. *P < 0.05 vs. older.

Figure 3. Forearm hyperaemic responses to mild rhythmic handgrip exercise before and during ascorbic acid infusion

Prior to ascorbic acid, absolute forearm blood flow tended to be lower in older vs. young adults during mild intensity steady-state exercise (A; *P = 0.06–0.09 for minutes 1–6). When expressed as percentage increases from baseline, forearm hyperaemic responses were significantly reduced in older adults (B; *P < 0.05 for minutes 1–10). Infusion of ascorbic acid significantly increased forearm blood flow in older, but not young adults during continued exercise. †P < 0.05 vs. steady-state exercise within older group for minutes 7–15.

Figure 4. Peak effect of ascorbic acid on forearm blood flow and vascular conductance during steady-state exercise

Acute infusion of ascorbic acid increased forearm blood flow by ∼30% in older adults, whereas the increase was minimal and non-significant in young adults (A). Similar responses were observed when quantified as changes in vascular conductance, indicating that the increase in blood flow was due to local vasodilatation (B). *P < 0.05 vs. young.

Figure 5. Effect of ascorbic acid on forearm blood flow from rest to steady-state handgrip exercise

When ascorbic acid was administered prior to the onset of exercise, forearm blood flow increased to similar levels within 1 min of exercise in young and older adults and this persisted throughout the exercise trial (A). In B, forearm blood flow at rest and after 5 min of steady-state exercise from Trial 1 (no ascorbic acid; control) and Trial 2 (concurrent ascorbic acid infusion) are shown. †P < 0.05 vs. without ascorbic acid within age group.

Figure 6. Forearm vasodilatation to intra-arterial infusion of acetylcholine and sodium nitroprusside in young and older adults

At baseline, percentage increases in forearm blood flow to acetylcholine (ACh) (endothelium dependent) were significantly impaired in older compared with young adults, and this age-associated impairment was abolished during ascorbic acid infusion (A). Older adults also had an impaired forearm blood flow response to sodium nitroprusside (SNP) (endothelium independent) at baseline, and this was unaffected during ascorbic acid infusion (B). *P < 0.05 vs. young; †P < 0.05 vs. without ascorbic acid within age group.