Impaired modulation of sympathetic α‐adrenergic vasoconstriction in contracting forearm muscle of ageing men

Abstract

Recent evidence indicates that older healthy humans demonstrate greater vasoconstrictor tone in their active muscles during exercise compared with young adults. Therefore, we tested the hypothesis that the normal ability of muscle contractions to blunt sympathetic α-adrenergic vasoconstriction (functional sympatholysis) is impaired with age in healthy humans. We measured forearm blood flow (FBF; Doppler ultrasound) and calculated the forearm vascular conductance (FVC) responses to α-adrenergic receptor stimulation during rhythmic handgrip exercise (15% maximum voluntary contraction) and during a control non-exercise vasodilator condition (intra-arterial adenosine infusion) in seven young (25 ± 2 years) and eight healthy older men (65 ± 2 year). FVC responses to intra-arterial tyramine (evokes endogenous noradrenaline release), phenylephrine (α 1 -agonist) and clonidine (α 2 -agonist) were assessed. In young men, the vasoconstrictor responses to tyramine (−25 ± 1 versus −56 ± 6%), phenylephrine (−11 ± 4 versus −39 ± 4%) and clonidine (−12 ± 4 versus −38 ± 5%; all P < 0.005) were blunted during exercise compared with adenosine. In contrast, exercise did not significantly blunt the response to tyramine (−30 ± 2 versus −36 ± 7%; P = 0.4) or phenylephrine (−16 ± 2 versus −19 ± 3%; P = 0.3) in older men, but did attenuate the response to clonidine (−22 ± 3 versus −37 ± 6%; P < 0.05). The magnitude of functional sympatholysis, calculated as the difference in the vasoconstrictor responses during adenosine infusion and exercise, was significantly lower in older compared with young men in the presence of tyramine (−6 ± 7 versus −31 ± 6%), phenylephrine (−3 ± 3 versus −28 ± 4%) and clonidine (−15 ± 4 versus −26 ± 3%; all P < 0.05). We conclude that ageing is associated with impaired functional sympatholysis in the vascular beds of contracting forearm muscle in healthy men. These findings might help explain the greater skeletal muscle vasoconstrictor tone and reduced blood flow during large muscle dynamic exercise in older adults.

Carotid baroreflex control of arterial blood pressure at rest and during dynamic exercise in aging humans

“…However, the results suggest that although the carotid baroreflex BP function curve was reset further upward and rightward during exercise in the older group, no age-related differences in the maximal gain were observed. As such, reports of exaggerated BP responses to exercise in older individuals do not appear to be related to impaired ABR gain and may be attributable to dysregulation in other mechanisms implicated in the control of the vasculature and BP during exercise [e.g., impaired metabolic vasodilatation (40) and exaggerated sympathetic vasoconstriction (13,17)]. …”

Reactive Oxygen Species Impair Sympathetic Vasoregulation in Skeletal Muscle in Angiotensin II–Dependent Hypertension

“…33,34 Similar to our findings in hypertensive rats, sympathetic vasoconstriction is enhanced in the exercising muscles of older humans and of heart failure rats. 29,35,36 We speculate that a ROS/NO disequilibrium may be a common factor underlying the increased sympathetic vasoconstrictor responsiveness in these conditions, resulting in reduced muscle perfusion during exercise. Excessive sympathetic vasoconstriction also may cause an exaggerated rise in blood pressure during exercise, which is often seen with aging and in hypertension and heart failure and is predictive of future cardiovascular risk.…”

Angiotensin II in the Elderly

“…These data are suggestive of a powerful mechanism within the active muscle tissue, likely multiple byproducts of aerobic and/or anaerobic metabolism, that is capable of overcoming the potent vasoconstrictor effects of Ang II and, again, indicates that age-related elevations in resting AT 1 receptor sensitivity do not contribute significantly to the blunted exercise hyperemia widely observed in the elderly. [12][13][14][15] Indeed, it seems that the profound "lysing" of both nonadrenergic ( Figure 1) and adrenergic 16 vasoconstriction may be nondiscriminate yet essential events in the overall series of reactions that collectively produce a sufficient increase in skeletal muscle blood flow, raising the degree of exercise hyperemia in the elderly cohort toward that of the young.…”

“…The mechanisms responsible for this apparent reduction in vasodilatory capacity remain unknown, although studies in the forearm suggest that the augmented sympathetic vasoconstriction seen at rest may carry over during handgrip exercise in older individuals, resulting in a lesser "magnitude of sympatholysis" in older individuals. 16,17 Again, the relatively higher vasoconstriction present during exercise in older individuals may not be adrenergic in nature, but rather may be partially attributed to altered sensitivity of nonadrenergic …”