Aging and Forearm Postjunctional α-Adrenergic Vasoconstriction in Healthy Men

Dinenno, Frank A.; Dietz, Niki M.; Joyner, Michael J.

doi:10.1161/01.cir.0000028819.64790.be

Cited by 161 publications

(217 citation statements)

References 32 publications

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“…Blood vessel preparations in skeletal muscle (26) and skin (10) have identified ␣ 1 -adrenoceptors primarily in the proximal vasculature and ␣ 2 -adrenoceptors primarily in the distal vasculature. In prior human studies, the arm and leg exhibited comparable ␣ 1 -and ␣ 2 -adrenergic responsiveness (8,25,35,43), when the responsiveness was evaluated based on the changes in blood flow or vascular conductance to infused adrenergic agonists. In this study, the peak CVC responses to the highest DEX concentration were not different from those to the highest PHE concentration in the forearm and calf (Figs.…”

Section: Discussionmentioning

confidence: 99%

Limb-specific differences in the skin vascular responsiveness to adrenergic agonists

Yamazaki

Yuge

2011

Journal of Applied Physiology

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Yamazaki F, Yuge N. Limb-specific differences in the skin vascular responsiveness to adrenergic agonists. J Appl Physiol 111: 170-176, 2011. First published April 28, 2011 doi:10.1152/japplphysiol.00068.2011In this study, to test the hypothesis that adrenergic vasoconstrictor responses of the legs are greater compared with the arms in human skin, cutaneous vascular conductance (CVC) in the forearm and calf were compared during the infusion of adrenergic agonists in healthy young volunteers. Under normothermic conditions, norepinephrine (NE, ␣-and ␤-agonist, 1 ϫ 10 Ϫ8 to 1 ϫ 10 Ϫ2 M), phenylephrine (PHE, ␣1-agonist, 1 ϫ 10 Ϫ8 to 1 ϫ 10 Ϫ2 M), dexmedetomidine (DEX, ␣2-agonist, 1 ϫ 10 Ϫ9 to 1 ϫ 10 Ϫ4 M), and isoproterenol (ISO, ␤-agonist, 1 ϫ 10 Ϫ8 to 1 ϫ 10 Ϫ3 M) were administered by intradermal microdialysis. Skin blood flow (SkBF) was measured by laserDoppler flowmetry, and the local temperature at SkBF-measuring sites was maintained at 34°C throughout the experiments. CVC was calculated as the ratio of SkBF to blood pressure and expressed relative to the baseline value before drug infusion. The dose of NE at the onset of vasoconstriction and the effective dose (ED50) resulting in 50% of the maximal vasoconstrictor response for NE were lower (P Ͻ 0.001) in the calf than forearm. The ED50 for PHE and DEX was also lower (P Ͻ 0.05) in the calf than forearm. Increases in CVC in response to ISO were potentially smaller in the calf, but the statistical differences in the responses were dependent on the expressions of CVC. These findings suggest that the cutaneous vasoconstrictor responsiveness to exogenous NE is greater in the legs than in the arms due to a higher ␣1-and ␣2-adrenoceptor reactivity, while the ␤-adrenoceptor function plays a minor role in regional differences in adrenergic vasoconstriction in normothermic humans. skin blood flow; exogenous norepinephrine; ␣-adrenergic receptor; ␤-adrenergic receptor; microdialysis IN HUMANS, peripheral vasoconstrictor responses to upright posture show heterogeneity between the upper and lower limbs (14,16,22,48). The findings from previous studies suggest that the leg vasculature is more responsive to orthostatic stimulation than the arm vasculature. The augmented vasoconstrictor response observed in the human lower-leg vasculature is influenced by sympathetic and local mechanisms (14,22,24,38) and could play an important regulatory role by limiting the degree to which blood accumulates in the legs during orthostatic stress (29,30).The vasoconstrictor response to the upright posture is via reflex and nonreflex (e.g., venoarteriolar response) mechanisms. The reflex vasoconstriction is influenced by centrally driven activity in sympathetic vasoconstrictor nerves and postjunctional adrenergic receptor responsiveness. With regard to the central sympathetic outflow, similar increases in muscle sympathetic nerve activity have been shown in the arm and leg during orthostatic stress (14, 31). In addition, similar increases in regional norepinephrine (NE) spillover have been re...

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Section: Discussionmentioning

confidence: 99%

Limb-specific differences in the skin vascular responsiveness to adrenergic agonists

Yamazaki

Yuge

2011

Journal of Applied Physiology

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“…Studies in both animal models and humans indicate an age-related impairment of norepinephrine-mediated vasoconstriction in multiple vascular beds, including muscle and cutaneous thermoregulatory circulations (8,24,41,54,58). MSNA and plasma norepinephrine concentrations are elevated with advancing age (15,24,27,39,53); therefore, impairments in norepinephrine-mediated vasoconstriction have generally been attributed to sustained agonist-mediated desensitization in ␣-adrenergic receptor responsiveness (24).…”

Section: Discussionmentioning

confidence: 99%

“…Conversely, the age-related increase in MSNA during cooling may be a compensatory response as a result of age-associated reductions in ␣-adrenergic receptor responsiveness. Intriguingly, studies also suggest an age-related impairment in tonic nitric oxide "buffering" of ␣ 2 -adrenergic receptor responsiveness (31) or perhaps diminished ␣ 2 -adrenergic receptor responsiveness reflective of more generalized reductions in nitric oxide bioavailability with aging (8). Furthermore, while the sympathetic cotransmitters NPY and ATP contribute to reflex cutaneous vasoconstriction in young adults, these mechanisms are functionally absent in healthy aging; therefore, older adults instead rely entirely on impaired adrenergic-mediated vasoconstriction during cold stress (55).…”

Section: Discussionmentioning

confidence: 99%

Muscle sympathetic nerve activity during cold stress and isometric exercise in healthy older adults

Greaney

Stanhewicz

Kenney

et al. 2014

Journal of Applied Physiology

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Greaney JL, Stanhewicz AE, Kenney WL, Alexander LM. Muscle sympathetic nerve activity during cold stress and isometric exercise in healthy older adults. J Appl Physiol 117: 648 -657, 2014. First published August 7, 2014 doi:10.1152/japplphysiol.00516.2014.-Cardiovascular mortality increases in cold weather in older adults, and physical activity may impart even greater cardiovascular risk than cold exposure alone. Human aging is associated with exaggerated pressor responses to whole body cooling; however, the sympathetic response to cold stress alone and in combination with isometric exercise is unknown. We hypothesized that cold stress would 1) increase muscle sympathetic nerve activity (MSNA) and 2) augment the MSNA response to isometric handgrip in older adults. Whole body cooling (water-perfused suit) was conducted in 11 young (23 Ϯ 1 yr) and 12 healthy older adults (60 Ϯ 2 yr). Blood pressure (BP; Finometer) and MSNA (microneurography) were measured throughout cooling and during isometric handgrip at 30% maximal voluntary contraction performed at a mean skin temperature (T sk) of 34 and 30.5°C. MSNA was greater in older adults at T sk ϭ 34.0°C and throughout cooling (P Ͻ 0.05). MSNA increased during cooling in older, but not young, adults (young: ⌬0 Ϯ 1 vs. older: ⌬8 Ϯ 1 bursts/min; P Ͻ 0.05). The cooling-induced increase in BP was greater in older adults (P Ͻ 0.05). During handgrip, the increases in MSNA and BP were not different between conditions in either young (⌬14 Ϯ 2 T sk 34°C vs. ⌬12 Ϯ 3 Tsk 30.5°C bursts/min; ⌬20 Ϯ 3 Tsk 34°C vs. ⌬19 Ϯ 3 Tsk 30.5°C mmHg; both P Ͼ 0.05) or older adults (⌬12 Ϯ 1 Tsk 34°C vs. ⌬8 Ϯ 1 Tsk 30.5°C bursts/min; ⌬18 Ϯ 3 Tsk 34°C vs. ⌬17 Ϯ 2 Tsk 30.5°C mmHg; both P Ͼ 0.05). In summary, MSNA increased during cold stress in older, but not young, adults. Furthermore, concomitant cold stress did not alter the sympathetic responses to isometric exercise in either age group, suggesting preserved sympathetic responsiveness during exercise in the cold in healthy aging. blood pressure; aging; handgrip; whole body cooling AGING IS A PRIMARY RISK FACTOR for cardiovascular disease, the leading cause of death in the United States (18). Furthermore, cardiovascular-related morbidity and mortality increase at low ambient temperatures, especially in older adults (5,38,44,50,63). The acute systemic physiological responses to cold exposure include peripheral and visceral vasoconstriction, elevated plasma norepinephrine, and increased blood pressure (BP) (9,52,62). Therefore, alterations in the acute responses to cold may contribute to the clinical relation between cold temperatures and increased cardiovascular-related mortality in primary aging. Perturbations that further challenge systemic physiological function during cold exposure, such as static or dynamic exercise, may result in increased sympathetic activation and excessive increases in BP, imparting even greater risk for an acute cardiovascular event in older adults. As such, understanding age-related changes in the acute sympathetic and...

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“…However, any potential amplifying effect on Ang II-mediated vasoconstriction would be miti- gated by the well-documented decrease in postjunctional ␣-adrenergic sensitivity with advancing age. 10 In addition, there is recent evidence for the presence of the ANG II type 2 receptor subtype in skeletal muscle microcirculation, which may promote Ang II-mediated vasodilation, although recent studies suggest that a minimal impact of this subtype on limb blood flow is in healthy adults. 29 Regarding the potential contribution of endothelium-mediated vasodilation, it is noteworthy that a decline in NO and prostanoid vasodilator pathways has been reported with advancing age, 30 such that the responses to Ang II in the elderly in the present study may have been amplified by virtue of a decrease in vasodilatory opposition in the form of endogenous NO and prostaglandins.…”

Section: At 1 Receptor Sensitivity At Restmentioning

confidence: 99%

“…It is well established that elevated vasoconstrictor tone as a consequence of high sympathetic nerve activity is present in healthy, older adults, [7][8][9] despite a reduction in the sensitivity of postjunctional adrenergic vascular receptors. 10 This capacity for sustained sympathetic vasoconstriction in the face of reduced adrenergic responsiveness may be suggestive of an age-related change in nonadrenergic vasoconstrictor pathways, such as Ang II. Clinically, further characterization of age-related changes in AT 1 receptor function are particularly important, given that the combination of sympathetic and renin-angiotensin system activation adversely affects prognosis in renal and cardiovascular diseases.…”

mentioning

confidence: 99%

Angiotensin II in the Elderly

et al. 2008

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Abstract-Exercise hyperemia is attenuated in the elderly, which may be attributed to local vasoregulatory pathways within the skeletal muscle vasculature. Therefore, we sought to determine whether healthy aging is associated with changes in angiotensin II (Ang II) receptor sensitivity through measurements of leg blood flow in resting and exercising skeletal muscle. In 12 (nϭ6 young, 24Ϯ1 years; nϭ6 older, 68Ϯ3 years) healthy volunteers, we determined changes in leg blood flow (ultrasound Doppler) before and during intra-arterial infusion of Ang II (0.8 ng/mL of leg blood flow per minute). Heart rate, arterial blood pressure, common femoral artery diameter, and mean blood velocity were measured at rest and during knee-extensor exercise at 20% and 40% of the maximal work rate (WR max ). At rest, Ang II infusion decreased leg blood flow to a greater extent in older (Ϫ61Ϯ8%) subjects compared with younger subjects (Ϫ31Ϯ5%). Compared with rest, Ang II-mediated vasoconstriction (leg blood flow) during exercise was diminished in both older and younger subjects at 20% (older: Ϫ7Ϯ5%; younger: Ϫ21Ϯ2%) and 40% WR max (older: Ϫ5Ϯ4%; younger: Ϫ9Ϯ3%). These data identify a clear age-related hypersensitivity to Ang II in the resting leg, which may contribute to the recognized decrement in leg blood flow in this cohort. However, the diminished vasoconstriction to Ang II during exercise suggests that the elevation in Ang II type 1 receptor sensitivity documented at rest does not contribute significantly to the blunted exercise hyperemia experienced with advancing age. Key Words: basic science Ⅲ elderly Ⅲ blood flow regulation Ⅲ exercise Ⅲ angiotensin receptors A ngiotensin II (Ang II) acts as a potent endogenous vasoconstrictor through binding to the Ang II type 1 (AT 1 ) receptor on arteriolar vascular smooth muscle. With advancing age, there is a notable decline in plasma renin activity 1 accompanied by small decrements in circulating Ang II 2 and an increase in AT 1 receptor density. 3,4 However, the functional consequence of this age-related adaptation of the renin-angiotensin system on the peripheral circulation is not well understood. Although the pressor response to systemic Ang II infusion is elevated with age, 5 no age-specific adaptation in AT 1 receptor sensitivity has been observed with local, intra-arterial Ang II infusion in the arm. 6 Together, these studies indicate a general decline in renin-angiotensin system function with age but with uncertainty as to the impact of these changes on end-organ function and skeletal muscle hemodynamics.AT 1 receptor sensitivity to Ang II in the elderly may be especially important in the context of underlying changes in autonomic function. It is well established that elevated vasoconstrictor tone as a consequence of high sympathetic nerve activity is present in healthy, older adults, 7-9 despite a reduction in the sensitivity of postjunctional adrenergic vascular receptors. 10 This capacity for sustained sympathetic vasoconstriction in the face of reduced adrenergic responsivenes...

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Aging and Forearm Postjunctional α-Adrenergic Vasoconstriction in Healthy Men

Cited by 161 publications

References 32 publications

Limb-specific differences in the skin vascular responsiveness to adrenergic agonists

Limb-specific differences in the skin vascular responsiveness to adrenergic agonists

Muscle sympathetic nerve activity during cold stress and isometric exercise in healthy older adults

Angiotensin II in the Elderly

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