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CELLULAR |
-adrenergic vasoconstrictor responsiveness in healthy men
1 Department of Health and Exercise Science, Colorado State University, Fort Collins, CO 80523-1582, USA
2 Heart Center of the Rockies, Poudre Valley Health System, Fort Collins, CO 80528, USA
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Abstract |
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1-adrenoceptor responsiveness. In contrast, the leg circulation of older adults is under greater tonic sympathetic vasoconstriction, but it is unclear whether -adrenoceptor responsiveness is altered with age. In the present study, we tested the hypothesis that postjunctional -adrenergic vasoconstrictor responsiveness is reduced in the leg circulation with age. We measured femoral blood flow (Doppler ultrasound) and calculated the femoral vascular conductance (FVC) responses to -adrenoceptor stimulation during local blockade of 
-adrenoceptors in 12 young (24 ± 1 year) and seven healthy older men (62 ± 2 year). Whole-leg vasoconstrictor responses to local intrafemoral artery infusions of tyramine (evokes noradrenaline (NA) release), phenylephrine (1-agonist) and dexmedetomidine (2-agonist) were assessed. Consistent with previous data, resting femoral blood flow and FVC were 
30% lower in older compared with young men (P < 0.05). Maximal vasoconstrictor responses to tyramine (–30 ± 3 versus
–41 ± 3%), phenylephrine (–25 ± 4 versus
–45 ± 5%), and dexmedetomidine (–22 ± 4 versus
–44 ± 3%) were all significantly lower in older compared with young men (all P < 0.05). Our results indicate that human ageing is associated with a reduction in leg postjunctional -adrenoceptor responsiveness to endogenous NA release, and this reduction is evident for both 1- and 2-adrenoceptors. However, given that basal leg vascular conductance is reduced with age and is primarily mediated by sympathetic vasoconstriction, impaired -adrenoceptor responsiveness does not negate the ability of the sympathetic nervous system to evoke greater tonic vasoconstriction in the leg vasculature of older men.
(Received 16 February 2007;
accepted after revision 24 April 2007;
first published online 26 April 2007)
Corresponding author F. A. Dinenno: Department of Health and Exercise Science, Colorado State University, 220 Moby-B Complex, Fort Collins, CO 80523-1582, USA. Email: fdinenno{at}cahs.colostate.edu
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Introduction |
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2- to 3-fold with age in healthy adults (Sundlof & Wallin, 1978; Ng et al. 1993; Davy et al. 1998). Recent evidence indicates that this age-related increase in MSNA does not translate to the same control of basal limb vascular tone when comparing the upper and lower extremities. For example, in the forearm circulation, resting blood flow and vascular conductance are typically not different in young and older healthy men (Hogikyan & Supiano, 1994; Davy et al. 1998; Dinenno et al. 1999), and the contribution of sympathetic -adrenergic vasoconstriction to vascular tone is reduced with age (Dinenno et al. 2002). This latter observation has been attributed to a reduction in -adrenoceptor responsiveness to endogenous noradrenaline (NA) release, and appears to be selective for 1-adrenoceptors (Dinenno et al. 2002). By contrast, whole-leg blood flow and vascular conductance are reduced 25–30% with age (Dinenno et al. 1999; Moreau et al. 2003), and this has been shown to be primarily mediated by augmented sympathetic -adrenergic vasoconstriction (Dinenno et al. 2001).
In this context, it is currently not known whether any changes in -adrenoceptor responsiveness occur in the leg circulation with human ageing. To date, we have derived the only available evidence (Dinenno et al. 2001) by performing a cold pressor test in young and older healthy men and measuring the resulting changes in leg haemodynamics. We reported that the older men demonstrated vasoconstrictor responses that were 10–15% lower during sympathetic stimulation than the responses in young men. Although -adrenoceptors were blocked with propranolol to limit the potential confounding effect of circulating adrenaline and subsequent -adrenoceptor stimulation during the cold pressor test, there are some limitations that preclude clear interpretation of these data. First, the cold pressor test causes significant elevations in blood pressure which could cause baroreflex-mediated reductions in sympathetic outflow. Given that there was no measure of sympathetic activity in this study, the stimulus for vasoconstriction is unknown. Second, the elevated blood pressure during the cold pressor test could have caused local myogenic vasoconstriction. Recent evidence indicates that the myogenic response is reduced with age (Muller-Delp et al. 2002), thus further confounding the interpretation of the data with respect to sympathetically mediated vasoconstriction. Taken together, the effect of ageing on leg -adrenoceptor responsiveness to endogenous NA release remains unclear. Further, it is currently unknown whether any change in -adrenoceptor responsiveness in the leg vasculature is selective for postjunctional 1- or 2-adrenoceptors.
Therefore, we directly tested the hypothesis that ageing is associated with reduced postjunctional -adrenoceptor responsiveness in the leg circulation of healthy men. To do so, we measured whole-leg haemodynamics (Doppler ultrasound) at rest and determined the vasoconstrictor responses to -adrenoceptor stimulation in discrete groups of young and older healthy men. Our findings indicate that human ageing is associated with impaired vasoconstrictor responsiveness to endogenous NA release, and this impairment is evident for both 1- and 2-adrenoceptors.
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Methods |
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Twelve young (20–35 years) and seven older (56–71 years) healthy, non-obese men participated in the present study. All subjects were normotensive and free from overt cardiovascular disease as assessed from casual blood pressure measurements and a medical history. Older subjects were further evaluated for clinical evidence of cardiopulmonary disease with a physical examination and resting and maximal exercise electrocardiograms. All subjects were sedentary to moderately active, non-smokers, and not taking any medications. No subjects had Doppler flow characteristics suggestive of the presence of peripheral artery disease (Nomura et al. 1996). Subjects provided written, informed consent after all potential risks and procedures were explained. This study was approved by the Human Research committee of Colorado State University and was performed according to the Declaration of Helsinki.
Arterial and venous catheterization
Under aseptic conditions, a 7.6 cm, 18 gauge catheter was inserted into the common femoral artery of the right leg under local anaesthesia (2% lidocaine). The arterial catheter was connected to a pressure transducer for determination of mean arterial blood pressure (MAP) and continuously flushed at 3 ml h–1 with heparinized saline (2 U ml–1) (Dinenno et al. 2001; Halliwill et al. 2003). Subsequently, in a subgroup of five young and four older adults, another catheter (7.6 cm, 18 gauge) was also inserted into the femoral vein. Both catheters were placed 1–2 cm below the inguinal ligament.
Body composition and leg volume
Body composition was determined by dual-energy X-ray absorptiometry (DEXA; DPX-IQ, Lunar Radiation). Total leg volume and fat-free mass (FFM) were calculated from regional analysis of the right leg from whole-body DEXA scans with Lunar software version 4.7e for normalization of individual drug doses (Dinenno et al. 2001; Halliwill et al. 2003). Body mass index was calculated as body weight (kg) divided by height (metres) squared.
Whole-leg blood flow and vascular conductance
Mean blood velocity (MBV) of the common femoral artery was measured using a 4 MHz pulsed Doppler probe (Model 500V, Multigon Industries, Yonkers, NY, USA) as previously described (Dinenno et al. 1999, 2001; Halliwill et al. 2003). In order to minimize any turbulence from the bifurcation, measurements were performed 2–3 cm above the bifurcation but below the inguinal ligament and catheter insertion sites (catheter tip 7 cm proximal to measurement site). MBV measurements were performed with an insonation angle of 45 deg and the sample volume gate was adjusted to cover the width of the vessel and thus blood velocity distribution. Femoral artery diameter was measured in triplicate at each time point using a 7.0 MHz echo Doppler ultrasound probe (Hewlett-Packard Sonos 4500, Andover, MA, USA). For all subjects, femoral artery diameter was measured by the same investigator (F.A.D.) using on-screen calipers immediately following velocity measurements at the same site of the vessel. These diameters were verified off-line by another investigator (E.G.S.) who was blinded to the age of the subject.
Femoral blood flow (FBF) was calculated as:
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Femoral vascular conductance (FVC) was calculated as FBF/MAP x 100 and expressed as ml min–1 (100 mmHg)–1. Fans were directed toward the experimental leg throughout the study to minimize the contribution of skin blood flow to leg haemodynamics.
Blood samples
Plasma concentrations of cholesterol were determined after a 12 h overnight fast. Arterial and venous blood samples were obtained at selected time points for determination of NA concentrations. These samples were centrifuged and stored at –70°C for later determination of plasma NA concentrations via high-performance liquid chromatography as previously described (Dinenno et al. 2002).
Experimental protocol
All measurements were performed in the supine position after a 12 h overnight fast in a dimly lit temperature-controlled (20–22°C) room, and study drugs were administered via the femoral artery catheter. All drug doses were normalized per 100 g of leg FFM and infused via a Harvard infusion syringe pump. Drug concentrations in the syringes were calculated to keep the rates of our vasoactive infusions at 2 ml min–1 in an effort to minimize systemic effects of the study drugs. After 30 min of supine rest following catheterization, an arterial blood sample was taken for measurement of plasma NA level. Subsequently, saline was infused for 5 min and baseline measures of femoral blood flow were determined for 2 min. Next, propranolol was infused at a rate of 10 µg (100 g FFM)–1 min–1 for 5 min to block -adrenoceptors. This dose of propranolol has been shown to block forearm vasodilatation in response to isoprenaline (isoproteronol) (Johnsson, 1967). As previously described by us, -adrenergic blockade was performed to control for any direct or indirect -mediated vasodilatory effects of the study drugs (Frewin & Whelan, 1968; Torp et al. 2001), and to eliminate any potential age-related differences in -adrenoceptor responsiveness that may confound the interpretation of the data regarding -adrenoceptors (van Brummelen et al. 1981).
Postjunctional -adrenoceptor responsiveness
Tyramine was administered at 2, 4 and 8 µg (100 g FFM)–1 min–1 for 2 min to evoke endogenous NA release (Frewin & Whelan, 1968) and subsequent stimulation of both 1- and 2-adrenoceptors (Jie et al. 1987). Tyramine does not have any intrinsic vasoconstrictor properties (Frewin & Whelan, 1968). Phenylephrine was administered at 0.05, 0.1 and 0.2 µg (100 g FFM)–1 min–1 for 2 min to selectively stimulate 1-adrenoceptors, and dexmedetomidine was administered at 3.125, 6.25 and 12.5 (100 g FFM)–1 min–1for 1 min to selectively stimulate 2-adrenoceptors. We chose to administer each dose of dexmedetomidine for a shorter period of time to minimize the risk of stimulating central 2-adrenoceptors and subsequently inhibiting sympathetic outflow (Lang et al. 1997). The order of -agonist administration was randomized and counterbalanced across all subjects. Infusion trials were separated by 30 min of quiet rest and propranolol was given for 2 min at 10 µg (100 g FFM)–1 min–1 prior to -agonist infusion to ensure continuous -blockade. Because the effects of human ageing on tyramine-induced NA release and on the ability of presynaptic 2-adrenoceptors to inhibit NA release in the leg circulation are unknown, we determined venous plasma NA concentrations at baseline and at the end of each dose during tyramine and dexmedetomidine administration. Given that we were unable to obtain venous blood samples from all subjects, the presented venous NA responses to tyramine and dexmedetomidine represent the values from five young and four older men.
Data analysis and statistics
Heart rate (HR) was determined from the ECG signal (three-lead ECG) and MAP was derived from the arterial pressure waveform. HR, MAP and MBV were digitized and stored on a computer at 250 Hz and analysed off-line with signal processing software (Windaq, Dataq Instruments, Akron, OH, USA). For tyramine, phenylephrine and dexmedetomidine, the data reported represent an average of the last minute of baseline prior to drug infusion and the first 30 s immediately following each dose. Percentage changes in femoral blood flow were calculated as (baseline FBF – post-constrictor FBF)/baseline FBF x 100, and percentage changes in FVC were calculated in a similar fashion. Percentage changes in FBF and FVC were used as our primary index of vasoconstrictor responses because, under conditions of relatively constant arterial blood pressure, they are directly related to percentage changes in blood vessel radius (i.e. vasoconstriction) independent of the level of baseline vascular tone (Buckwalter & Clifford, 2001). In an effort to be comprehensive, we have also expressed the data as absolute changes in FBF and FVC from baseline.
Group differences in subject characteristics and baseline values were assessed with one-way ANOVA. Group differences in the leg haemodynamic responses to the administration of study drugs were determined by repeated-measures ANOVA. All data expressed are means ± S.E.M. Statistical significance was set a priori at P < 0.05.
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Results |
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6%; P
= 0.2), basal leg blood flow and vascular conductance were 30% lower in older men (P < 0.05; Table 1).
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-adrenoceptor responsivenessTyramine (endogenous NA release). The percentage changes from baseline in FBF and FVC in response to all three doses of tyramine were significantly less in older than in younger individuals (P < 0.05; Fig. 1). Because of the group differences in basal leg haemodynamics, age-related impairments in leg vasoconstrictor responses to tyramine were even greater when expressed as absolute changes from baseline (maximal reduction in FBF, –80 ± 10 versus –142 ± 15 ml min–1; FVC, –82 ± 14 versus –148 ± 14 ml min–1 (100 mmHg)–1 in older versus young subjects, P < 0.005). In the subgroup of subjects we obtained venous NA samples from, tyramine-evoked increases in NA tended to be greater in the older men (changes in concentration: older, 38 ± 14, 132 ± 23 and 526 ± 196 pg ml–1; young, 21 ± 19, 84 ± 19 and 224 ± 80 pg ml–1). MAP and HR were unaffected by local administration of tyramine (Table 2).
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1-adrenoceptor stimulation).
The percentage change from baseline in FBF and FVC in response to all three doses of phenylephrine was significantly less in older than in younger individuals (P < 0.05; Fig. 2). Again, the age-related impairments in leg vasoconstrictor responses to phenylephrine were greater when expressed as absolute changes in FBF and FVC (maximal reduction in FBF, –63 ± 11 versus
–150 ± 19 ml min–1; FVC, –65 ± 13 versus
–159 ± 20 ml min–1 (100 mmHg)–1 in older versus young subject, P < 0.005). MAP and HR were unaffected by local administration of phenylephrine (Table 2).
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2-adrenoceptor stimulation).
The percentage change from baseline in FBF and FVC in response to all three doses of dexmedetomidine was significantly less in older than in younger individuals (P < 0.05; Fig. 3). The age-related impairment in leg vasoconstrictor responses to dexmedetomidine were greater when expressed as absolute changes in FBF and FVC (maximal reduction in FBF, –63 ± 11 versus
–150 ± 19 ml min–1; FVC, –57 ± 11 versus
–151 ± 9 ml min–1 (100 mmHg)–1 in older versus young subjects, P < 0.005). Dexmedetomidine caused minimal and inconsistent changes in venous NA concentrations in both young (–6 ± 16, –15 ± 11 and –7 ± 29 pg ml–1) and older men (–13 ± 13, –12 ± 15 and –21 ± 14 pg ml–1). MAP and HR were unaffected by local administration of dexmedetomidine (Table 2).
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Resting femoral artery diameter was not different in young (9.3 ± 0.2 mm) and older men (9.5 ± 0.3 mm; P
= 0.7). In both groups of men, common femoral artery diameter changed minimally and non-significantly in response to tyramine (maximal change, < 2% for each group). By contrast, phenylephrine evoked significant reductions in femoral artery diameter in the young (maximal change, –0.25 ± 0.02 mm; 25%), whereas the reductions were significantly less in the older men (maximal change, –0.05 ± 0.02 mm; 5%; P < 0.05; Fig. 4A). Although the responses were less than those observed following administration of phenylephrine, young men demonstrated significant reductions in femoral diameter in response to dexmedetomidine (maximal change, –0.06 ± 0.01 mm; 6%) whereas the older men demonstrated no change (maximal change, 0.00 ± 0.00 mm; P < 0.05; Fig. 4B).
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Discussion |
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-adrenergic vasoconstrictor responsiveness to endogenous NA release is significantly reduced in older compared with young healthy men. Second, the age-related reduction in -adrenoceptor responsiveness is evident for both postjunctional 1- and 2-adrenoceptors. Third, femoral artery (conduit vessel) vasoconstriction evoked via direct 1- and 2-receptor agonists is significantly impaired in the older men. In light of the observations that (a) basal leg blood flow and vascular conductance are reduced with age, and (b) that this is mediated primarily by greater tonic sympathetic -adrenergic vasoconstriction (Dinenno et al. 2001), the reduction in 1- and 2-adrenoceptor responsiveness in the leg circulation with age does not negate the ability of the sympathetic nervous system to evoke greater tonic vasoconstriction in the leg vasculature of older men.
Ageing and postjunctional -adrenergic responsiveness
Previous studies have demonstrated that sympathetic vasoconstrictor responsiveness is reduced with age in the human forearm (Hogikyan & Supiano, 1994; Davy et al. 1998; Dinenno et al. 2002). Specifically, we recently demonstrated that postjunctional -adrenergic responsiveness to endogenous NA release stimulated via tyramine infusion via the brachial artery was significantly impaired in older men (Dinenno et al. 2002). Further, we also determined whether this impairment observed with age was selective for postjunctional 1- and 2-adrenergic receptors. Our findings indicated that the forearm vasoconstrictor responses to the selective 1-agonist (phenylephrine) were reduced, whereas the responses to the 2-agonist (clonidine) were preserved with age. Taken together, these data indicated that older men have a reduced forearm vasoconstrictor response to endogenous NA release and that this reduction might be specific for postjunctional 1-adrenoceptors (Dinenno et al. 2002).
Prior to the present investigation, no studies had directly tested whether postjunctional -adrenergic responsiveness is reduced in the leg circulation of older healthy humans. Because of differential sympathetic control of upper and lower limb basal vascular tone (i.e. greater tonic constriction in the leg with age; Dinenno & Joyner, 2006), we believed it was important to isolate the leg vasculature and directly determine -adrenoceptor responsiveness in young and older adults. The results of our study provide the first direct evidence of reduced postjunctional -adrenoceptor responsiveness in the leg circulation with age. We found that leg vasoconstrictor responses to endogenous NA release (evoked via tyramine) were reduced at each dose of drug in the older men. Additionally, leg vasoconstrictor responses to direct 1- and 2-adrenoceptor stimulation (via phenylephrine and dexmedetomidine, respectively) were also significantly impaired with age. Thus, in contrast to the forearm, age-associated reductions in -adrenergic responsiveness in the leg circulation are evident for both 1- and 2-adrenoceptors and do not appear to be specific for a single receptor subtype.
The physiological reason underlying the contrasting effect of ageing on 2-adrenoceptor responsiveness in the arm and leg vasculature is currently unknown. In young healthy subjects, tonic and/or stimulated (via endothelial 2-adrenoceptors) nitric oxide has been shown to limit the vasoconstrictor responses to 2-agonists (Lembo et al. 1997, 2000). Thus, in our original study in the forearm circulation, we speculated that the observed age-related reductions in tonic and/or stimulated nitric oxide might ‘mask’ a possible age-related reduction in 2-vasoconstrictor responsiveness (Dinenno et al. 2002). In other words, it is possible that forearm 2-adrenoceptor responsiveness is in fact impaired with age, but the buffering of the vasoconstrictor response via nitric oxide is also reduced with age. Together, the net effect of these influences on vascular tone would be observed as ‘normal’
2-vasoconstrictor responsiveness in older adults. With respect to the leg circulation, it is interesting to note that recent evidence indicates that endothelium-dependent vasodilatation (evoked by acetylcholine or substance P infusion via the femoral artery) is preserved with age even though smooth muscle cell responsiveness to nitric oxide is reduced (Newcomer et al. 2005). Therefore, if this reflects maintained or possibly augmented tonic and/or stimulated nitric oxide bioavailability in the leg circulation with age, a similar buffering of 2-mediated vasoconstriction in young and older adults would occur and might explain our observation of reduced 2-adrenoceptor responsiveness in the leg vasculature of ageing humans. Clearly, future studies will be needed to directly test this hypothesis.
Ageing and common femoral artery diameter: conduit vessel constriction
During our experiments, it was apparent that some of the -agonists were causing significant vasoconstriction of the common femoral artery (i.e. reductions in femoral artery diameter). Tyramine, which stimulates endogenous NA release, did not result in a significant change in femoral artery diameter in the young or older subjects. This most probably reflects the fact that sympathetic nerves primarily innervate small resistance vessels, whereas the large common femoral artery may not be highly innervated. By contrast, phenylephrine (1-agonist) and dexmedetomidine (2-agonist) both elicited significant femoral artery vasoconstriction in the young subjects, with the responses to phenylephrine being the greatest in magnitude. These data are in agreement with recent findings by Wray et al. (2004) who also observed significantly greater femoral artery vasoconstriction in response to direct 1-stimulation compared with 2-stimulation. Evidence of more pronounced vasoconstriction in response to 1-agonists in young subjects may indicate that 1-adrenoceptors are primarily located upstream in larger arterioles and conduit arteries, while 2-adrenoceptors are primarily located in the smaller resistance vessels. This idea is consistent with data in various animal models (McGillivray-Anderson & Faber, 1990; Anderson & Faber, 1991). To the best of our knowledge, changes in common femoral artery diameter in response to -agonists have not previously been studied in older individuals. Our findings clearly indicate that older men were much less responsive to both 1- and 2-mediated vasoconstriction of the common femoral artery.
Experimental considerations
In the present study, we calculated our vasoactive drug doses relative to whole-leg FFM (versus whole-limb volume) in an effort to minimize any systemic effects. In this context, we were successful in this process as there were no significant changes in MAP or HR during infusion of any of the -adrenergic agonists. It is important to note that given that there were no significant age-related differences in leg FFM or leg volume, the relative amount of drug administered to young and older subjects was similar, and therefore cannot explain the reduced -adrenergic responsiveness with age. Additionally, based on recent findings, we chose to administer dexmedetomidine to directly stimulate 2-adrenoceptors (Masuki et al. 2005). Thus, one could question whether the age-related reduction in 2-adrenergic responsiveness in the leg circulation (compared with the forearm) is due to the use of this particular agonist, as we used clonidine in our previous study in the forearm (Dinenno et al. 2002). However, given that dexmedetomidine has greater selectivity for 2-adrenoceptors than clonidine (Masuki et al. 2005), this clearly cannot explain the discrepancy between leg and arm 2-adrenoceptor responsiveness in older healthy adults. Finally, in the present study, there were no age-group differences in basal plasma NA concentrations. Although plasma NA concentrations are not an ideal marker of sympathetic outflow to skeletal muscle under resting conditions (Davy et al. 1998; Seals & Esler, 2000), it is possible that this could indicate a lack of elevation in sympathetic activity in this group of older men. If this were the case, we may have underestimated the age-related impairments in -adrenoceptor responsiveness in the leg vasculature.
Experimental limitations
To date, the mechanisms responsible for the reduction in postjunctional -adrenergic responsiveness observed with age are unknown. Several possibilities exist that could contribute to these age-related changes including reductions in -adrenoceptor density, which could be due to an agonist-mediated down-regulation of -adrenoceptors as a result of chronically elevated sympathetic nerve activity (Seals & Dinenno, 2004). Additionally, impairments in NA binding to postjunctional receptors and/or impairments in the intracellular signalling pathways could also be involved. Finally, it is also possible that elevated MSNA and subsequent NA release with age could result in more occupied -adrenoceptors, and that further increases in NA release via tyramine or direct binding of the 1- and 2-agonists may be limited because of less unoccupied binding sites.
In the present study, we obtained femoral venous blood samples from only a subgroup of young and older men. This is important in that tyramine and dexmedetomidine can affect NA release from sympathetic nerve endings. With respect to tryamine, our data indicate that, if anything, the older men released more NA in response to each dose of drug as compared with the young men. This is consistent with what we found in our previous study in the forearm (Dinenno et al. 2002). Thus, the age-related impairment in leg vasoconstrictor responses to tyramine most probably cannot be explained by age-group differences in NA release. In fact, if we had been able to obtain venous samples from all subjects and these trends had continued, the age-related reduction in vasoconstrictor responsiveness to tyramine would have been even more pronounced after accounting for NA release. With respect to dexmedetomidine, the reductions in venous NA in response to dexmedetomidine were small and inconsistent in both groups of men, and thus cannot explain the age-group differences 2-vasoconstrictor responsiveness.
Local infusions of phenylephrine and dexmedetomidine into the femoral artery evoked significant reductions in common femoral artery diameter, which clearly influences our calculated vasoconstrictor responses. Given that the common femoral artery most probably is not exposed to chronic neurally released NA and subsequent -adrenoceptor stimulation, these receptors might be influenced by the ageing process differently than smaller, highly innervated resistance vessels. However, the responses to direct 1- and 2-adrenoceptor stimulation are consistent with the responses observed to endogenous NA release via tyramine and together, indicate an age-associated impairment in -adrenoceptor responsiveness.
Potential significance
There are several physiological implications associated with a reduction in -adrenergic control of skeletal muscle circulation in older individuals. A reduction in postjunctional -adrenoceptor responsiveness to NA released from sympathetic nerve endings can disrupt sympathetic control of vascular conductance/resistance thereby influencing blood pressure regulation. Specifically, this reduction can contribute to impairments in baroreflex buffering (Jones et al. 2003) which can adversely affect the ability of older adults to maintain perfusion pressure in response to vasoactive drugs, as well as physiological conditions that challenge blood pressure regulation (e.g. orthostasis and postprandial stress). Presently, the overall functional significance of 1-and 2-mediated vasoconstriction of the femoral artery is not known. Our findings of no change in femoral artery diameter in response to tyramine but clear vasoconstriction to direct 1- and 2-agonists lead us to speculate that these postjunctional luminal receptors might be involved in the regulation of peripheral vascular resistance under extreme stress conditions (e.g. haemorrhagic shock, prolonged orthostasis and/or heat stress) that are associated with large rises in circulating catecholamines (Bond & Johnson, 1985; Rowell, 1986). If this were the case, the impaired vasoconstrictor responses in older adults at this level of the vasculature would significantly reduce their ability to regulate arterial pressure under such conditions.
Although not directly related to the present study, our findings provide some insight into impaired sympathetic control of vascular tone during exercise in ageing humans. Recent findings from our laboratory and others indicate that the ‘normal’ ability of muscle contractions to limit the degree of vasoconstriction (functional sympatholysis) is significantly impaired in older healthy adults (Koch et al. 2003; Fadel et al. 2004; Dinenno et al. 2005). Specifically, a recent study by Koch et al. (2003) demonstrated that the sympathetic vasoconstrictor responses evoked via cold pressor test were greater in exercising leg muscles of older adults, whereas the responses were virtually absent in the young. The findings of the present study indicate a significant impairment in both postjunctional 1- and 2-adrenoceptor responsiveness in the leg vasculature at rest, and are consistent with our earlier findings in response to a cold pressor test (Dinenno et al. 2001). Taken together, we believe this highlights a shift in -adrenoceptor responsiveness with age, such that it is reduced at rest but augmented in contracting muscle of older adults. As discussed in a recent review (Dinenno & Joyner, 2006), we believe the age-associated increases in basal sympathetic vasoconstrictor tone and impaired modulation of -adrenoceptor responsiveness in older adults could have significant implications for reduced muscle blood flow and augmented blood pressure during exercise, and potentially contribute to exercise intolerance in ageing humans.
Conclusions
The results from the present investigation demonstrate that leg postjunctional -adrenergic vasoconstrictor responsiveness to endogenous NA release is reduced with age in healthy men, and this reduction in responsiveness is evident for both 1- and 2-adrenergic receptors. However, given that basal leg blood flow and vascular conductance are significantly reduced with age and that this is mediated primarily by augmented sympathetic vasoconstriction, the age-related reduction in 1- and 2-adrenoceptor responsiveness with age does not negate the ability of the sympathetic nervous system to evoke greater tonic vasoconstriction in the leg vasculature of older men.
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