Ageing and vascular adrenoceptor desensitization: too little, too late?



Elevated sympathetic nervous system (SNS) activity is a hallmark of healthy human ageing (Seals & Esler, 2000). Through its powerful control of blood pressure, the SNS is the primary means of ensuring adequate perfusion of vital organs during tasks ranging from standing upright to maximal exercise. One mechanism by which the SNS achieves cardiovascular homeostasis is modulation of adrenergic vasoconstriction of peripheral resistance arteries. Chronic elevations in SNS activity in older adults are targeted to specific tissues such as the heart, liver/mesentery and skeletal muscle, and may be a consequence of age-related increases in adiposity or a direct effect of ageing on the central nervous system (Seals & Esler, 2000). Thus, chronic increases in the muscle SNS activity will affect the vasculature residing in the skeletal muscle, producing an interesting physiological dilemma in older adults. How does the vasculature adapt to chronically elevated SNS activity (that acts to produce sustained α-adrenergic mediated vasoconstriction) and yet maintain adequate skeletal muscle perfusion and the ability to modulate vascular conductance in order to retain cardiovascular homeostasis?

In this issue of The Journal of Physiology Dinenno and colleagues (Smith et al. 2007) contribute another key study to an ongoing series of investigations on the interactions between human ageing, the sympathetic nervous system and vascular adrenoceptors. Earlier work demonstrated that elevations in muscle sympathetic nerve activity were associated with lower resting leg blood flow and vascular conductance in middle aged and older adults compared to their young counterparts (Dinenno et al. 1999). An elegant follow-up study established vascular α-adrenergic receptor blockade in older adults restored leg blood flow and vascular conductance to that of young individuals (Dinenno et al. 2001). These studies provided conclusive evidence of enhanced α-adrenergic vasoconstriction in the leg resistance arteries of older adults. Still, resting muscle sympathetic nerve activity, a direct measure of SNS activity, is elevated 200–300%, while resting leg blood flow is only 25–30% lower in older adults. Therefore, it appears that the elevation in SNS activity with ageing is far greater than the reduction in leg blood flow, suggesting an adaptation in the leg vasculature of older adults.

These observations led to the hypothesis that there is an age-related attenuation of α-adrenergic vasoconstriction in the leg. The present experiments by Dinenno and colleagues (Smith et al. 2007) test this hypothesis and determine if the putative impairment in vasoconstriction involves postjunctional α1- and/or α2-adrenergic receptors. Intra-femoral artery infusion of tyramine, which causes endogenous noradrenaline release from the sympathetic nerve endings, resulted in a blunted vasoconstriction in older adults (Fig. 1 in Smith et al. 2007). Furthermore, infusion of selective agonists to the α1- and α2-adrenergic receptors (phenylephrine and dexmedetomidine, respectively), resulted in diminished vasoconstriction in the older subjects suggesting an impairment of both adrenoceptor subtypes (Figs 2 and 3 in Smith et al.). These data demonstrate that ageing induces an impaired α-adrenergic vasoconstriction in the leg and this impairment is due to desensitization of both α1- and α2-adrenoceptors.

In addition to the aforementioned findings, Smith et al. have revealed age-related reductions in large muscular artery adrenergic vasoconstriction. Intrafemoral infusion of α1- and α2-adrenergic agonists induces vasoconstriction in the common femoral artery of young adults (Wray et al. 2004). The present study confirms and extends this initial observation by demonstrating that common femoral artery vasoconstriction to α1- and α2-adrenergic agonists is blunted with ageing (Fig. 4 in Smith et al.). This, indicates that the impairments in larger conduit artery adrenergic constriction are similar to the decrements seen in resistance arteries in older adults (Figs 2 and 3 in Smith et al.).

A caveat to these observations was that tyramine infusion did not alter common femoral diameter in younger or older subjects, suggesting several possibilities: first, the common femoral arteries may not be innervated with sympathetic nerve fibres; second, tyramine diffusion from the lumen of the artery to the sympathetic nerve fibres is inhibited due to the thicker femoral arterial wall leading to less noradrenaline release. Third, that tyramine-dependent noradrenaline release is occurring, but that the amount of shear stress on the vascular endothelium and tonic release of endothelium derived relaxation factors are great enough to oppose the sympathetic constriction. If femoral arteries are not innervated with SNS adrenergic neurons it would refute current dogma that these neurons innervate nearly all arterial vessels. The obvious question then would be why are adrenoceptors located on these vessels but not innervated? These observations warrant further inquiry.

The findings of Smith et al. (2007) when integrated with a previous study done in the forearm circulation (Dinenno et al. 2002) once again demonstrate profound differences in vascular regulation between the forearm and leg circulation. The forearm vasculature of older adults displays an impaired α1-adrenoceptor vasoconstriction, but this impairment appears to be sufficient to offset enhanced SNS activity. The cumulative effect is resting forearm blood flow that is similar in young and older adults. This is unlike the vasculature in the legs of older adults, which exhibits an impairment in both α1- and α2-adrenoceptor vasoconstriction and, despite this adrenoceptor desentization, has elevated adrenergic vasoconstriction that results in lower leg blood flow in older adults. Therefore, it appears that in the face of chronic elevations in SNS activity with ageing the vasculature has chosen to lower perfusion in order to minimize the impairments in adrenoceptor vasoconstriction. This may be a necessary adaptation to ensure the SNS can adequately counteract challenges to cardiovascular homeostasis.

Dinenno's aggregate work in the area of human ageing, the sympathetic nervous system, and vascular adrenoceptor function spans nearly a decade and has incorporated numerous techniques and experimental paradigms to answer salient questions. With these answers, as always, come even more questions. Therefore, we in the ageing and vascular control fields will be excited to see what comes of the next 10 years.