Two important aspects which contribute to plasma NA spillover should be additionally considered: (a) the release of NA from sympathetic nerve endings is modulated at presynaptic level by adrenergic receptors and (b) active reuptake processes are implicated in getting back up to the 80–90 % of the released neurotransmitter. Therefore, age-dependent alterations within these mechanisms may considerably contribute to changes in plasma NA spillover (Fig. 9.1). To this regard, an age-related reduction of presynaptic α2 receptors function has been reported in the rat [26–28] which may participate in elevating the amount of the released NA. In the rat heart, xylazine, an α2 agonist, showed an age-associated reduced potency at inhibiting cardioacceleration to nerve stimulation [28]. In humans, the status of these receptors in the heart is not known; however, at peripheral level, it has been demonstrated that changes in α2 adrenoceptor expression in the setting of heart failure do lead to altered NA spillover [29]. Presynaptic β-adrenoceptors have been documented on some noradrenergic nerve terminals, where they favor neurotransmitter release and are mainly represented by β2 adrenoceptors [30]. It has been hypothesized that they are targeted by circulating adrenaline, which manifests a much higher affinity than NA [31]. The β2 agonists procaterol and isoprenaline are significantly less able to enhance the stimulation-evoked release of NA in atria from old animals with respect to young rats [32], thus suggesting an age-related reduction of presynaptic β-adrenoceptors function. However, the precise role of these receptors in the regulation of neurotransmission and whether their aged-associated alterations are important still remain to be established.

Concerning reuptake mechanisms, a variety of studies, performed both in humans and animals, documented that in the heart, a reduction in NA reuptake is involved in the apparent age-dependent rise of NA release [33–35]. Indeed, a diminished NA reuptake has been implicated in the almost double increase of cardiac plasma NA spillover rate found in older healthy in comparison to young men [1]. The effectiveness of neuronal reuptake mechanisms can be examined employing cocaine, where a decline in these processes would correspond to a decreased capability of cocaine to improve neurotransmission. Indeed, in rat atria from old animals, cocaine has little effect in potentiating the stimulation-evoked release of NA in comparison to young rats [32]. Focusing on the heart, it has been postulated that the reduction in the efficacy of reuptake mechanisms is a cellular strategy useful to compensate the age-related decline in NA responsiveness, thus helping to preserve the contractile function.

Aging is associated with several changes involving noradrenergic transmission, resulting in a modified response to the transmitters (Fig. 9.1). Within this context, α-adrenoreceptor antagonists have been used to determine age-dependent modifications of blood pressure. No changes in hypotensive effects of α1-adrenoreceptors antagonists have been documented with senescence; indeed, in men, the hypotensive actions of prazosin and phentolamine have been reported unchanged by senescence [28].

Following catecholamine release, myocardial responses are mainly mediated by beta-adrenergic receptors, being β1 receptors significantly predominant. Therefore, β-adrenoceptor antagonists can be employed to evaluate age-dependent alterations in noradrenergic control of cardiac output and heart rate. To this regard, it has been found that β-antagonists are effective in lowering blood pressure in older subjects [36] and that, in the elderly, propranolol (a nonselective β-blocker) is as effective in decreasing heart rate and cardiac output during exercise [37], although causes larger falls in systolic blood pressure. Moreover, it has been demonstrated that isoproterenol (a β1-selective agonist) induces a reduced response in older subjects, thus suggesting a decline of cardiac β1-receptors during senescence [25, 38]. Although the issue regarding the age-associated decline of β1-receptors is still controversial, more consistent data support the existence of an impairment of post-receptor signaling during senescence [39]. Accordingly, Brodde et al. [40] demonstrated that in aged human atria, besides only a tendency of a reduction of β1-receptors, there is a significant impairment in the activation of the adenylyl cyclase by isoproterenol, terbutaline (a β2-selective agonist), and forskolin (an activator of adenylyl cyclase). However, it was reported that neither G protein-coupled receptor kinases nor inhibitory G proteins seem to contribute to the age-related decline of cardiac β-adrenergic receptors responsiveness [41]. Maximum exercise heart rate diminishes with senescence, thus potentially limiting the performance during acute exercise [42]. The intrinsic pacemaker rate of the heart, examined in the absence of outside influence (i.e., following blocking both sympathetic and vagal control via propranolol and atropine administration, respectively), also declines with aging [43], and this has been related to a reduced number of pacemaker cells [44]. Hence, a reduced intrinsic pacemaker rate coupled with a weakened responsiveness of pacemaker cells to β-receptor activation may account for the decreased maximal heart rate observed during senescence [32].

Concerning the parasympathetic branch, several studies have documented an age-associated decrease in the parasympathetic control of heart rate [45], although the underlying mechanisms are still uncertain. Within this context, it has been postulated that alterations in presynaptic control of acetylcholine release, a decline in muscarinic M2 receptor density, and changes in postsynaptic cholinergic signaling may all contribute to this dysfunction [46, 47]. In particular, in human atria, the reduction of M2 receptors was associated with a decreased capability of carbachol (a muscarinic agonist) to inhibit both the activation of adenylyl cyclase and the force of contraction mediated by forskolin [48]. Curiously, Liu et al. [49] found the presence of antibodies against M2 receptors in healthy subjects, reporting an increase of the frequency with increasing age. Taken together, these data indicate that in the human heart, the number and the functional responsiveness of M2 receptors are impaired with senescence.