Moreover, a decrease in the catecholamine stimulated adenylate cyclase activity in rat myocardium [
69] and in the sensitivity of βARs, measured by isoproterenol-induced changes in pulse rate and blood pressure [
70], had been reported. The age-linked decline in cardiac βAR response, which is consistent across species, seems to be primarily due to a down-regulation of β
1ARs, as reported in aged explanted human hearts [
71]. Intriguingly, such feature is similar to what seen in patients with heart failure. Actually, whether ageing causes a selective downregulation of cardiac βAR (β
1AR
vs β
2AR) remains a moot point. Whereas a non-selective decline in both β
1AR and β
2AR has been reported in rat senescent cardiac tissue [
67], a selective decrease in β
1AR has been described in ventricular myocytes isolated from aged rats [
72]. Many of the modifications that occur in the sympathetic nervous system with ageing (increased circulating catecholamines and hyposensitivity to adrenergic stress, as with exercise, isoproterenol infusion and other agents used to assess cardiovascular reserve) are also common in patients with heart failure [
32]. Other potential mechanisms underlying these peculiar aspects are decreased agonist binding of β
1AR, uncoupling of β
2AR, involvement of cardiac β
3AR and abnormal G-protein mediated transduction. Remarkably, unlike heart failure, there is no evidence of upregulation of G
i proteins with ageing [
67,
73]. The compartmentalization of the receptors may also partake in the decreased βAR responsiveness. Indeed, whereas β
1ARs are widely distributed on the plasma membrane, β
2ARs are usually located in the transverse tubules, which are invaginations of the plasma membrane containing several proteins that couple membrane depolarization (excitation) to calcium-mediated myofilament shortening (contraction). Thus, the peculiar localization of β
2AR in cardiac cells leads to the generation of spatially restricted cAMP production, affecting thereby calcium dependent proteins that control the contraction of myofilaments [
74,
75]. A disrupted localization of β
2AR has been recently described in chronically failing cardiomyocytes [
76], with significant functional sequelae [
77]. A similar remodeling of cell surface topography may be involved in ageing, but no specific studies are currently available to confirm such hypothesis. Importantly, conditions presenting a depressed cardiac function elicit activity (fight or flight response [
78]) from the sympathetic nervous system to increase cardiac output and to divert blood flow to critical organs. Catecholamines are fundamental actors of this system. The fact that the release of these hormones is strictly controlled by GPCRs relates the adrenal gland and the heart in a ’long-distance affair’ [
79,
80]. Unfortunately, the relationship between ageing and βARs has not been extensively investigated in chromaffin cells. However, several studies have demonstrated that β
2AR is definitively involved in the regulation of cathecolamines secretion by the adrenal gland [
81‐
84].