Age-Related Characterization of Atrial Adenosine A1 Receptor Activation: Direct Effects on Chronotropic and Inotropic Function in the Fischer 344 Rat

Abstract

Adenosine, an endogenously produced nucleoside, has direct negative chronotropic and inotropic effects on right and left atrial tissues, respectively. Age-related differences in the effects of A1 adenosine receptor activation on atrial rhythmic and contractile function were investigated in adult (6-8 months) and senescent (23-24 months) Fischer 344 (F344) rats. Senescent right atria (RA) were more sensitive to the negative chronotropic effects of R-phenylisopropyladenosine (R-PIA), a selective A1 receptor agonist, than adult RA (EC50: 4.8 +/- 0.7 vs 10.8 +/- 1.5 nM). However, senescent left atria (LA) were 15.4% less responsive to the maximal negative inotropic effects of R-PIA than adult LA. R-PIA did not significantly change resting force from basal values in either age group, but 90% relaxation time was prolonged threefold in senescent LA compared with adults. Radioligand binding experiments with 1,3-[3H]dipropyl-8-cyclopentylxanthine, a selective adenosine A1 receptor antagonist, showed a 56% greater density (Bmax) of adenosine A1 receptor in senescent than adult without differences in affinities (Kd). The increased sensitivity of senescent RA to the negative chronotropic effects of adenosine A1 receptor stimulation suggests a role for adenosine in abnormal sinus node function that occurs more frequently with age. Adenosine A1 receptor stimulation has more effect on relaxation than contraction in senescent LA compared with LA from adult F344 rats. However, the increase in density of adenosine A1 receptors suggests a functional dissociation between the availability of binding sites and receptor activation.

Adenosine-mediated cardioprotection in the aging myocardium

“…Other work confirms the importance of changes in receptor-effector coupling, rather than A 1 AR expression, in dictating cardiac AR sensitivity [90]. Consistent with impaired A 1 AR activation of downstream effectors, we show A 1 AR overexpression overcomes age-related failure in adenosinergic protection and restores ischemic tolerance to levels in young tissue [16].…”

Effect of aging on the ability of preconditioning to protect rat hearts from ischemia-reperfusion injury

“…A large number of signal transduction pathways have been extensively studied in physiologically healthy young rat hearts; however, a developing body of research already demonstrates abnormalities within various signaling cascades in the aged rat heart. Age-related changes in local adenosine release, membrane-receptor sensitivity, and cardiac responses to adenosine (33) may account for the increase in susceptibility to ischemia-reperfusion injury (15,22). Alterations in G proteins do occur in different physiological and pathological states [e.g., hypertension, heart failure, and aging (25,31,38)] and probably contribute to altered responses associated with those conditions.…”

Age-related changes in A1-adenosine receptor-mediated bradycardia

“…Endogenous adenosine is thought to operate as a feedback regulator of cardiac function during periods of increased metabolic demand or impaired O 2 delivery (36). Alterations in this feedback loop may lead to age-related changes in local adenosine release, membrane receptor sensitivity, or cardiac responses to adenosine (32). During aging, myocardial contractile responses decline (9,12), coronary dilator reserve decreases (12,24), ␤-adrenergic responsiveness declines (9,21,35,36), and sensitivity to ischemic injury increases (12,18,30).…”

“…Conflicting data exist regarding the impact of age on A 1 -adenosine receptors. Some investigators have reported increased A 1 density with aging (32,40) and during development and maturation (31). Other investigators have reported no changes in A 1 receptor density with aging and an age-related decline in coupling between A 1 receptors and G␣ proteins (4).…”