Age-Related Effects in Rabbit Hearts of N6-R-Phenylisopropy ladenosine, an Adenosine A1 Receptor Agonist

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Abstract
Interventions known to increase cytoplasmic Ca2+ appear to amplify age-related impairment of cardiac function. In addition, increased release of interstitial adenosine, an endogenous nucleoside, has been suggested to mediate the diminished β-adrenergic responsiveness in senescent heart. However, the direct effects of adenosine A, receptor activation on senescent myocardium have not been investigated thoroughly. Therefore, the effects of N6-Rphenylisopropyladenosine (R-PIA), an A1 agonist, on atrial rate and contractility ( + dF/dt) in adult (6–8 months) and senescent (5–7years) New Zealand White rabbits were compared in spontaneously beating right atria and electrically stimulated isolated right papillary muscles. Although senescent right atria appeared to be more sensitive to the negative chronotropic-effects of R-PIA, the effective concentrations producing 50% of the maximum response (EC50 values) of R-PIA were not significantly different between adult (26 nM, 95% confidence limits: 12–52 nM) and senescent (13 nM; 95% confidence limits: 10–16 nM). However, senescent right ventricular papillary muscles were more sensitive to the negative inotropic effects of R-PIA. For example, at 90 contractions/min, 100 nM R-PIA decreased + dF/dt 25.3 ± 7.4% and 61.9 ± 4.8% in adult and senescent papillary muscles, respectively. To investigate whether R-PIA might alter sarcoplasmic reticulum (SR) function as a mechanism of decreased inotropy, we determined the inotropic effects of R-PIA on steady-state and 30s postrest-potentiated contractions (PRP; an index of SR Ca2+ release) of left atria. R-PIA did not selectively decrease contractility of PRP compared to steady state in either adult or senescent left atria. Binding experiments in crude ventricular homogenates using 1,3 [3H]dipropyl-8-cycopentyLeanthine (PHJDPCPX), a selective A, receptor antagonist radioligand, showed a 50% greater density (Bmax of A1 receptor in senescent than adult without differences in affinities (Kd. The age-related direct inhibitory effect of R-PIA on contractility appears to be unrelated to alterations in SR function, but may be due, in part, to an age-related increase in the density of A1 receptor. These results suggest that A1 receptor activity may contribute to regulation of the inotropic state of senescent myocardium.

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