AGE-RELATED EFFECTS IN RABBIT HEARTS OF N-6-R-PHENYLISOPROPYLADENOSINE, AN ADENOSINE A(1) RECEPTOR AGONIST

Interventions known to increase cytoplasmic Ca2+ appear to amplify age -related impairment of cardiac function. In addition, increased releas e of interstitial adenosine, an endogenous nucleoside, has been sugges ted to mediate the diminished beta-adrenergic responsiveness in senesc ent heart. However, the direct effects of adenosine A(1) receptor acti vation on senescent myocardium have not been investigated thoroughly. Therefore, the effects of N-6-R-phenylisopropyladenosine (R-PIA), an A (1) agonist, on atrial rate and contractility (+dF/dt) in adult (6-8 m onths) and senescent (5-7 years) New Zealand White rabbits were compar ed in spontaneously beating right atria and electrically stimulated is olated right papillary muscles. Although senescent right atria appeare d to be more sensitive to the negative chronotropic-effects of R-PIA, the effective concentrations producing 50% of the maximum response (EC (50) values) of R-PIA were not significantly different between adult ( 26 nM, 95% confidence limits: 12-52 nM) and senescent (13 nM; 95% conf idence limits: 10-16 nM). However, senescent right ventricular papilla ry muscles were more sensitive to the negative inotropic effects of R- PIA. For example, at 90 contractions/min, 100 nM R-PIA decreased +dF/d t 25.3 +/- 7.4% and 61.9 +/- 4.8% in adult and senescent papillary mus cles, respectively. To investigate whether R-PIA might alter sarcoplas mic reticulum (SR) function as a mechanism of decreased inotropy, we d etermined the inotropic effects of R-PIA on steady-state and 30-s post rest-potentiated contractions (PRP; art index of SR Ca2+ release) of l eft atria. R-PIA did not selectively decrease contractility of PRP com pared to steady state in either adult or senescent left atria. Binding experiments in crude ventricular homogenates using 1,3-[H-3]dipropyl- 8-cyclopentylxanthine ([H-3]DPCPX), a selective A(1) receptor antagoni st radioligand, showed a 50% greater density (B-max) of A(1) receptor in senescent than adult without differences in affinities (K-d). The a ge-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 A(1) receptor. These re sults suggest that A(1) receptor activity may contribute to regulation of the inotropic state of senescent myocardium.