title: 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.
authors.affiliation: Clinical Pharmacology and Gerontology Research Unit, Department of Veterans Affairs Medical Center, Boise, Idaho, USA.
authors.forename: S C
authors.initials: SC
authors.lastname: Montamat
authors.forename: R D
authors.initials: RD
authors.lastname: Olson
authors.forename: R V
authors.initials: RV
authors.lastname: Mudumbi
authors.forename: R E
authors.initials: RE
authors.lastname: Vestal
mesh_terms: D000241:Adenosine / Q000502:physiology; D000375:Aging / Q000502:physiology*; D000818:Animals; D016275:Atrial Function / Q000187:drug effects; D016279:Atrial Function, Left / Q000187:drug effects; D016280:Atrial Function, Right / Q000187:drug effects; D001665:Binding Sites / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D010660:Phenylisopropyladenosine / Q000494:pharmacology; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D011916:Rats, Inbred F344; D018047:Receptors, Purinergic P1 / Q000502:physiology*; D012849:Sinoatrial Node / Q000187:drug effects / Q000502:physiology; D014316:Tritium; D014970:Xanthines / Q000494:pharmacology
chemical_list: D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1; D014970:Xanthines; D014316:Tritium; D010660:Phenylisopropyladenosine; C051360:1,3-dipropyl-8-cyclopentylxanthine; D000241:Adenosine