Aging: changes in cardiac alpha 1-adrenoceptor responsiveness and expression.
Several investigators have reported a diminished responsiveness of senescent cardiac muscle to norepinephrine and beta-adrenoceptor agonists. In contrast, relatively little is known regarding the effects of aging on myocardial actions mediated specifically by alpha-adrenoceptor stimulation. Thus, the current study examined aging-dependent changes in: (a) the inotropic response to methoxamine, an alpha-adrenoceptor agonist; (b) characteristics of myocardial alpha 1-adrenoceptors as monitored by specific [3H]prazosin binding; and (c) steady state levels of alpha 1-adrenoceptor mRNA as determined by Northern blot analysis. Cardiac preparations were isolated from 4-, 14-, and 25-month-old F344 rats. An aging-associated decline was observed in the maximum positive inotropic effect elicited by methoxamine in right ventricular strips (160 +/- 23, 134 +/- 13 and 79 +/- 26% increase above control developed tension in 4, 14 and 25 months, respectively) with no change in ED50 values. [3H]Prazosin binding to ventricular sarcolemmal membranes revealed a reduction in receptor number (82 +/- 7, 69 +/- 6 and 59 +/- 5 fmol/mg protein in 4, 14 and 25 months, respectively); the apparent dissociation constant was not affected. Steady state levels of alpha 1-adrenoceptor mRNA decreased progressively between 4 and 25 months of age (14- and 25-month levels were approximately 71 and 38% of 4 months, respectively), while steady state levels of beta-actin mRNA did not change with age. These results suggest that the aging-related decline in alpha 1-adrenergic responsiveness in rat ventricular muscle is mediated, at least in part, by a decrease in cardiac alpha 1-adrenoceptor density.(ABSTRACT TRUNCATED AT 250 WORDS)
Kimball
K A
KA
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock 72205.
Cornett
L E
LE
Seifen
E
E
Kennedy
R H
RH
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000375:Aging / Q000502:physiology*; D000818:Animals; D001665:Binding Sites; D015152:Blotting, Northern; D002316:Cardiotonic Agents / Q000494:pharmacology; D006321:Heart / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008729:Methoxamine / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism / Q000648:ultrastructure*; D011224:Prazosin / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D011916:Rats, Inbred F344; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology; D014316:Tritium; D016278:Ventricular Function, Right / Q000187:drug effects
D000316:Adrenergic alpha-Agonists; D002316:Cardiotonic Agents; D012333:RNA, Messenger; D011942:Receptors, Adrenergic, alpha; D014316:Tritium; D008729:Methoxamine; D011224:Prazosin