Impaired alpha1-adrenergic responses in aged rat hearts.
To determine age-related changes in the cardiac effect of alpha1-adrenergic stimulation, both cardiomyocyte Ca2+-transient and cardiac protein kinase C (PKC) activity were measured in 3-month- (3MO) and 24-month- (24MO) old Wistar rats. Ca2+ transients obtained under 1 Hz pacing by microfluorimetry of cardiomyocyte loaded with indo-1 (405/480 nm fluorescence ratio) were compared in control conditions (Kreb's solution alone) and after alpha1-adrenergic stimulation (phenylephrine or cirazoline, an alpha1-specific agonist). PKC activity and PKC translocation index (particulate/total activity) were also assayed before and after alpha1-adrenergic stimulation. In 3MO, cirazoline induced a significant increase in Ca2+ transient for a 10(-9) M concentration which returned to control values for larger concentrations. In contrast, in 24MO, we observed a constant negative effect of cirazoline on the Ca2+ transient with a significant decrease at 10(-6) M compared with both baseline and Kreb's solution. Preliminary experiments showed that, in a dose-response curve to phenylephrine, the response of Ca2+ transient was maximal at 10(-7) M. This concentration induced a significant increase in Ca2+ transient in 3MO and a significant decrease in 24MO. The same concentration was chosen to perform PKC activity measurements under alpha1-adrenergic stimulation. In the basal state, PKC particulate activity was higher in 24MO than that in 3MO but was not different in cytosolic fractions; so that the translocation index was higher in 24MO (P < 0.01). After phenylephrine, a translocation of PKC toward the particulate fraction was observed in 3MO but not in 24MO. In conclusion, cardiac alpha1-adrenoceptor response was found to be impaired in aged hearts. The negative effect of alpha1-adrenergic stimulation on Ca2+ transient in cardiomyocytes obtained from old rats can be related to an absence of alpha1-adrenergic-induced PKC translocation.
Montagne
Olivier
O
Unité INSERM U400, Faculté de Médecine de Créteil, Université Paris 12, 94000 Créteil, France.
Le Corvoisier
Philippe
P
Guenoun
Thierry
T
Laplace
Monique
M
Crozatier
Bertrand
B
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000375:Aging / Q000502:physiology*; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects; D002469:Cell Separation; D004558:Electric Stimulation; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects; D009929:Organ Size / Q000187:drug effects; D010656:Phenylephrine / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects*
D000316:Adrenergic alpha-Agonists; D007093:Imidazoles; D018340:Receptors, Adrenergic, alpha-1; D010656:Phenylephrine; D011493:Protein Kinase C; C014282:cirazoline