Functional coupling of overexpressed beta 1-adrenoceptors in the myocardium of transgenic mice.
To assess functional and cellular effects of myocardial beta 1-adrenoceptor overexpression, alterations of the beta-adrenergic signal transduction pathway and contractile function in transgenic mice with atrial overexpression of the human beta 1-adrenoceptor were investigated. Radioligand binding experiments confirmed a 5- to 6-fold increase in beta-adrenoceptor density and a 2.7-fold increase in high-affinity binding sites in atria of transgenic mice. Dose-response curves for isoprenaline-induced force of contraction showed unchanged maximum effects but significantly increased pD2 values. Basal, MnCl2- and isoprenaline-stimulated adenylyl cyclase activities did not significantly differ, whereas the Gpp(NH)p and forskolin effect tends to be reduced in transgenic mice. The level of Gi alpha (pertussis toxin-catalyzed ADP-ribosylation) was unchanged, whereas the bioactivity of Gs alpha (reconstitution experiments into S49 cyc- cell membranes) was reduced by about 19% in the transgenic group. These results suggest that overexpressed beta 1-adrenoceptors act as functional spare receptors. In addition, increased beta 1-adrenoceptor density is associated with a decrease in Gs alpha-activity.
Klinik III für Innere Medizin, Universität zu Köln, Germany.
O
O
Zolk
H
H
Kilter
M
M
Flesch
P
P
Mansier
B
B
Swynghedauw
P
P
Schnabel
M
M
Böhm
D000246:Adenosine Diphosphate Ribose / Q000378:metabolism; D037361:Adenylate Cyclase Toxin; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002712:Chlorides / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D003433:Crosses, Genetic; D019204:GTP-Binding Proteins / Q000378:metabolism; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006325:Heart Atria; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D007700:Kinetics; D017895:Manganese Compounds / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D037342:Pertussis Toxin; D018342:Receptors, Adrenergic, beta-1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D037361:Adenylate Cyclase Toxin; D002712:Chlorides; D017895:Manganese Compounds; D018342:Receptors, Adrenergic, beta-1; D010566:Virulence Factors, Bordetella; D005576:Colforsin; D000246:Adenosine Diphosphate Ribose; D006165:Guanylyl Imidodiphosphate; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D007545:Isoproterenol; C025340:manganese chloride