caa a22 4500 469078952 CHVBK 20180323132944.0 cr unu---uuuuu 170328e19920101xx s 000 0 eng 10.1007/BF00175468 doi (NATIONALLICENCE)springer-10.1007/BF00175468 Isoprenaline-induced increase in the 40/41 kDa pertussis toxin substrates and functional consequences on contractile response in rat heart [Elektronische Daten] [Ulrike Mende, Thomas Eschenhagen, Birgit Geertz, Wilhelm Schmitz, Hasso Scholz, Jan Schulte am Esch, Rainer Sempell, Markus Steinfath] Summary: Chronic β-adrenoceptor stimulation leads to desensitization of the myocardial adenylyl cyclase signalling pathway which includes β-adrenoceptor downregulation and upregulation of Gi-protein α-subunits. However, these investigations have mainly been done in cellular preparations. In this study we report that isoprenaline infusion in vivo leads to an increase in myocardial Gia and present evidence for functional consequences of this increase. Rats were treated by a 4-day subcutaneous infusion with isoprenaline (2.4 mg/kg·d), propranolol (9.9 mg/kg·d) and triiodothyronine (T3, 0.5 mg/kg·d) for comparison. Isoprenaline treatment increased the pertussis toxin-sensitive amount of Gia by 22±6% and decreased β1- and β2-adrenoceptor density from 35±4 to 23±6 fmol/mg protein and 24±4 to 8±6 fmol/mg protein, respectively. Contraction experiments on electrically driven papillary muscles revealed that the negative inotropic potency of the M-cholinoceptor agonist carbachol in the presence of isoprenaline was increased as compared to control (mean EC50-values: 0.04 μmol/l vs. 0.28 μmol/l). All isoprenaline-induced effects were antagonized by simultaneously administered propranolol. T3 treatment had no influence on the parameters investigated. The results suggest that chronic β-adrenoceptor stimulation desensitizes myocardial adenylyl cyclase by at least two mechanisms: β-adrenoceptor downregulation leading to diminished signal transduction in the stimulatory pathway and Giα upregulation leading to sensitization of the inhibitory pathway. Such adaptation might protect the heart from chronic exposure to catecholamines in heart diseases with elevated plasma catecholamine levels. Springer-Verlag, 1992 Gi-protein nationallicence Force of contraction nationallicence β-Adrenoceptor nationallicence Isoprenaline infusion nationallicence Rat heart nationallicence Mende Ulrike Abteilung Allgemeine Pharmakologie, Universitäts-Krankenhaus Eppendorf, Universität Hamburg, Martinistrasse 52, W-2000, Hamburg 20, Federal Republic of Germany aut Eschenhagen Thomas Abteilung Allgemeine Pharmakologie, Universitäts-Krankenhaus Eppendorf, Universität Hamburg, Martinistrasse 52, W-2000, Hamburg 20, Federal Republic of Germany aut Geertz Birgit Abteilung Allgemeine Pharmakologie, Universitäts-Krankenhaus Eppendorf, Universität Hamburg, Martinistrasse 52, W-2000, Hamburg 20, Federal Republic of Germany aut Schmitz Wilhelm Abteilung Allgemeine Pharmakologie, Universitäts-Krankenhaus Eppendorf, Universität Hamburg, Martinistrasse 52, W-2000, Hamburg 20, Federal Republic of Germany aut Scholz Hasso Abteilung Allgemeine Pharmakologie, Universitäts-Krankenhaus Eppendorf, Universität Hamburg, Martinistrasse 52, W-2000, Hamburg 20, Federal Republic of Germany aut Schulte am Esch Jan Abteilung Allgemeine Pharmakologie, Universitäts-Krankenhaus Eppendorf, Universität Hamburg, Martinistrasse 52, W-2000, Hamburg 20, Federal Republic of Germany aut Sempell Rainer Abteilung Allgemeine Pharmakologie, Universitäts-Krankenhaus Eppendorf, Universität Hamburg, Martinistrasse 52, W-2000, Hamburg 20, Federal Republic of Germany aut Steinfath Markus Abteilung Allgemeine Pharmakologie, Universitäts-Krankenhaus Eppendorf, Universität Hamburg, Martinistrasse 52, W-2000, Hamburg 20, Federal Republic of Germany aut Naunyn-Schmiedeberg's Archives of Pharmacology Springer-Verlag 345/1(1992-01-01), 44-50 0028-1298 345:1<44 1992 345 210 https://doi.org/10.1007/BF00175468 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/BF00175468 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Mende Ulrike Abteilung Allgemeine Pharmakologie, Universitäts-Krankenhaus Eppendorf, Universität Hamburg, Martinistrasse 52, W-2000, Hamburg 20, Federal Republic of Germany aut NATIONALLICENCE 700 1- Eschenhagen Thomas Abteilung Allgemeine Pharmakologie, Universitäts-Krankenhaus Eppendorf, Universität Hamburg, Martinistrasse 52, W-2000, Hamburg 20, Federal Republic of Germany aut NATIONALLICENCE 700 1- Geertz Birgit Abteilung Allgemeine Pharmakologie, Universitäts-Krankenhaus Eppendorf, Universität Hamburg, Martinistrasse 52, W-2000, Hamburg 20, Federal Republic of Germany aut NATIONALLICENCE 700 1- Schmitz Wilhelm Abteilung Allgemeine Pharmakologie, Universitäts-Krankenhaus Eppendorf, Universität Hamburg, Martinistrasse 52, W-2000, Hamburg 20, Federal Republic of Germany aut NATIONALLICENCE 700 1- Scholz Hasso Abteilung Allgemeine Pharmakologie, Universitäts-Krankenhaus Eppendorf, Universität Hamburg, Martinistrasse 52, W-2000, Hamburg 20, Federal Republic of Germany aut NATIONALLICENCE 700 1- Schulte am Esch Jan Abteilung Allgemeine Pharmakologie, Universitäts-Krankenhaus Eppendorf, Universität Hamburg, Martinistrasse 52, W-2000, Hamburg 20, Federal Republic of Germany aut NATIONALLICENCE 700 1- Sempell Rainer Abteilung Allgemeine Pharmakologie, Universitäts-Krankenhaus Eppendorf, Universität Hamburg, Martinistrasse 52, W-2000, Hamburg 20, Federal Republic of Germany aut NATIONALLICENCE 700 1- Steinfath Markus Abteilung Allgemeine Pharmakologie, Universitäts-Krankenhaus Eppendorf, Universität Hamburg, Martinistrasse 52, W-2000, Hamburg 20, Federal Republic of Germany aut NATIONALLICENCE 773 0- Naunyn-Schmiedeberg's Archives of Pharmacology Springer-Verlag 345/1(1992-01-01), 44-50 0028-1298 345:1<44 1992 345 210 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer