Isoprenaline-induced increase in the 40/41 kDa pertussis toxin substrates and functional consequences on contractile response in rat heart.
Chronic beta-adrenoceptor stimulation leads to desensitization of the myocardial adenylyl cyclase signalling pathway which includes beta-adrenoceptor downregulation and upregulation of Gi-protein alpha-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 Gi alpha 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 Gi alpha by 22 +/- 6% and decreased beta 1- and beta 2-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 mumol/l vs. 0.28 mumol/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 beta-adrenoceptor stimulation desensitizes myocardial adenylyl cyclase by at least two mechanisms: beta-adrenoceptor downregulation leading to diminished signal transduction in the stimulatory pathway and Gi alpha 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.
Mende
U
U
Abteilung Allgemeine Pharmakologie, Universitäts-Krankenhaus Eppendorf, Universität Hamburg, Federal Republic of Germany.
Eschenhagen
T
T
Geertz
B
B
Schmitz
W
W
Scholz
H
H
Schulte am Esch
J
J
Sempell
R
R
Steinfath
M
M
D000246:Adenosine Diphosphate Ribose / Q000378:metabolism; D037361:Adenylate Cyclase Toxin; D000818:Animals; D004591:Electrophoresis, Polyacrylamide Gel; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006321:Heart / Q000187:drug effects*; D007545:Isoproterenol / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism*; D037342:Pertussis Toxin; D011433:Propranolol / Q000008:administration & dosage; D051381:Rats; D011919:Rats, Inbred Strains; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D013268:Stimulation, Chemical; D014284:Triiodothyronine / Q000008:administration & dosage; D010566:Virulence Factors, Bordetella / Q000378:metabolism*
D037361:Adenylate Cyclase Toxin; D011943:Receptors, Adrenergic, beta; D010566:Virulence Factors, Bordetella; D014284:Triiodothyronine; D000246:Adenosine Diphosphate Ribose; D011433:Propranolol; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D007545:Isoproterenol