Bovine hereditary cardiomyopathy: an animal model of human dilated cardiomyopathy.
Bovine hereditary cardiomyopathy (bCMP) displays clinical characteristics of human idiopathic dilated cardiomyopathy (DCM). We studied isometric force of contraction in right ventricular trabeculae, plasma and tissue catecholamines, beta- and alpha 1-adrenoceptor density, Gi proteins and adenylyl cyclase activity in eight hearts with bCMP and eight control hearts (right and left atria and ventricles each).


RESULTS
Compared to control, the potency of isoprenaline in bCMP was eight-fold decreased, whereas the maximal positive inotropic effect of isoprenaline as well as the efficacy and potency of calcium were unchanged. Plasma noradrenaline was increased by 240%. Tissue noradrenaline and adrenaline were decreased by 36-63% and 58-69%, whereas dopamine was increased by 105-218%. beta-adrenoceptor density was drastically reduced by 90%, but binding affinity was unchanged. alpha-Adrenoceptor density and binding affinity were unchanged. Total PTX-substrates were increased in bCMP by 28-99%. Basal adenylyl cyclase activity was decreased by 36-47%. Similarly, stimulation by GTP, GMPPNP, isoprenaline, sodium fluoride, manganese or forskolin was attenuated by 26-62% (atria) and 45-66% (ventricles). In conclusion, we found marked activation of the sympatho-adrenergic system, downregulation of beta-adrenoceptors, upregulation of Gi proteins, global desensitization of adenylyl cyclase and selective subsensitivity to beta-adrenergic inotropic stimulation. These results closely resemble the characteristic alterations in the beta-adrenoceptor-G protein-adenylyl cyclase pathway in human heart failure, indicating that they are general features of heart failure. The similarity to human DCM, the inheritance and the availability of large tissue samples make bCMP a suitable model for human DCM.
Eschenhagen
T
T
Abteilung Allgemeine Pharmakologie, Universitäts-Krankenhaus Eppendorf, Hamburg, FRG.
Diederich
M
M
Kluge
S H
SH
Magnussen
O
O
Mene
U
U
Müller
F
F
Schmitz
W
W
Scholz
H
H
Weil
J
J
Sent
U
U
D037361:Adenylate Cyclase Toxin; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D009202:Cardiomyopathies / Q000235:genetics / Q000503:physiopathology / Q000662:veterinary*; D002311:Cardiomyopathy, Dilated / Q000503:physiopathology*; D002395:Catecholamines / Q000378:metabolism; D002417:Cattle; D002418:Cattle Diseases; D005576:Colforsin / Q000494:pharmacology; D004195:Disease Models, Animal; D019204:GTP-Binding Proteins / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000494:pharmacology; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D006321:Heart / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D006325:Heart Atria; D006352:Heart Ventricles; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D008345:Manganese / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D012016:Reference Values; D012969:Sodium Fluoride / Q000494:pharmacology; D016278:Ventricular Function, Right; D010566:Virulence Factors, Bordetella / Q000378:metabolism
D037361:Adenylate Cyclase Toxin; D002395:Catecholamines; D018340:Receptors, Adrenergic, alpha-1; D011943:Receptors, Adrenergic, beta; D010566:Virulence Factors, Bordetella; D005576:Colforsin; D006165:Guanylyl Imidodiphosphate; D008345:Manganese; D006160:Guanosine Triphosphate; D012969:Sodium Fluoride; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D007545:Isoproterenol