Bovine hereditary cardiomyopathy: an animal model of human dilated cardiomyopathy

Bovine heriditary 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, β- and α 1-adrenoceptor density, G i> 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 moradrenaline was increased by 240%. Tissue noradrenaline and adrenaline were decreased by 36–63% and 58–69%, whereas dopamine was increased by 105–218%. β-adrenoceptor density was drastically reduced by 90%, but binding affinity was unchanged. α-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 β-adrenoceptors, upregulation of G i proteins, global desensitization of adenylyl cyclase and selective subsentivity to β-adrenergic inotropic stimulation. These results closely resemble the characteristic alterations in the β-adrenoceptor-G protein-adenylyl cyclase pathway in the 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 asuitable model for human DCM.