Isoproterenol-induced creatine kinase leakage in Langendorff-perfused rat heart associated with significant myocardial edema

Since the mechanism of creatine kinase (CK) leakage induced by β-adrenoceptor activation remains unclear, we studied the effects of incremental application (10^-9 to 10^-4 M) of isoproterenol (ISP) on the CK efflux from Langendorff-perfused isolated rat hearts under aerobic conditions. Tissue water content was estimated after the perfusion experiment. ISP-induced dose-dependent CK leakage was noted in a sigmoidal fashion, which showed low temperature-dependency (Q₁₀ of 2.41), sensitivity to cepharantine (10^-6 M) and propranolol (10^-7 to 10^-6 M) without any signs of demand ischemia or oxidant stress. CK liberation was not replicated at all by maneuvers activating cAMP-dependent protein kinase (A-kinase). Myocardial edema noted in the control ISP application was ameliorated by exposure to 10^-6 M propranolol or cepharantine (i.e., significant fall in tissue water content; p < 0.05). Histological study revealed nonspecific myocardial fiber swelling and separation without any myocyte necrosis for all the perfusion groups. These results suggest that ISP-induced CK leakage in this model is not mediated by β-adrenoceptor stimulation, subsequent A-kinase activation or related demand ischemia, but is attributed most to the direct effects of ISP augmenting sarcolemmal CK and water permeability.