Myocardial alterations induced by prolonged noradrenaline administration in various doses

Prolonged noradrenaline administration to rats in steadily increasing dosages for a period of one to four weeks (cumulative doses 25-35 mg/kg) resulted in the development of focal necrotic areas with abundant collagen fibers and marked hypertrophy of cardiomyocytes. Cellular diameter was higher by 37-44% and extracellular space area by 70-100%. A combination of overcontracted and overdistended sarcomeres in some cardiomyocytes and a twofold rise in serum creatine kinase presumably reflected cellular calcium overload. Myocardial high energy phosphate content was depleted to 50-62% of the control level. The extent of this depletion positively correlated with a decrease in heart rate and cardiac output of the isolated heart. The latter may be attributed to limited left ventricular filling caused by elevated LV diastolic pressure and stiffness. Minimal metabolic and functional changes were observed after lowest noradrenaline dose (5 mg/kg for nine days) that was followed by only moderate depletion of myocardial phosphocreatine content and moderate rise in LV diastolic stiffness. Results suggest that energy-deficient increase in myofibrillar stiffness may form the basis for decreased myocardial distensibility and cardiac pump failure.