Catecholamine-induced myocardial cell damage: catecholamines or adrenochrome

Recent evidence suggests that catecholamine-induced myocardial damage may be due to the cardiotoxic property of its non-physiological metabolite, adrenochrome. We investigated whether catecholamine-mediated myocardial damage is the result of catecholamine stimulation per se or the consequence of physiological or non-physiological metabolites. In the Langendorff perfused rat heart, fresh epinephrine (10(-6) M) solution increased cumulative lactate dehydrogenase (LDH) release when the perfusion pressure was 100 cm but not 65 cm, 3640 +/- 665 v. control 545 +/- 45 mIU/g/35 min respectively (P less than 0.01). In the left atrial perfused rat heart working against a hydrostatic pressure of 100 cm, fresh epinephrine (10(-6) M) solution produced the greatest increase in cumulative LDH release, 9346 +/- 1806 v. control 472 +/- 47 mIU/g/45 min respectively (P less than 0.01). Beta 1 but not alpha 1 adrenergic stimulation provoked enzyme leakage. Beta-adrenoceptor antagonism with atenolol 10(-5) M prevented catecholamine-induced leakage. Physiological metabolites of epinephrine viz metanephrine 10(-6) M, dihydroxymandelic acid 10(-6) M, vanillylmandelic acid 10(-6) M, and the non-physiological metabolite adrenochrome 10(-6) M to 10(-4) M did not increase the cumulative LDH release over 45 min. When adrenochrome 10(-4) M was perfused for 120 min enzyme release occurred, albeit only a third of that induced by epinephrine 10(-6) M over 45 min. We demonstrate that epinephrine-induced myocardial cellular damage is due to the direct effect of catecholamine stimulation acting on the beta-adrenergic receptor. The amount of left ventricular work appears to determine the extent of cellular damage. Physiological metabolites and the non-physiological metabolite, adrenochrome are not responsible for catecholamine-induced myocardial cellular damage. Epinephrine 10(-6) M caused a positive inotropic effect, whereas adrenochrome 10(-4) M induced contractile failure. Contractile failure was due to a negative inotropic effect and coronary artery vasoconstriction. Adrenochrome induces myocardial cellular damage and contractile failure but only in a concentration of 10(-4) M, this concentration does not appear to have pathophysiological relevance.