Acute and chronic cardiovascular effects of doxorubicin in the dog: the cardiovascular pharmacology of drug-induced histamine release.
We evaluated the acute hemodynamic effects of doxorubicin in the open-chest dog. Doxorubicin at doses of 1-4 mg/kg administered over 2 min produced profound hemodynamic changes that were similar to those produced by histamine. These changes persisted despite administering the drug as a slow infusion. Histamine release in peripheral tissues was documented by a marked increase in venous histamine levels following doxorubicin administration. The heart extracted histamine during a period when arterial levels were increased, as indicated by consistently low coronary sinus/aortic ratios. Secondary catecholamine release occurred in response to histamine and histamine-mediated hemodynamic effects. Immunoreactive prostaglandins E and F were increased in coronary sinus blood beginning 30 min after the initiation of a continuous infusion of doxorubicin, and increased slowly thereafter. H1- and H2-receptor blockade with diphenhydramine and cimetidine prevented the early (2-30 min postinfusion) effects of doxorubicin, and combined histaminergic and adrenergic blockade prevented the late effects. A dose of doxorubicin (1 mg/kg) that released histamine and catecholamines produced primary cardiac effects acutely and a cardiomyopathy when administered chronically. The release of vasoactive substances could be part of the pathogenetic mechanism of anthracycline cardiomyopathy.
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D004285:Dogs; D004317:Doxorubicin / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006632:Histamine / Q000494:pharmacology; D006636:Histamine Release / Q000187:drug effects*; D008954:Models, Biological; D013997:Time Factors; D014655:Vascular Resistance / Q000187:drug effects
D004317:Doxorubicin; D006632:Histamine