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Comparative Cardiovascular Toxicity in Dogs Given Inotropic Agents by Continuous Intravenous Infusion

Toxicology Division, Lilly Research Laboratories, A Division of Eli Lilly and Company, Greenfield, Indiana 46140

Jeffrey R. Means

Toxicology Division, Lilly Research Laboratories, A Division of Eli Lilly and Company, Greenfield, Indiana 46140

Glen C. Todd

Toxicology Division, Lilly Research Laboratories, A Division of Eli Lilly and Company, Greenfield, Indiana 46140

A comparative study of the toxicity of the inotropic amines isoproterenol hydrochloride (IP), 1-norepi-nephrine bitartrate (NE), dopamine hydrochloride (DP), and dobutamine hydrochloride (DB) was conducted in beagle dogs (2/sex/dose group). All drugs were administered at doses that produced maximal contractile tension in dog myocardium. Doses, continuously infused for 96 hr, were 0.625, 1.25, and 2.5 µg/kg/min IP, 2.5 and 5 µg/kg/min NE, and 25, 50, and 100 µg/kg/min DP and DB. Three of 4 dogs that received 5 µg/kg/min NE and one of 4 given 100 µg/kg/min DP died. Pronounced tachycardia (mean peak rate increases from baseline of 88-104 beats/min) was observed at all doses of IP. DB produced a transient moderate tachycardia (mean peak rate increases from baseline of 25-27 beats/min) at 25 and 50 µg/kg/min and pronounced tachycardia (mean peak rate increases from baseline of 74 beats/min) at 100 µg/kg/min. Moderate bradycardia occurred at both doses of NE and at 25 and 50 µg/kg/min DP (mean peak rate decreases from baseline of 42-46 and 22-38 beats/min, respectively). At high doses the 4 inotropes produced focal to multifocal myocardial necrosis located mainly in left ventricle and segmental medial necrosis of the coronary arteries, mainly in small intramural muscular branches. Segmental medial hemorrhage was also seen following administration of high doses of NE and DP. An additional intramural coronary arterial lesion produced by all of the inotropes consisted of a mild periadventitial cellular infiltrate and fibroplasia. The results indicated that NE and DP produced the most severe cardiovascular lesions, followed by IP which produced lesions of more moderate severity. DB produced only slight lesions in comparison to the other 3 inotropic amines.

Key Words: Cardiotoxicity • vascular injury • myocardial necrosis drug induced • extramural/intramural coronary arterial lesions

Toxicologic Pathology, Vol. 18, No. 2, 268-278 (1990)
DOI: 10.1177/019262339001800205


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