An assessment of the cardiac toxicity of compounds that cause methemoglobinemia using a non-vascularized fish heart model Public Deposited

http://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/8623j1033

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  • Non-vascularized hearts of buffalo sculpin (Enophrys bison) were used to investigate the cardiac toxicity of compounds that cause methemoglobinemia. The affinity of sculpin cardiac myoglobin for oxygen (P50 = 1.10 torr at 20 C°, pH 7.8) was lower than that of mammals studied (P50 = .44 and .76 torr for sperm whale red skeletal and rat cardiac muscle myoglobin, respectively, at 20 C°, pH 7.8). This difference probably reflects an adaptation to temperature and should not compromise sculpin myoglobin as a model for vertebrate myoglobins generally. Hemoglobin in the buffalo sculpin was oxidized rapidly and reversibly following intraperitoneal injection with sublethal levels of sodium nitrite (NaNO ₂ ) or hydroxylamine. Myoglobin in hearts excised at the time of peak effect on hemoglobin was also oxidized. For NaNO₂, the oxidation of myoglobin exceeded that of hemoglobin. The reverse was true of hydroxylamine. In both cases, the effect was dose-dependent. The demonstration of oxidation of cardiac myoglobin in vivo by heme oxidants raises the possibility that cardiac myoglobin is oxidized in occupational or other exposures to these compounds. The cardiac toxicity of NaNO₂, aniline, and the aniline metabolite, phenylhydroxylamine (PHA), was investigated in isolated perfused sculpin hearts. NaNO₂ had little effect on myoglobin oxidation state or cardiac performance, except at high concentrations (> 1.0 x 10-3 M). Aniline did not oxidize myoglobin but was acutely toxic to the heart at concentrations exceeding 1.0 x 10-3 M. The character of the response to aniline (rapid arrest, AV block) suggested an electrical effect, although electrically paced hearts also exhibited dimished levels of contractile performance. Low concentrations (1.0 x 10-5 M) of PHA oxidized 100% of myoglobin in the heart but did not affect cardiac performance at ambient (150 torr) or physiological (32 torr) oxygen tensions. Thus, functional myoglobin did not appear to be necessary to maintain' cardiac performance. I conclude that the test conditions of 0₂ supply and demand did not provide an adequate test of the importance of functional myoglobin. I have shown that myoglobin can be oxidized in vivo in sculpin by two compounds (NaNO₂, hydroxylamine) that cause methemoglobinemia in humans. I was unable, however, to verify the recently reported role of myoglobin in maintaining cardiac performance and oxygen consumption in the isolated heart.
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