A rat modell to assess interventions to reduce cardiotoxicity of anthracyclines Does pre-treatment with morphine reduce the cardiotoxicity of doxorubicin?
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A rat model to assess interventions to reduce cardiotoxicity of anthracyclines is of interest. The model should be able to induce significant myocardial damage rapidly but at the same time allow for measurement of protective interventions. A proposed model includes an in vivo model where rats are treated with repeated intraperitoneal injections of an anthracycline for a relatively short period of time. Effects on physiological variables of cardiotoxicity are subsequently assessed in an ex vivo isolated rat heart model (Langendorff), and effects on biochemical variables by measurement of heat shock proteins (HSP) in myocardial tissue. A model with these elements was tested in this thesis. The model was designed to include a pilot study to assess whether pre-treatment with morphine, an opioid, could reduce cardiotoxicity of the anthracycline doxorubicin. The use of morphine as an analgesic is established in human cancer treatment, and opioids have been reported to induce protection against ischemia and oxidative stress in animal models. Proposed mechanisms of cardiotoxicity of anthracycklines include elements of oxidative stress and impaired calcium homeostasis. Thus, morphine could represent an intervention to reduce cardiotoxicity of anthracyclines. Doxorubicin (DOX), an anthracycline, was administered to female Wistar rats (n = 16) every second day in a dose of 3 mg/kg for 11 days intraperitonealt. A subgroup of rats (n = 8) received pre-treatment with morphine (MO) 3 mg/kg 60 minutes prior to DOX (MO-DOX), while the other eight rats received saline (SAL) of identical volume (SAL-DOX). In the MO-DOX group, 6 out of 8 rats died prior to the end of the protocol, while the remaining two animals were moribund and therefore put to death before end of the protocol to collect tissue for analysis of HSP. The remaining animals (SAL-DOX) were tested in an isolated rat heart model (Langendorff) to measure physiological parameters. Due to loss of the intervention group, a group of animals (n = 5) with no treatment with MO, DOX or SAL were used as control (control hearts) for reduction in physiological parameters. The SAL-DOX group showed a significant reduction (40-60%) in physiologic parameters compared to control hearts irrespective of flow mode (pressure regulated or volume regulated perfusion) in the isolated rat heart model. Furthermore, this group showed a trend for higher (40%) coronary perfusion pressure, an index of coronary resistance during volume regulated perfusion. Analysis of HSP demonstrated no significant differences in the HSP expression except from HSP94 which only gave positive results in the SAL-DOX treated group. We also analyzed content of DOX (2.7 + 0.8 nmol/g wet weight) and the major metabolite doxorubicinol (0.14 + 0.1 nmol/g wet weight) in hearts from SAL-DOX group, respectively. The results demonstrate that the present model can be used for rapid induction of cardiotoxicity in rats, and this has been reported by others. The cardiotoxicity can be measured irrespective of flow mode in the isolated rat heart model, and treatment results in significant accumulation of doxorubicine and its major metabolite in heart tissue. Treatment with doxorubicine in this protocol upregulates expression of HSP 94, but not other HSPs. Pre-treatment with morphine increased mortality when combined with doxorubicine. The results of the pilot study are in conflict with recent...