TY - JOUR
T1 - Doxorubicin activates ryanodine receptors in rat lymphatic muscle cells to attenuate rhythmic contractions and lymph flow
AU - Stolarz, Amanda J.
AU - Sarimollaoglu, Mustafa
AU - Marecki, John C.
AU - Fletcher, Terry W.
AU - Galanzha, Ekaterina I.
AU - Rhee, Sung W.
AU - Zharov, Vladimir P.
AU - Suzanne Klimberg, V.
AU - Rusch, Nancy J.
N1 - Funding Information:
Research was supported by the National Institutes of Health [R21 CA187325 (N.J.R.), R01 CA131164 (V.Z.), R01 EB017217 (V.Z.), and R21 EB022698 (E.I.G.)] and from the National Science Foundation [OIA 1457888 (V.Z.) and DBI 1556068 (V.Z.)]. Other sources of funding included a Pharmaceutical Research and Manufacturers of America (PhRMA) Predoctoral Fellowship (A.J.S.), Rho Chi American Foundation for Pharmaceutical Education (AFPE) First Year Graduate Fellowship (A.J.S.), pilot grant from the UAMS Translational Research Institute (V.P.Z.), UAMS College of Medicine Pilot Grant (N.J.R.), and pilot grant from the Center for Studies of Host Response to Cancer Therapy through Center of Biomedical Research Excellence Award P20GM109005 (A.J.S.). https://doi.org/10.1124/jpet.119.257592. s This article has supplemental material available at jpet.aspetjournals.org.
Publisher Copyright:
Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics
PY - 2019
Y1 - 2019
N2 - Doxorubicin is a risk factor for secondary lymphedema in cancer patients exposed to surgery or radiation. The risk is presumed to relate to its cytotoxicity. However, the present study provides initial evidence that doxorubicin directly inhibits lymph flow and this action appears distinct from its cytotoxic activity. We used real-time edge detection to track diameter changes in isolated rat mesenteric lymph vessels. Doxorubicin (0.5-20 mmol/l) progressively constricted lymph vessels and inhibited rhythmic contractions, reducing flow to 24.2% 6 7.7% of baseline. The inhibition of rhythmic contractions by doxorubicin paralleled a tonic rise in cytosolic Ca21 concentration in lymphatic muscle cells, which was prevented by pharmacological antagonism of ryanodine receptors. Washout of doxorubicin partially restored lymph vessel contractions, implying a pharmacological effect. Subsequently, high-speed optical imaging was used to assess the effect of doxorubicin on rat mesenteric lymph flow in vivo. Superfusion of doxorubicin (0.05-10 mmol/l) maximally reduced volumetric lymph flow to 34% 6 11.6% of baseline. Likewise, doxorubicin (10 mg/kg) administered intravenously to establish clinically achievable plasma concentrations also maximally reduced volumetric lymph flow to 40.3% 6 6.0% of initial values. Our findings reveal that doxorubicin at plasma concentrations achieved during chemotherapy opens ryanodine receptors to induce “calcium leak” from the sarcoplasmic reticulum in lymphatic muscle cells and reduces lymph flow, an event linked to lymph vessel damage and the development of lymphedema. These results infer that pharmacological block of ryanodine receptors in lymphatic smooth muscle cells may mitigate secondary lymphedema in cancer patients subjected to doxorubicin chemotherapy.
AB - Doxorubicin is a risk factor for secondary lymphedema in cancer patients exposed to surgery or radiation. The risk is presumed to relate to its cytotoxicity. However, the present study provides initial evidence that doxorubicin directly inhibits lymph flow and this action appears distinct from its cytotoxic activity. We used real-time edge detection to track diameter changes in isolated rat mesenteric lymph vessels. Doxorubicin (0.5-20 mmol/l) progressively constricted lymph vessels and inhibited rhythmic contractions, reducing flow to 24.2% 6 7.7% of baseline. The inhibition of rhythmic contractions by doxorubicin paralleled a tonic rise in cytosolic Ca21 concentration in lymphatic muscle cells, which was prevented by pharmacological antagonism of ryanodine receptors. Washout of doxorubicin partially restored lymph vessel contractions, implying a pharmacological effect. Subsequently, high-speed optical imaging was used to assess the effect of doxorubicin on rat mesenteric lymph flow in vivo. Superfusion of doxorubicin (0.05-10 mmol/l) maximally reduced volumetric lymph flow to 34% 6 11.6% of baseline. Likewise, doxorubicin (10 mg/kg) administered intravenously to establish clinically achievable plasma concentrations also maximally reduced volumetric lymph flow to 40.3% 6 6.0% of initial values. Our findings reveal that doxorubicin at plasma concentrations achieved during chemotherapy opens ryanodine receptors to induce “calcium leak” from the sarcoplasmic reticulum in lymphatic muscle cells and reduces lymph flow, an event linked to lymph vessel damage and the development of lymphedema. These results infer that pharmacological block of ryanodine receptors in lymphatic smooth muscle cells may mitigate secondary lymphedema in cancer patients subjected to doxorubicin chemotherapy.
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U2 - 10.1124/jpet.119.257592
DO - 10.1124/jpet.119.257592
M3 - Article
C2 - 31439806
AN - SCOPUS:85073184133
SN - 0022-3565
VL - 371
SP - 278
EP - 289
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 2
ER -