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Pharmacological inhibition of CB1 cannabinoid receptor protects against doxorubicin-induced cardiotoxicity.
J Am Coll Cardiol. 2007 Aug 07; 50(6):528-36.JACC

Abstract

OBJECTIVES

We aimed to explore the effects of pharmacologic inhibition of cannabinoid-1 (CB1) receptor in in vivo and in vitro models of doxorubicin (DOX)-induced cardiotoxicity.

BACKGROUND

Doxorubicin is one of the most potent antitumor agents available; however, its clinical use is limited because of the risk of severe cardiotoxicity. Endocannabinoids mediate cardiodepressive effects through CB1 receptors in various pathophysiological conditions, and these effects can be reversed by CB1 antagonists.

METHODS

Left ventricular function was measured by Millar pressure-volume system. Apoptosis markers, CB1/CB2 receptor expression, and endocannabinoid levels were determined by immunohistochemistry, Western blot, reverse transcription-polymerase chain reaction, real-time polymerase chain reaction, flow cytometry, fluorescent microscopy, and liquid chromatography/in-line mass spectrometry techniques.

RESULTS

Five days after the administration of a single dose of DOX (20 mg/kg intraperitoneally) to mice, left ventricular systolic pressure, maximum first derivative of ventricular pressure with respect to time (+dP/dt), stroke work, ejection fraction, cardiac output, and load-independent indexes of contractility (end-systolic pressure-volume relation, preload-recruitable stroke work, dP/dt-end-diastolic volume relation) were significantly depressed, and the myocardial level of the endocannabinoid anandamide (but not CB1/CB2 receptor expression) was elevated compared with vehicle-treated control mice. Treatment with the CB1 antagonists rimonabant or AM281 markedly improved cardiac dysfunction and reduced DOX-induced apoptosis in the myocardium. Doxorubicin also decreased cell viability and induced apoptosis in the H9c2 myocardial cell line measured by flow cytometry and fluorescent microscopy, which were prevented by the preincubation of the cells with either CB1 antagonist, but not with CB1 and CB2 agonists and CB2 antagonists.

CONCLUSIONS

These data suggest that CB1 antagonists may represent a new cardioprotective strategy against DOX-induced cardiotoxicity.

Authors+Show Affiliations

Laboratory of Physiological Studies, NIH/NIAAA, Bethesda, Maryland 20892, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Intramural

Language

eng

PubMed ID

17678736

Citation

Mukhopadhyay, Partha, et al. "Pharmacological Inhibition of CB1 Cannabinoid Receptor Protects Against Doxorubicin-induced Cardiotoxicity." Journal of the American College of Cardiology, vol. 50, no. 6, 2007, pp. 528-36.
Mukhopadhyay P, Bátkai S, Rajesh M, et al. Pharmacological inhibition of CB1 cannabinoid receptor protects against doxorubicin-induced cardiotoxicity. J Am Coll Cardiol. 2007;50(6):528-36.
Mukhopadhyay, P., Bátkai, S., Rajesh, M., Czifra, N., Harvey-White, J., Haskó, G., Zsengeller, Z., Gerard, N. P., Liaudet, L., Kunos, G., & Pacher, P. (2007). Pharmacological inhibition of CB1 cannabinoid receptor protects against doxorubicin-induced cardiotoxicity. Journal of the American College of Cardiology, 50(6), 528-36.
Mukhopadhyay P, et al. Pharmacological Inhibition of CB1 Cannabinoid Receptor Protects Against Doxorubicin-induced Cardiotoxicity. J Am Coll Cardiol. 2007 Aug 7;50(6):528-36. PubMed PMID: 17678736.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacological inhibition of CB1 cannabinoid receptor protects against doxorubicin-induced cardiotoxicity. AU - Mukhopadhyay,Partha, AU - Bátkai,Sándor, AU - Rajesh,Mohanraj, AU - Czifra,Nora, AU - Harvey-White,Judith, AU - Haskó,György, AU - Zsengeller,Zsuzsanna, AU - Gerard,Norma P, AU - Liaudet,Lucas, AU - Kunos,George, AU - Pacher,Pál, Y1 - 2007/07/23/ PY - 2006/12/20/received PY - 2007/02/23/revised PY - 2007/03/06/accepted PY - 2007/8/7/pubmed PY - 2007/9/25/medline PY - 2007/8/7/entrez SP - 528 EP - 36 JF - Journal of the American College of Cardiology JO - J Am Coll Cardiol VL - 50 IS - 6 N2 - OBJECTIVES: We aimed to explore the effects of pharmacologic inhibition of cannabinoid-1 (CB1) receptor in in vivo and in vitro models of doxorubicin (DOX)-induced cardiotoxicity. BACKGROUND: Doxorubicin is one of the most potent antitumor agents available; however, its clinical use is limited because of the risk of severe cardiotoxicity. Endocannabinoids mediate cardiodepressive effects through CB1 receptors in various pathophysiological conditions, and these effects can be reversed by CB1 antagonists. METHODS: Left ventricular function was measured by Millar pressure-volume system. Apoptosis markers, CB1/CB2 receptor expression, and endocannabinoid levels were determined by immunohistochemistry, Western blot, reverse transcription-polymerase chain reaction, real-time polymerase chain reaction, flow cytometry, fluorescent microscopy, and liquid chromatography/in-line mass spectrometry techniques. RESULTS: Five days after the administration of a single dose of DOX (20 mg/kg intraperitoneally) to mice, left ventricular systolic pressure, maximum first derivative of ventricular pressure with respect to time (+dP/dt), stroke work, ejection fraction, cardiac output, and load-independent indexes of contractility (end-systolic pressure-volume relation, preload-recruitable stroke work, dP/dt-end-diastolic volume relation) were significantly depressed, and the myocardial level of the endocannabinoid anandamide (but not CB1/CB2 receptor expression) was elevated compared with vehicle-treated control mice. Treatment with the CB1 antagonists rimonabant or AM281 markedly improved cardiac dysfunction and reduced DOX-induced apoptosis in the myocardium. Doxorubicin also decreased cell viability and induced apoptosis in the H9c2 myocardial cell line measured by flow cytometry and fluorescent microscopy, which were prevented by the preincubation of the cells with either CB1 antagonist, but not with CB1 and CB2 agonists and CB2 antagonists. CONCLUSIONS: These data suggest that CB1 antagonists may represent a new cardioprotective strategy against DOX-induced cardiotoxicity. SN - 1558-3597 UR - https://www.unboundmedicine.com/medline/citation/17678736/Pharmacological_inhibition_of_CB1_cannabinoid_receptor_protects_against_doxorubicin_induced_cardiotoxicity_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0735-1097(07)01625-7 DB - PRIME DP - Unbound Medicine ER -