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Anthracycline-associated cardiac and renal damage in rabbits. Evidence for mediation by vasoactive substances
Abstract:
We tested the hypothesis that anthracycline-induced cardiac and renal damage is mediated by vasoactive substances. A 1-minute exposure to 5 micrograms per ml. of doxorubicin (DXR, Adriamycin) produced cardiac histamine release in isolated rabbit hearts. Under conditions in which histamine uptake and metabolism were impaired, the administration of DXR, 2 mg. per kg., over 1 minute was associated with elevations in arterial histamine and catecholamines. The chronic weekly administration of DXR produced severe cardiac and renal damage. The administration of combined histaminic and adrenergic blockade with diphenhydramine, cimetidine, phentolamine, and propranolol (DCPP) pre- and immediately post-DXR resulted in near total protection against DXR-mediated cardiac damage and prevented the majority of the renal lesions. The combined administration of diphenhydramine, cimetidine, phentolamine, and propranolol did not appear to be acting by mechanisms other than blockade of vasoactive amine receptors as cardiac uptake of DXR and the DXR antitumor response were not altered by diphenhydramine, cimetidine, phentolamine, and propranolol. This study demonstrates that anthracycline-associated cardiac and renal toxicity may be mediated by vasoactive substances and that anthracycline cardiomyopathy is potentially preventable.
Insights
Anthracycline chemotherapy causes cardiac and kidney damage through vasoactive substances. Blocking these substances with diphenhydramine, cimetidine, phentolamine, and propranolol protected against this toxicity, suggesting preventable cardiotoxicity.
Area of Science:
- Pharmacology
- Cardiology
- Nephrology
Background:
- Anthracyclines, such as doxorubicin (DXR), are potent chemotherapy agents.
- DXR treatment is associated with significant cardiac and renal toxicity.
- The underlying mechanisms of DXR-induced organ damage are not fully understood.
Purpose of the Study:
- To investigate the role of vasoactive substances in anthracycline-induced cardiac and renal damage.
- To determine if blocking vasoactive amines can prevent DXR toxicity.
Main Methods:
- Isolated rabbit heart model to assess histamine release after DXR exposure.
- In vivo studies with DXR administration in rats, with and without combined histaminic and adrenergic blockade (diphenhydramine, cimetidine, phentolamine, propranolol - DCPP).
- Assessment of cardiac and renal damage, arterial histamine and catecholamine levels, DXR uptake, and antitumor response.
Main Results:
- DXR induced cardiac histamine release and elevated arterial histamine and catecholamines.
- Chronic DXR administration led to severe cardiac and renal damage.
- Combined DCPP blockade significantly protected against DXR-induced cardiac damage and prevented most renal lesions.
- DCPP did not alter DXR cardiac uptake or antitumor efficacy.
Conclusions:
- Anthracycline-associated cardiac and renal toxicity is potentially mediated by vasoactive substances.
- Pharmacological blockade of vasoactive amines offers a promising strategy for preventing anthracycline cardiomyopathy and nephrotoxicity.