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Platinum accumulation in the brain and alteration in the central regulation of cardiovascular and respiratory functions in oxaliplatin-treated rats

Abstract

Oxaliplatin is a platinum-based alkylating chemotherapeutic agent used for cancer treatment. Neurotoxicity is one of its major adverse effects that often demands dose limitation. However, the effects of chronic oxaliplatin on the toxicity of the autonomic nervous system regulating cardiorespiratory function and adaptive reflexes are unknown. Male Sprague Dawley rats were treated with intraperitoneal oxaliplatin (3 mg kg−1 per dose) 3 times a week for 14 days. The effects of chronic oxaliplatin treatment on baseline mean arterial pressure (MAP); heart rate (HR); splanchnic sympathetic nerve activity (sSNA); phrenic nerve activity (PNA) and its amplitude (PNamp) and frequency (PNf); and sympathetic reflexes were investigated in anaesthetised, vagotomised and artificially ventilated rats. The same parameters were evaluated after acute oxaliplatin injection, and in the chronic treatment group following a single dose of oxaliplatin. The amount of platinum in the brain was determined with atomic absorption spectrophotometry. Chronic oxaliplatin treatment significantly increased MAP, sSNA and PNf and decreased HR and PNamp, while acute oxaliplatin had no effects. Platinum was accumulated in the brain after chronic oxaliplatin treatment. In the chronic oxaliplatin treatment group, further administration of a single dose of oxaliplatin increased MAP and sSNA. The baroreceptor sensitivity and somatosympathetic reflex were attenuated at rest while the sympathoexcitatory response to hypercapnia was increased in the chronic treatment group. This is the first study to reveal oxaliplatin-induced alterations in the central regulation of cardiovascular and respiratory functions as well as reflexes that may lead to hypertension and breathing disorders which may be mediated via accumulated platinum in the brain.

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Abbreviations

AAS:

Atomic absorption spectrophotometry

ANS:

Autonomic nervous system

BP:

Blood pressure

DRG:

Dorsal root ganglia

HR:

Heart rate

i.p.:

Intraperitoneal

i.v.:

Intravenous

MAP:

Mean arterial pressure

NO:

Nitric oxide

PE:

Phenylephrine hydrochloride

PNA:

Phrenic nerve activity

PNamp:

Phrenic nerve amplitude

PNf:

Phrenic nerve frequency

SNP:

Sodium nitroprusside

sSNA:

Splanchnic sympathetic nerve activity

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Acknowledgements

This work was supported by a research support grant from Victoria University. KN and AAR obtained funding.

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AAR: conception and design, collection, analysis and interpretation of data, manuscript writing; VS: collection, analysis and interpretation of data, manuscript revision; PP: interpretation of data, manuscript revision; KN: conception and design, interpretation of data, manuscript revision. All authors approved the final version of the manuscript.

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Correspondence to Kulmira Nurgali.

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Rahman, A.A., Stojanovska, V., Pilowsky, P. et al. Platinum accumulation in the brain and alteration in the central regulation of cardiovascular and respiratory functions in oxaliplatin-treated rats. Pflugers Arch - Eur J Physiol 473, 107–120 (2021). https://doi.org/10.1007/s00424-020-02480-4

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  • DOI: https://doi.org/10.1007/s00424-020-02480-4

Keywords

  • Chemotherapy
  • Oxaliplatin
  • Platinum
  • Blood pressure
  • Sympathetic nerve