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The effect of flunarizine on erythrocyte suspension viscosity under conditions of extreme hypoxia, low pH, and lactate treatment.

Publication ,  Journal Article
Kavanagh, BD; Coffey, BE; Needham, D; Hochmuth, RM; Dewhirst, MW
Published in: Br J Cancer
April 1993

Flunarizine is a class IV calcium channel blocker which increases oxygen delivery to hypoxic regions in solid tumours, exerting a radiosensitising effect in vivo in animal tumour models. Precisely how the drug improves oxygenation is not well understood. We hypothesised that metabolic conditions present within solid tumours reduce red blood cell (RBC) deformability and that flunarizine exerts its in vivo effect by preventing this loss of RBC deformability. A microrheometer was used to compare the viscosity of rat and human RBC suspensions in conditions of hypoxia (pO2 < 10 mmHg), acidic environment (pH 6.8), and elevated lactate concentration (lactate 5 mMol l-1), without or with flunarizine at concentrations of 5, 10, and 50 mg l-1. The effects of flunarizine on RBC density and morphology were also recorded. Hypoxia, low pH, and lactate exposure together increased both human and rat RBC suspension viscosity. Flunarizine at concentrations of 5 and 10 mg l-1 prevented the increases in viscosity. The drug caused dose-dependent shifts toward lower cell density while inducing a characteristic cupped shape (stomatcytic morphology), suggesting a mechanism involving calmodulin inhibition. The results support the hypothesis that flunarizine improves tumour blood flow and oxygenation by enhancing flow properties of RBC's in solid tumours.

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Published In

Br J Cancer

DOI

ISSN

0007-0920

Publication Date

April 1993

Volume

67

Issue

4

Start / End Page

734 / 741

Location

England

Related Subject Headings

  • Rheology
  • Rats, Inbred F344
  • Rats
  • Oxygen
  • Oncology & Carcinogenesis
  • Lactic Acid
  • Lactates
  • Kinetics
  • Hydrogen-Ion Concentration
  • Humans
 

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Kavanagh, B. D., Coffey, B. E., Needham, D., Hochmuth, R. M., & Dewhirst, M. W. (1993). The effect of flunarizine on erythrocyte suspension viscosity under conditions of extreme hypoxia, low pH, and lactate treatment. Br J Cancer, 67(4), 734–741. https://doi.org/10.1038/bjc.1993.134
Kavanagh, B. D., B. E. Coffey, D. Needham, R. M. Hochmuth, and M. W. Dewhirst. “The effect of flunarizine on erythrocyte suspension viscosity under conditions of extreme hypoxia, low pH, and lactate treatment.Br J Cancer 67, no. 4 (April 1993): 734–41. https://doi.org/10.1038/bjc.1993.134.
Kavanagh BD, Coffey BE, Needham D, Hochmuth RM, Dewhirst MW. The effect of flunarizine on erythrocyte suspension viscosity under conditions of extreme hypoxia, low pH, and lactate treatment. Br J Cancer. 1993 Apr;67(4):734–41.
Kavanagh, B. D., et al. “The effect of flunarizine on erythrocyte suspension viscosity under conditions of extreme hypoxia, low pH, and lactate treatment.Br J Cancer, vol. 67, no. 4, Apr. 1993, pp. 734–41. Pubmed, doi:10.1038/bjc.1993.134.
Kavanagh BD, Coffey BE, Needham D, Hochmuth RM, Dewhirst MW. The effect of flunarizine on erythrocyte suspension viscosity under conditions of extreme hypoxia, low pH, and lactate treatment. Br J Cancer. 1993 Apr;67(4):734–741.

Published In

Br J Cancer

DOI

ISSN

0007-0920

Publication Date

April 1993

Volume

67

Issue

4

Start / End Page

734 / 741

Location

England

Related Subject Headings

  • Rheology
  • Rats, Inbred F344
  • Rats
  • Oxygen
  • Oncology & Carcinogenesis
  • Lactic Acid
  • Lactates
  • Kinetics
  • Hydrogen-Ion Concentration
  • Humans