Effects of the calcium channel blocker flunarizine on the hemodynamics and oxygenation of tumor microvasculature

M. W. Dewhirst, E. T. Ong, D. Madwed, B. Klitzman, T. Secomb, D. Brizel, J. Bonaventura, Gary Rosner, B. Kavanagh, J. Edwards, J. Gross

Research output: Contribution to journalArticle

Abstract

Flunarizine is a diphenylpiperazine calcium entry blocker that has been shown previously to increase tumor blood flow and sensitivity to radiotherapy via reduction in the radiobiologically significant hypoxic fraction. Two mechanisms of action have been proposed previously (vasodilation, altered blood viscosity), but no studies have been performed to examine its mechanisms of action in vivo. Such information would be invaluable in determining the role of flunarizine in multimodality approaches to reduce tumor hypoxia. Fisher-344 rats bearing R3230Ac tumors transplanted into dorsal flap window chambers were used to examine microcirculatory changes after administration of flunarizine (1.0 mg/kg, iv). The drug increased the diameters of the microvasculature and red cell velocities specifically in central tumor regions (producing an average increase in vessel flow by a factor of 1.96), which was accompanied by an increase in perivascular pO2 of 12 mm Hg, on the average. The drug did not change the diameters of tumor 'feeding' vessels, nor did it change vascular length densities. Thus the improvement in central tumor blood flow and oxygenation could not be attributed to dilation of feeding vessels. The oxygen-carrying capacity of the blood was not altered either since hemoglobin saturation (measured in vitro) and the hematocrits of the microvasculature were unchanged after drug administration. Therefore, by a process of elimination, the most likely explanation for the effect of the drug is modification of blood viscosity. Additional studies are under way in this laboratory to examine whether changes in viscosity occur after flunarizine administration.

Original languageEnglish (US)
Pages (from-to)61-68
Number of pages8
JournalRadiation Research
Volume132
Issue number1
DOIs
StatePublished - 1992
Externally publishedYes

Fingerprint

Flunarizine
calcium channel blockers
hemodynamics
oxygenation
Calcium Channel Blockers
Microvessels
calcium
tumors
Hemodynamics
neoplasms
drugs
Blood Viscosity
blood viscosity
blood
vessels
Neoplasms
Pharmaceutical Preparations
viscosity
blood flow
mechanism of action

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Radiology Nuclear Medicine and imaging
  • Biophysics
  • Radiation

Cite this

Dewhirst, M. W., Ong, E. T., Madwed, D., Klitzman, B., Secomb, T., Brizel, D., ... Gross, J. (1992). Effects of the calcium channel blocker flunarizine on the hemodynamics and oxygenation of tumor microvasculature. Radiation Research, 132(1), 61-68. https://doi.org/10.2307/3578334

Effects of the calcium channel blocker flunarizine on the hemodynamics and oxygenation of tumor microvasculature. / Dewhirst, M. W.; Ong, E. T.; Madwed, D.; Klitzman, B.; Secomb, T.; Brizel, D.; Bonaventura, J.; Rosner, Gary; Kavanagh, B.; Edwards, J.; Gross, J.

In: Radiation Research, Vol. 132, No. 1, 1992, p. 61-68.

Research output: Contribution to journalArticle

Dewhirst, MW, Ong, ET, Madwed, D, Klitzman, B, Secomb, T, Brizel, D, Bonaventura, J, Rosner, G, Kavanagh, B, Edwards, J & Gross, J 1992, 'Effects of the calcium channel blocker flunarizine on the hemodynamics and oxygenation of tumor microvasculature', Radiation Research, vol. 132, no. 1, pp. 61-68. https://doi.org/10.2307/3578334
Dewhirst, M. W. ; Ong, E. T. ; Madwed, D. ; Klitzman, B. ; Secomb, T. ; Brizel, D. ; Bonaventura, J. ; Rosner, Gary ; Kavanagh, B. ; Edwards, J. ; Gross, J. / Effects of the calcium channel blocker flunarizine on the hemodynamics and oxygenation of tumor microvasculature. In: Radiation Research. 1992 ; Vol. 132, No. 1. pp. 61-68.
@article{d4bfd85285a64e3a9cab3a9395f7f278,
title = "Effects of the calcium channel blocker flunarizine on the hemodynamics and oxygenation of tumor microvasculature",
abstract = "Flunarizine is a diphenylpiperazine calcium entry blocker that has been shown previously to increase tumor blood flow and sensitivity to radiotherapy via reduction in the radiobiologically significant hypoxic fraction. Two mechanisms of action have been proposed previously (vasodilation, altered blood viscosity), but no studies have been performed to examine its mechanisms of action in vivo. Such information would be invaluable in determining the role of flunarizine in multimodality approaches to reduce tumor hypoxia. Fisher-344 rats bearing R3230Ac tumors transplanted into dorsal flap window chambers were used to examine microcirculatory changes after administration of flunarizine (1.0 mg/kg, iv). The drug increased the diameters of the microvasculature and red cell velocities specifically in central tumor regions (producing an average increase in vessel flow by a factor of 1.96), which was accompanied by an increase in perivascular pO2 of 12 mm Hg, on the average. The drug did not change the diameters of tumor 'feeding' vessels, nor did it change vascular length densities. Thus the improvement in central tumor blood flow and oxygenation could not be attributed to dilation of feeding vessels. The oxygen-carrying capacity of the blood was not altered either since hemoglobin saturation (measured in vitro) and the hematocrits of the microvasculature were unchanged after drug administration. Therefore, by a process of elimination, the most likely explanation for the effect of the drug is modification of blood viscosity. Additional studies are under way in this laboratory to examine whether changes in viscosity occur after flunarizine administration.",
author = "Dewhirst, {M. W.} and Ong, {E. T.} and D. Madwed and B. Klitzman and T. Secomb and D. Brizel and J. Bonaventura and Gary Rosner and B. Kavanagh and J. Edwards and J. Gross",
year = "1992",
doi = "10.2307/3578334",
language = "English (US)",
volume = "132",
pages = "61--68",
journal = "Radiation Research",
issn = "0033-7587",
publisher = "Radiation Research Society",
number = "1",

}

TY - JOUR

T1 - Effects of the calcium channel blocker flunarizine on the hemodynamics and oxygenation of tumor microvasculature

AU - Dewhirst, M. W.

AU - Ong, E. T.

AU - Madwed, D.

AU - Klitzman, B.

AU - Secomb, T.

AU - Brizel, D.

AU - Bonaventura, J.

AU - Rosner, Gary

AU - Kavanagh, B.

AU - Edwards, J.

AU - Gross, J.

PY - 1992

Y1 - 1992

N2 - Flunarizine is a diphenylpiperazine calcium entry blocker that has been shown previously to increase tumor blood flow and sensitivity to radiotherapy via reduction in the radiobiologically significant hypoxic fraction. Two mechanisms of action have been proposed previously (vasodilation, altered blood viscosity), but no studies have been performed to examine its mechanisms of action in vivo. Such information would be invaluable in determining the role of flunarizine in multimodality approaches to reduce tumor hypoxia. Fisher-344 rats bearing R3230Ac tumors transplanted into dorsal flap window chambers were used to examine microcirculatory changes after administration of flunarizine (1.0 mg/kg, iv). The drug increased the diameters of the microvasculature and red cell velocities specifically in central tumor regions (producing an average increase in vessel flow by a factor of 1.96), which was accompanied by an increase in perivascular pO2 of 12 mm Hg, on the average. The drug did not change the diameters of tumor 'feeding' vessels, nor did it change vascular length densities. Thus the improvement in central tumor blood flow and oxygenation could not be attributed to dilation of feeding vessels. The oxygen-carrying capacity of the blood was not altered either since hemoglobin saturation (measured in vitro) and the hematocrits of the microvasculature were unchanged after drug administration. Therefore, by a process of elimination, the most likely explanation for the effect of the drug is modification of blood viscosity. Additional studies are under way in this laboratory to examine whether changes in viscosity occur after flunarizine administration.

AB - Flunarizine is a diphenylpiperazine calcium entry blocker that has been shown previously to increase tumor blood flow and sensitivity to radiotherapy via reduction in the radiobiologically significant hypoxic fraction. Two mechanisms of action have been proposed previously (vasodilation, altered blood viscosity), but no studies have been performed to examine its mechanisms of action in vivo. Such information would be invaluable in determining the role of flunarizine in multimodality approaches to reduce tumor hypoxia. Fisher-344 rats bearing R3230Ac tumors transplanted into dorsal flap window chambers were used to examine microcirculatory changes after administration of flunarizine (1.0 mg/kg, iv). The drug increased the diameters of the microvasculature and red cell velocities specifically in central tumor regions (producing an average increase in vessel flow by a factor of 1.96), which was accompanied by an increase in perivascular pO2 of 12 mm Hg, on the average. The drug did not change the diameters of tumor 'feeding' vessels, nor did it change vascular length densities. Thus the improvement in central tumor blood flow and oxygenation could not be attributed to dilation of feeding vessels. The oxygen-carrying capacity of the blood was not altered either since hemoglobin saturation (measured in vitro) and the hematocrits of the microvasculature were unchanged after drug administration. Therefore, by a process of elimination, the most likely explanation for the effect of the drug is modification of blood viscosity. Additional studies are under way in this laboratory to examine whether changes in viscosity occur after flunarizine administration.

UR - http://www.scopus.com/inward/record.url?scp=0026482591&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0026482591&partnerID=8YFLogxK

U2 - 10.2307/3578334

DO - 10.2307/3578334

M3 - Article

VL - 132

SP - 61

EP - 68

JO - Radiation Research

JF - Radiation Research

SN - 0033-7587

IS - 1

ER -