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OtherCARDIOVASCULAR PHARMACOLOGY

Substantially Attenuated Hemodynamic Responses toEscherichia coli-Derived Vascular Endothelial Growth Factor Given by Intravenous Infusion Compared with Bolus Injection

Renhui Yang, Stuart Bunting, Annie Ko, Bruce A. Keyt, Nishit B. Modi, Thomas F. Zioncheck, Napoleone Ferrara and Hongkui Jin
Journal of Pharmacology and Experimental Therapeutics January 1998, 284 (1) 103-110;
Renhui Yang
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Stuart Bunting
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Annie Ko
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Bruce A. Keyt
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Nishit B. Modi
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Thomas F. Zioncheck
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Napoleone Ferrara
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Hongkui Jin
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Abstract

Vascular endothelial growth factor (VEGF) produces beneficial angiogenesis in animal models of coronary and peripheral ischemia. However, intravenous bolus injection of Chinese hamster ovary cell (CHO)-derived VEGF produces adverse effects on hemodynamics. The present study examined pharmacokinetic and hemodynamic responses toEscherichia coli-derived VEGF, which will be used in clinical patients, compared with responses to CHO-derived VEGF, and tested whether intravenous infusion of E. coli-derived VEGF attenuates the hemodynamic responses compared with the responses observed with intravenous bolus injection. Hemodynamic parameters were measured before and after administration of VEGF in conscious, instrumented rats. Intravenous injection of both CHO- and E. coli-derived VEGF produced a similar maximal reduction in arterial pressure, although E. coli-derived VEGF exhibited less of a depressor effect in the initial phase after injection. Either infusion or injection of E. coli-derived VEGF caused hypotension, tachycardia and reduced cardiac output and stroke volume, which were significantly attenuated when given by infusion compared with injection. The maximal hypotensive and tachycardic responses to infusion were decreased by 50 to 60% compared with those responses observed after injection. Cardiac output was maximally reduced by 34% after injection, but only 18% after infusion. A sustained elevation in systemic vascular resistance observed after injection was avoided after infusion. Thus, the hemodynamic side effects of VEGF administration can be substantially attenuated by controlling the rate of VEGF infusion. The data indicate that infusion, instead of bolus injection, is a more appropriate regimen for VEGF administration.

Footnotes

  • Send reprint requests to: Hongkui Jin, M.D., Department of Cardiovascular Research, Genentech, Inc., 460 Point San Bruno Blvd., South San Francisco, CA 94080.

  • Abbreviations:
    VEGF
    vascular endothelial growth factor
    CHO
    Chinese hamster ovary cell
    MAP
    mean arterial pressure
    HR
    heart rate
    HSPG
    heparan sulfate proteoglycans
    ELISA
    enzyme-linked immunosorbent assay
    • Received May 28, 1997.
    • Accepted September 12, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 284, Issue 1
1 Jan 1998
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OtherCARDIOVASCULAR PHARMACOLOGY

Substantially Attenuated Hemodynamic Responses toEscherichia coli-Derived Vascular Endothelial Growth Factor Given by Intravenous Infusion Compared with Bolus Injection

Renhui Yang, Stuart Bunting, Annie Ko, Bruce A. Keyt, Nishit B. Modi, Thomas F. Zioncheck, Napoleone Ferrara and Hongkui Jin
Journal of Pharmacology and Experimental Therapeutics January 1, 1998, 284 (1) 103-110;

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OtherCARDIOVASCULAR PHARMACOLOGY

Substantially Attenuated Hemodynamic Responses toEscherichia coli-Derived Vascular Endothelial Growth Factor Given by Intravenous Infusion Compared with Bolus Injection

Renhui Yang, Stuart Bunting, Annie Ko, Bruce A. Keyt, Nishit B. Modi, Thomas F. Zioncheck, Napoleone Ferrara and Hongkui Jin
Journal of Pharmacology and Experimental Therapeutics January 1, 1998, 284 (1) 103-110;
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