Substantially attenuated hemodynamic responses to Escherichia coli-derived vascular endothelial growth factor given by intravenous infusion compared with bolus injection.
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 to Escherichia 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 tachycardiac 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.
Yang
R
R
Department of Cardiovascular Research, Genentech, Inc., South San Francisco, California, USA.
Bunting
S
S
Ko
A
A
Keyt
B A
BA
Modi
N B
NB
Zioncheck
T F
TF
Ferrara
N
N
Jin
H
H
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D016228:Endothelial Growth Factors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects*; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008222:Lymphokines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors