Low-volume hydrodynamic gene delivery to the rat liver via an isolated segment of the inferior vena cava: efficiency, cardiovascular response and intrahepatic vascular dynamics.
BACKGROUND
Clinical application of hydrodynamic gene delivery to the liver requires the use of small volumes, an evaluation of the cardiovascular consequences of acute volume overload, and a better understanding of the intrahepatic vascular pressures driving gene delivery. Injection of DNA solution into the isolated segment of inferior vena cava (IVC) draining the hepatic veins is a potentially valuable low-volume approach.


METHODS
Various volumes of DNA solution (pGL3 plasmid) were injected at 100 ml/min either systemically or into the isolated IVC segment in the DA rat. Arterial pressure, portal venous pressure, heart rate and electrocardiogram, in addition to reporter gene expression in the liver, were monitored.


RESULTS
The 2% volume was > 10 000-fold more effective when delivered via the IVC segment than when given systemically, and as effective as 6% systemically. Isolation of the IVC segment caused profound falls in arterial pressure, with electrocardiogram signs of myocardial ischemia. On release of the IVC ties, without DNA infusion (no volume overload), arterial pressure recovered rapidly. However, with DNA infusion (volume overload) there was a brief recovery of arterial pressure, followed by complete heart block and fall in arterial pressure and pulse for several minutes. Portal venous pressure rose steeply to 30-33 mm Hg during the infusion.


CONCLUSIONS
The IVC segment approach enables excellent gene delivery to the whole liver with small volumes, but causes severe cardiovascular disturbances in the rat. Portal venous pressures are slightly higher than in the mouse, and suggest functional outflow obstruction by the capillary bed of the intestines.
Sawyer
Greta J
GJ
Department of Hepatology and Transplantation, King's College London School of Medicine, James Black Centre, 125 Coldharbour Lane, London SE5 9NU, UK.
Grehan
Aidan
A
Dong
Xuebin
X
Whitehorne
Michael
M
Seddon
Michael
M
Shah
Ajay M
AM
Zhang
Xiaohong
X
Salehi
Siamak
S
Fabre
John W
JW
D000818:Animals; D001794:Blood Pressure; D002320:Cardiovascular Physiological Phenomena / Q000187:drug effects*; D004247:DNA / Q000008:administration & dosage*; D004562:Electrocardiography; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D006339:Heart Rate; D007262:Infusions, Intravenous / Q000009:adverse effects / Q000379:methods; D008099:Liver / Q000098:blood supply / Q000378:metabolism*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D014682:Vena Cava, Inferior
D004247:DNA