Cardiovascular function following acute volume overload for hydrodynamic gene delivery to the liver.
Hydrodynamic gene delivery to the liver is a valuable experimental tool and an attractive option for nonviral gene therapy of liver disease. However, little attention has been paid to the major obstacle to clinical application: acute volume overload of the cardiovascular system. We delivered volumes of DNA solution (pGL3 plasmid) corresponding to 1, 2, 4, 6 and 8% of the body weight at 100 ml/min to the inferior vena cava (IVC) of DA strain rats. Central venous pressure (CVP), arterial pressure, pulse and electrocardiogram (ECG) were continuously recorded for subsequent analysis. Each volume produced a characteristic response, but all (including the 1% volume) caused severe falls in blood pressure and pulse within 1-2 s of the infusion, with ectopic beats and widening of the QRS complex in the ECG. The response to volumes of 4% and higher suggested that the liver acted as a volume sink, mitigating the immediate effects of volume overload. The 6 and 8% volumes caused profound and protracted falls in blood pressure and pulse, with a multitude of severe electrical abnormalities in the heart, including electromechanical dissociation. Vagal blockade with atropine, and the use of Ringer's solution to prevent electrolyte disturbances, did not ameliorate this picture.
Sawyer
G J
GJ
Department of Hepatology and Transplantation, King's College London School of Medicine, The Rayne Institute, and Department of Clinical Perfusion Sciences, King's College Hospital, London, UK.
Dong
X
X
Whitehorne
M
M
Grehan
A
A
Seddon
M
M
Shah
A M
AM
Zhang
X
X
Fabre
J W
JW
D000818:Animals; D001011:Aorta; D001285:Atropine / Q000008:administration & dosage; D001794:Blood Pressure; D002320:Cardiovascular Physiological Phenomena; D002496:Central Venous Pressure; D004247:DNA / Q000008:administration & dosage*; D004562:Electrocardiography; D015316:Genetic Therapy / Q000009:adverse effects* / Q000379:methods*; D007261:Infusions, Intra-Arterial; D007552:Isotonic Solutions; D008099:Liver / Q000201:enzymology* / Q000473:pathology; D008156:Luciferases / Q000235:genetics; D008297:Male; D010276:Parasympatholytics / Q000008:administration & dosage; D011674:Pulse; D051381:Rats; D011919:Rats, Inbred Strains; D000077331:Ringer's Solution; D012815:Signal Processing, Computer-Assisted; D014682:Vena Cava, Inferior; D014741:Video Recording
D007552:Isotonic Solutions; D010276:Parasympatholytics; D001285:Atropine; D000077331:Ringer's Solution; D004247:DNA; D008156:Luciferases