Expression of biologically active atrial natriuretic factor following intrahepatic injection of a replication-defective adenoviral vector in dogs

Atrial natriuretic factor (ANF) is a potent natriuretic, diuretic, and vaso active hormone produced and released by atrial cardiomyocytes, We investiga ted whether adenovirus-mediated ANF gene delivery to dogs leads to a sustai ned increase in circulating ANF levels resulting in long-lasting biological effects. An adenoviral vector containing the canine ANF cDNA under the con trol of the Rous sarcoma virus 3' long terminal repeat (AdRSV-ANF) was inje cted via the intrahepatic route to nonvaccinated 2-month-old dogs. In the f irst group of four dogs injected with AdRSV-ANF (10(10.2) TCID50), a short- lived increase in plasma ANF concentrations not associated with biological effects occurred 8-10 days after the injection, as compared with four contr ol dogs injected with an adenovirus encoding a luciferase reporter gene (Ad RSV-luc), In a second series of experiments, six dogs received AdRSV-ANF at a dose of 10(10) TCID50 and a replication-defective type 5 adenovirus harb oring a modified VAI gene (Ad-VAr) at the same dose. Sustained increases in plasma ANF concentrations and urinary cGMP excretion starting on day 2 and persisting until day 20 were seen, as well as concomitant elevations in na triuresis and diuresis, a transient increase in cardiac output, and a delay in body weight gain, as compared with control dogs injected with AdRSV-luc /Ad-VAr. These results show that adenovirus-mediated ANF gene expression ca n lead to systemic biological effects in dogs, a finding of potential relev ance for the treatment of cardiovascular diseases and sodium-retaining diso rders.