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Effect of angiotensinogen on blood pressure regulation in normotensive rats: application of a loss of function approach

Objective To investigate the effect of plasma angiotensinogen on blood pressure regulation in normotensive rats, by a loss of function approach using antisense oligonucleotides. Design and methods Eight-week-old male Wistar rats were transfected with antisense, sense or scrambled oligonucleotides using liposomes containing viral agglutinins, which are reported to be highly efficient in promoting fusion with target cells. The abdomen was opened with a median incision, and the liver and portal vein were exposed. Then 2.5 ml of hemagglutinating virus–liposome complex containing oligonucleotides was introduced into the liver by multiple direct injections or infusion via the portal vein. Blood pressure, plasma angiotensinogen and angiotensin II levels were measured after transfection. The hepatic angiotensinogen level was examined by Northern blotting and radioimmunoassay. Results The in vivo injection of antisense oligonucleotides against rat angiotensinogen by the hemagglutinating virus–liposome gene transfer method into normotensive rats resulted in a transient fall in blood pressure from day 1 to day 4 after injection. This was accompanied by a decrease in plasma angiotensinogen and hepatic angiotensinogen messenger RNA levels on day 2. No significant changes were noted in untreated rats or those treated with sense or scrambled oligonucleotides. Plasma angiotensin II concentration was also reduced by antisense treatment, but not sense or scrambled treatment. Conclusions In vivo administration of antisense angiotensinogen oligonucleotides resulted in a transient decrease in blood pressure accompanied by a decrease in plasma angiotensinogen and angiotensin II levels, which suggests that angiotensinogen plays a pivotal role in the regulation of blood pressure in normotensive rats.