INTRAVENOUS-INJECTION WITH ANTISENSE OLIGODEOXYNUCLEOTIDES AGAINST ANGIOTENSINOGEN DECREASES BLOOD-PRESSURE IN SPONTANEOUSLY HYPERTENSIVE RATS

In the renin-angiotensin system, renin is known to cleave angiotensino gen to generate angiotensin I, which is the precursor of angiotensin I I. Angiotensin II is a vasoactive peptide that plays an important role in blood pressure. On the other hand, the liver is the major organ re sponsible for the production of angiotensinogen in spontaneously hyper tensive rats (SHR). To test the hypothesis that a reduction of angiote nsinogen mRNA in the liver by antisense oligodeoxynucleotides (ODNs) m ay affect both plasma angiotensinogen and angiotensin II levels, as we ll as blood pressure, we intravenously injected antisense ODNs against rat angiotensinogen coupled to asialoglycoprotein carrier molecules, which serve as an important regulator of liver gene expression, into S HR via the tail vein. The SHR used in the present study were studied a t 20 weeks of age and were fed a standard diet throughout the experime nt. Plasma angiotensinogen, angiotensin II concentrations, and blood p ressure all decreased from the next day until up to 5 days after the i njection of antisense ODNs, These concentrations thereafter returned t o baseline by 7 days after injection. A reduction in the level of hepa tic angiotensinogen mRNA was also observed from the day after injectio n until 5 days after injection with antisense ODNs. However, in the SH R injected with sense ODNs, plasma angiotensinogen, angiotensin II con centrations, and blood pressure, as well as hepatic angiotensinogen mR NA, did not significantly change throughout the experimental period. A lthough the exact role of angiotensinogen in hypertension still remain s to be clarified, these findings showed that intravenous injection wi th antisense ODNs against angiotensinogen coupled to asialoglycoprotei n carrier molecules targeted to the liver could thus inhibit plasma an giotensinogen levels and, as a result, induce a decrease in blood pres sure in SHR.