HUMAN ATRIAL-NATRIURETIC-PEPTIDE GENE DELIVERY REDUCES BLOOD-PRESSUREIN HYPERTENSIVE RATS

Chronic infusion of atrial natriuretic peptide (ANP) has been shown to cause natriuresis, diuresis, and hypotension in rats and humans. We e xplored the effect of a continuous supply of ANP by somatic ANP delive ry on genetically hypertensive rats. A DNA construct containing the hu man ANP gene fused to the Rous sarcoma virus 3'-long terminal repeat ( RSV-LTR) was injected intravenously into spontaneously hypertensive ra ts (SHR) through the tail vein. Expression of human ANP in SHR was ide ntified in the heart, lung, and kidney by radioimmunoassay and reverse transcription-polymerase chain reaction followed by Southern blot ana lysis. A single injection of naked ANP plasmid DNA (12.3 kb) caused a significant reduction of systemic blood pressure in young SHR (4 weeks old), and the effect continued for 7 weeks. The differences were sign ificant at 1 to 2 weeks (n=6, P<.05) and 3 to 6 weeks after injection (n=6, P<.01) A maximal blood pressure reduction of 21 mm Hg in young S HR was observed 5 weeks after injection with ANP DNA (159.4 +/- 3.02 m m Hg, mean+/-SEM, n=6) compared with SHR injected with vector DNA alon e (180.2+/-3.02 mm Hg, mean+/-SEM; n=6 P<.01). Somatic gene delivery o f human ANP DNA had no effect on the blood pressure of adult SHR (12 w eeks old). After ANP gene delivery, there were significant increases i n urinary volume and urinary potassium output (n=6, P<.05) but not in body weight, heart rate, water intake, urinary sodium output, urinary creatinine, and urinary protein. Antibodies to human ANP or plasmid AN P DNA were not detected in rat sera. These results indicate that somat ic delivery of the human ANP gene induces a sustained reduction of sys temic blood pressure in young hypertensive rats and raise the feasibil ity of using ANP gene therapy for the treatment of human hypertension.