HUMAN ATRIAL-NATRIURETIC-PEPTIDE GENE DELIVERY REDUCES BLOOD-PRESSURE IN HYPERTENSIVE RATS

Chronic infusion of atrial natriuretic peptide (ANP) has been shown to cause natriuresis, diuresis, and hypotension in rats and humans. We explored the effect of a continuous supply of ANP by somatic ANP delivery on genetically hypertensive rats. A DNA construct containing the human ANP gene fused to the Rous sarcoma virus 3'-long terminal repeat (RSV-LTR) was injected intravenously into spontaneously hypertensive rats (SHR) through the tail vein. Expression of human ANP in SHR was identified in the heart, lung, and kidney by radioimmunoassay and reverse transcription-polymerase chain reaction followed by Southern blot analysis. 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 significant 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 SHR was observed 5 weeks after injection with ANP DNA (159.4 +/- 3.02 mm Hg, mean+/-SEM, n=6) compared with SHR injected with vector DNA alone (180.2+/-3.02 mm Hg, mean+/-SEM; n=6 P<.01). Somatic gene delivery of human ANP DNA had no effect on the blood pressure of adult SHR (12 weeks old). After ANP gene delivery, there were significant increases in 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 ANP DNA were not detected in rat sera. These results indicate that somatic delivery of the human ANP gene induces a sustained reduction of systemic blood pressure in young hypertensive rats and raise the feasibility of using ANP gene therapy for the treatment of human hypertension.