Adrenomedullin (ADM) is a potent vasoactive peptide. In this study, we explored the effects of a continuous supply of ADM by somatic gene delivery on spontaneously hypertensive rats (SHR). DNA constructs containing the human ADM cDNA fused to either the cytomegalovirus promoter (CMV-cADM) or Rous Sarcoma virus 3'-long terminal repeat (RSV-cADM) were intravenously injected into SHR through the tail vein. Expression of human ADM in SHR was identified in the kidney, adrenal gland, heart, and lung by radioimmunoassay and reverse transcription-polymerase chain reaction followed by Southern blot analysis. A single injection of ADM plasmid DNA in young adult SHR (7 wk old) caused a significant reduction in systolic blood pressure for up to 5 wk (p < 0.05). A second injection of CMV-cADM 5 wk after the first delivery resulted in a further reduction in blood pressure for another 3 wk (p < 0.001). A maximal blood pressure reduction of 22 mmHg in SHR was observed 7 wk after injection of CMV-cADM plasmid DNA (185 +/- 1.7 mmHg, n = 6, p < 0.001), and a reduction of 15 mmHg was observed after injection of RSV-cADM (192 +/- 2.7 mmHg, n = 6, p < 0.001), as compared with control rats given vector DNA (207 +/- 2.4 mmHg, n = 6). Similarly, injection of CMV-cADM plasmid DNA in adult SHR (10 wk old) resulted in a significant reduction in blood pressure for up to 6 wk. Antibodies to either human ADM or its plasmid DNA were not detected in rat sera after the second injection. These studies indicate that intravenous injection of the human ADM gene in hypertensive rats results in expression of the foreign gene and induces a long-lasting reduction in blood pressure.