D012: Angiotensin type 1 receptor antisense vs ACE antisense gene therapy in the SHR

Previously, we have demonstrated that neonatal delivery of angiotensin type I receptor antisense cDNA (AT1R-AS) by a retroviral vector circumvents the limitations imposed by pharmacological therapy, resulting in the permanent prevention of high blood pressure (BP) in the spontaneously hypertensive rat (SHR). In the current study, our aim was to compare the effects of antisense to the angiotensin I converting enzyme (ACE-AS) to AT1R-AS in both the prevention of the development of hypertension and in the pathophysiological alterations that occur the SHR. A single intracardiac injection of AT1R-AS resulted in a 47% reduction in BP when compared to SHRs treated with control vector alone. However ACE-AS treatment resulted in only a BP reduction of 27% compared to the vector-treated SHRs. In addition to the hypertension the following cardiovascular pathophysiology occurs in the SHR: left ventricular hypertrophy, increased vascular sensitivity to vasoconstrictor agents, endothelial dysfunction, increased levels of vascular smooth muscle (VSM) intracellular calcium, increased VSM calcium current, decreased VSM Kv current, and VSM depolarization. Both AT1R-AS and ACE-AS gene therapy equally prevented all of the above pathophysiological alterations. These results suggest that ACE-AS therapy may have actions on the tissue RAS to protect the vascular and cardiac pathophysiology, since BP changes were much more moderate than that exhibited by AT1R-AS delivery.