Angiotensin I-converting enzyme antisense prevents altered renal vascular reactivity, but not high blood pressure, in spontaneously hypertensive rats

The renin-angiotensin system plays a critical role in the control of blood pressure, and its hyperactivity is associated with the development of human primary hypertension. Because low-dose angiotensin I-converting enzyme (AC E) inhibitors cause small reductions in blood pressure that are associated with the complete reversal of altered vascular pathophysiology, our objecti ve in this study was to determine whether ACE antisense (ACE-AS) gene deliv ery prevents alterations in renal vascular physiology in the parents and F- 1 offspring of AS-treated spontaneously hypertensive rats (SHR). A single b olus intracardiac injection of ACE-AS (2X10(8) colony-forming units) in SHR neonates caused a modest (18+/-3 mm Hg, n=7 to 9) lowering of blood pressu re, which was maintained in the F-1 generation offspring (n=7 to 9). Altera tions in renal vascular reactivity, electrophysiology, and [Ca2+](i) homeos tasis are underlying mechanisms associated with the development and establi shment of hypertension. Renal resistance arterioles from truncated ACE sens e-treated SHR showed a significantly enhanced contractile response to KCl a nd phenylephrine (n=24 rings from 6 animals, P<0.01) and significantly atte nuated acetylcholine-induced relaxations (n=24 rings from 6 animals, P<0.01 ) compared with arterioles from ACE-AS-treated SHR. In addition, compared w ith cells dissociated from arterioles of ACE-AS-treated SHR, cells from tru ncated ACE sense-treated animal vessels had a resting membrane potential th at was 22+/-4 mV more depolarized (n=38, P<0.01), an enhanced L-type Ca2+ c urrent density (2.2+/-0.3 versus 1.2+/-0.2 pA/pF, n=23, P<0.01), a decrease d Ky current density (16.2+/-1.3 versus 5.4+/-2.2 pA/pF, n=34, P<0.01), and increased Ang II-dependent changes in [Ca2+](i) (n=142, P<0.01). Similar e ffects of ACE-AS treatment were observed in the F-1 offspring. These result s demonstrate that ACE-AS permanently prevents alterations in renal vascula r pathophysiology in spite of the modest effect that ACE-AS had on high blo od pressure in SHR.