Ch. Gelband et al., Angiotensin I-converting enzyme antisense prevents altered renal vascular reactivity, but not high blood pressure, in spontaneously hypertensive rats, HYPERTENSIO, 35(1), 2000, pp. 209-213
Citations number
25
Categorie Soggetti
Cardiovascular & Respiratory Systems","Cardiovascular & Hematology Research
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.