Em. Vankleef et al., ANGIOTENSIN-II-INDUCED PROGRESSION OF NEOINTIMAL THICKENING IN THE BALLOON-INJURED RAT CAROTID-ARTERY IS AT(1) RECEPTOR-MEDIATED, Arteriosclerosis, thrombosis, and vascular biology, 16(7), 1996, pp. 857-863
To investigate the relative importance of AT(2) and AT(2) receptors in
angiotensin II (Ang II-induced restimulation of neointimal smooth mus
cle cell (SMC) DNA synthesis and increased neointimal cross-sectional
area (CSA), male Wistar rats were subcutaneously infused for 2 weeks w
ith Ang II and losartan, an AT(1) receptor antagonist, or Ang IT and P
D123319, an AT(2) receptor antagonist, during the third and fourth wee
k after balloon injury of the left common carotid artery. Concomitantl
y, all rats received 5-bromo-2'-deoxyuridine to label DNA-synthesizing
SMCs. Neointimal CSAs and SMC DNA synthesis were compared with contro
l groups that received Ang II, 0.9% NaCl, losartan, or PD123319. Systo
lic blood pressure (SEP) was measured at different times during the in
fusion. Ang II induced an increase in SEP that was significantly diffe
rent from the SEP in the NaCI group. Infusion of Ang II together with
losartan reduced the Ang II induced increase in SEP to levels comparab
le with those obtained in the NaCl group. Infusion of Ang II+PD123319
caused an increase in SEP that was comparable with the increase in SBP
of the Ang II group and significantly different from the SEP of the N
aCl group. Infusion of losartan or PD123319 alone did not affect SEP.
Ang II significantly enhanced neointimal CSA (47%, P<.05) compared wit
h the control group infused with NaCl. Losartan significantly reduced
Ang II-induced neointimal thickening (neointimal CSA, -37%, P<.05). In
fusion of PD123319 together with Ang II did not affect Ang II-induced
neointimal thickening. Losartan or PD123319 alone did not reduce neoin
timal thickening, since the neointimal CSAs in these groups did not di
ffer from the neointimal CSA of the NaCl group. Comparable effects wer
e found for SMC DNA synthesis in the neointima. Ang II infusion increa
sed neointimal SMC DNA synthesis. Addition of losartan reduced the fra
ction of DNA-synthesizing neointimal SMCs from 23.7+/-2.1% in the Ang
II group to 12.8+/-1.8% in the Ang II+losartan group, whereas the labe
ling fraction in the neointima remained 26.6+/-3.1% in the Ang II+PD12
3319 group. The labeling fractions in the neointimas of the groups tha
t received losartan or PD123319 alone did not differ from the labeling
fraction in the NaCl group. These data indicate that AT(1) but not AT
(2) receptors mediate the progression of neointimal thickening induced
by delayed application of Ang II in the injured left carotid artery i
n the rat. Furthermore, these data suggest that AT(1) and AT(2) recept
ors are not involved in the regulation of normal growth of a neointima
in the third and fourth week after balloon injury.