C. Peiro et al., EFFECTS OF CAPTOPRIL, LOSARTAN, AND NIFEDIPINE ON CELL HYPERTROPHY OFCULTURED VASCULAR SMOOTH-MUSCLE FROM HYPERTENSIVE REN-2 TRANSGENIC RATS, British Journal of Pharmacology, 121(7), 1997, pp. 1438-1444
1 We hypothesized that tissular renin-angotensin system (RAS) induces
vascular hypertrophy in hypertensive Ren-2 transgenic rats (TGR; strai
n name TGR(mRen2)L27). This assumption was tested in cell cultures of
vascular smooth muscle (VSMC) from both hypertensive TGR and control n
ormotensive Sprague-Dawley (SD) rats. Planar cell surface area, protei
n synthesis, and protein content per cell were studied, the role for l
ocally produced angiotensin II (AII) was evaluated and the possible ph
armacological interference by different drugs was analysed. 2 By use o
f radioimmunoassay techniques, AII could be determined in TGR cultures
(10.25+/-0.12 pg per 10(7) cells) while it could not be detected in S
D ones. 3 Under serum-free conditions, VSMC from hypertensive TGR were
hypertrophic when compared to SD VSMC, as they presented a higher pro
tein content per cell (335+/-18 and 288+/-7 pg per cell respectively;
P<0.05) and increased mean planar cell surface area, as determined by
image analysis (4,074+/-238 and 4,764+/-204 mu m(2), respectively; P <
0.05). 4 When exogenously added to cultured SD and TGR VSMC, AII (100
pM to 1 mu M) promoted protein synthesis and protein content in a con
centration-dependent manner without affecting DNA synthesis. Maximal e
ffects were observed at 100 nM. At this concentration, AII effectively
increased planar cell surface area in both SD and TGR cultures by sim
ilar to 20%. 5 Treatment of TGR cultures, in the absence of exogenous
AII, with the angiotensin-converting enzyme inhibitor captopril or the
angiotensin AT(1) receptors antagonist losartan (100 nM to 10 mu M) r
educed planar cell surface area in a concentration-dependent manner. I
n addition, both captopril and losartan (10 mu M), decreased protein s
ynthesis by Alpha similar to 15%. 6 Treatment of SD VSMC, in the absen
ce of exogenous AII, with both captopril and losartan had no effect ei
ther on planar cell surface area or protein synthesis. 7 Treatment wit
h the Ca2+ antagonist nifedipine (100 nM to 10 mu M) reduced cell size
in both SD and TGR cultures. Maximal cell reduction reached by nifedi
pine averaged 906+/-58 and 1,292+/-57 mu m(2), in SD and TGR, respecti
vely (P<0.005). In addition, nifedipine, nitrendipine End nisoldipine
(all at 10 mu M) decreased protein synthesis in both cell types by 15-
25%. 8 We concluded that cultured VSMC from TGR are hypertrophic in co
mparison with those from SD. This cell hypertrophy can be the conseque
nce of the expression of the transgene Ren-2 that activates a tissular
RAS and locally produces AII, which acts in a paracrine, autocrine, o
r intracrine manner. Cell hypertrophy in TGR cultures could be selecti
vely reduced by RAS blockade, while nifedipine decreased cell size and
protein synthesis in both hypertrophic and non hypertrophic cells.