title: Effects of captopril, losartan, and nifedipine on cell hypertrophy of cultured vascular smooth muscle from hypertensive Ren-2 transgenic rats.
abstract: 1. We hypothesized that tissular renin-angotensin system (RAS) induces vascular hypertrophy in hypertensive Ren-2 transgenic rats (TGR; strain name TGR(mRen2)L27). This assumption was tested in cell cultures of vascular smooth muscle (VSMC) from both hypertensive TGR and control normotensive Sprague-Dawley (SD) rats. Planar cell surface area, protein synthesis, and protein content per cell were studied, the role for locally produced angiotensin II (AII) was evaluated and the possible pharmacological interference by different drugs was analysed. 2. By use of 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 SD ones. 3. Under serum-free conditions, VSMC from hypertensive TGR were hypertrophic when compared to SD VSMC, as they presented a higher protein 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 microm2, respectively; P < 0.05). 4. When exogenously added to cultured SD and TGR VSMC, AII (100 pM to 1 microM) promoted protein synthesis and protein content in a concentration-dependent manner without affecting DNA synthesis. Maximal effects were observed at 100 nM. At this concentration, AII effectively increased planar cell surface area in both SD and TGR cultures by approximately 20%. 5. Treatment of TGR cultures, in the absence of exogenous AII, with the angiotensin-converting enzyme inhibitor captopril or the angiotensin AT1 receptors antagonist losartan (100 nM to 10 microM) reduced planar cell surface area in a concentration-dependent manner. In addition, both captopril and losartan (10 microM), decreased protein synthesis by approximately 15%. 6. Treatment of SD VSMC, in the absence of exogenous AII, with both captopril and losartan had no effect either on planar cell surface area or protein synthesis. 7. Treatment with the Ca2+ antagonist nifedipine (100 nM to 10 microM) reduced cell size in both SD and TGR cultures. Maximal cell reduction reached by nifedipine averaged 906 +/- 58 and 1,292 +/- 57 microm2, in SD and TGR, respectively (P<0.05). In addition, nifedipine, nitrendipine and nisoldipine (all at 10 microM) decreased protein synthesis in both cell types by 15-25%. 8. We concluded that cultured VSMC from TGR are hypertrophic in comparison with those from SD. This cell hypertrophy can be the consequence of the expression of the transgene Ren-2 that activates a tissular RAS and locally produces AII, which acts in a paracrine, autocrine, or intracrine manner. Cell hypertrophy in TGR cultures could be selectively reduced by RAS blockade, while nifedipine decreased cell size and protein synthesis in both hypertrophic and non hypertrophic cells.
authors.affiliation: Departamento de Farmacología y Terapeutica, Facultad de Medicina, Universidad Autónoma de Madrid, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Peiró
authors.forename: J L
authors.initials: JL
authors.lastname: Llergo
authors.forename: J
authors.initials: J
authors.lastname: Angulo
authors.forename: J M
authors.initials: JM
authors.lastname: López-Novoa
authors.forename: A
authors.initials: A
authors.lastname: Rodríguez-López
authors.forename: L
authors.initials: L
authors.lastname: Rodríguez-Mañas
authors.forename: C F
authors.initials: CF
authors.lastname: Sánchez-Ferrer
mesh_terms: D000804:Angiotensin II / Q000032:analysis / Q000502:physiology*; D000818:Animals; D030801:Animals, Genetically Modified; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002216:Captopril / Q000494:pharmacology*; D002478:Cells, Cultured; D006973:Hypertension / Q000473:pathology*; D006984:Hypertrophy; D007093:Imidazoles / Q000494:pharmacology*; D019808:Losartan; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000473:pathology; D009543:Nifedipine / Q000494:pharmacology*; D014176:Protein Biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000235:genetics; D013777:Tetrazoles / Q000494:pharmacology*
chemical_list: D001713:Biphenyl Compounds; D007093:Imidazoles; D013777:Tetrazoles; D000804:Angiotensin II; D002216:Captopril; D012083:Renin; D009543:Nifedipine; D019808:Losartan