DOXAZOSIN BLOCKS THE ANGIOTENSIN-II-INDUCED SMOOTH-MUSCLE CELL-DNA SYNTHESIS IN THE MEDIA, BUT NOT IN THE NEOINTIMA OF THE RAT CAROTID-ARTERY AFTER BALLOON INJURY

Objective: Infusion of angiotensin II (AngII) during the third and fou rth week after balloon injury of the left common carotid artery of the rat induces smooth muscle cell (SMC) DNA synthesis. In this study we wanted to investigate whether alpha(1)-adrenoreceptors are involved in AngII-induced SMC DNA synthesis in the neointima. Methods: Adult male Wistar Kyoto rats were subcutaneously infused for 2 weeks with AngII and the alpha(1)-adrenoreceptor antagonist doxazosin during the 3rd an d the 4th week after balloon injury of the left common carotid artery. Control groups received AngII, 0.9% NaCl, AngII + 50% dimethylsulfoxi de (DMSO, the solvent of doxazosin), doxazosin or 50% dimethylsulfoxid e. Each rat received 5-bromo-2'-deoxyuridine in a separate osmotic min ipump to label DNA-synthesizing SMC. Systolic blood pressures were mea sured in all groups. Results: Angiotensin II caused an increase in sys tolic blood pressure, whereas addition of doxazosin did not affect the increase in SBP caused by AngII. In the media of the non-injured caro tid artery, AngII increased SMC DNA synthesis, as the BrdUrd labeling fraction increased from 0.2 +/- 0.1% (mean +/- s.e.m.) in the NaCl gro up towards 3.4 +/- 0.6% in the AngII group. Coinfusion with doxazosin reduced the AngII-induced increase in BrdUrd labeling fraction from 3. 2 +/- 0.8% in the AngII + DMSO group towards 0.6 +/- 0.2% in the AngII + doxazosin group. A similar effect of doxazosin was found in the med ia of the injured left carotid artery, in which coinfusion with doxazo sin also reduced the BrdUrd labeling fraction from 2.6 +/- 0.8% in the AngII + DMSO group towards 0.3 +/- 0.1% in the AngII + doxazosin grou p. In the neointima of the injured left carotid artery, AngII increase d the BrdUrd labeling fraction from 11.7 +/- 1.6% in the NaCl group to wards 28.0 +/- 3.4% in the AngII group. Coinfusion with doxazosin did not influence the AngII-induced SMC DNA synthesis, since the BrdUrd la beling fraction in the neointima of the AngII + doxazosin group was 22 .5 +/- 2.9%, whereas the neointimal BrdUrd labeling fraction in the An gII + DMSO group was 22.9 +/- 2.3%. Little effect was found on the med ial cross-sectional area. The neointimal cross-sectional area was incr eased as a result of infusion of AngII (0.12 +/- 0.01 mm(2) vs. 0.18 /- 0.01 mm(2)), and coinfusion of doxazosin did not reduce the AngII-i nduced increase in neointimal cross-sectional area (0.18 +/- 0.03 mm(2 )). Conclusions: These data suggest that alpha(1)-adrenoreceptors are not involved in AngII-induced neointimal SMC DNA synthesis and cross-s ectional area, but only play a role in the media of the carotid artery .