THE EFFECTS OF EXOGENOUS NITRIC-OXIDE ON SMOOTH-MUSCLE CELL-PROLIFERATION FOLLOWING PORCINE CAROTID ANGIOPLASTY

Objectives: Nitric oxide reduces platelet adhesion and platelet-thromb us formation following angioplasty and inhibits smooth muscle cell (SM C) proliferation in vitro. In this study we investigated the effects o f the nitric oxide donor molsidomine on SMC proliferation and intimal growth following experimental angioplasty. Methods: Bilateral carotid angioplasty was performed in 24 anesthetized pigs. Animals were random ized to receive oral molsidomine (whose active metabolite is SIN-1; 0. 3 mg/kg every 8 h; n = 12) or placebo (n = 12) for 48 h before angiopl asty and until the arteries were removed either 7 or 21 days (n = 12 e ach group) later. SMC proliferation was quantified by immunocytochemic al staining with an antibody to the proliferating cell nuclear antigen (PCNA) and morphometric changes by computerized planimetry. SMC's wer e identified by alpha-actin staining. Results: After 3 weeks treatment with molsidomine there was a significant prolongation in bleeding tim e [mean +/- SEM] (151 +/- 6 to 187 +/- 7 s. P < 0.01) and a sustained increase in arterial wall cyclic GMP (6.57 +/- 1.29 to 13.24 +/- 1.02 pmol/mg protein, P < 0.05). Molsidomine significantly reduced intimal proliferation when compared with placebo in arteries with an intact in ternal elastic lamina at 7 days (4.3 +/- 0.7 vs. 9.6 +/- 1.9 PCNA inde x, P < 0.005) and medial proliferation at 7 days (2.4 +/- 0.2 vs. 4.2 +/- 0.7 PCNA index, P < 0.05) and at 21 days (1.3 +/- 0.1 us. 1.9 +/- 0.2 PCNA index, P < 0.05) after angioplasty. In arteries with rupture of the internal elastic lamina, intimal and medial SMC proliferation w ere similar in molsidomine- and placebo-treated animals. Intimal cell number and intimal area were uninfluenced by treatment with molsidomin e in either the presence or absence of rupture of the internal elastic lamina, Conclusions: These results show for the first time that exoge nous nitric oxide inhibits SMC proliferation following balloon angiopl asty in vivo. The antiproliferative effects of nitric oxide are overwh elmed when injury is severe and are not associated with a reduction in intimal thickening. The inhibitory effects of nitric oxide on platele t adhesion and SMC proliferation identify a possible role for high loc al concentrations of nitric oxide to modify the vascular response to b alloon angioplasty.