Synergistic interaction between enalapril, L-arginine and tetrahydrobiopterin in smooth muscle cell apoptosis and aortic remodeling induction in SHR

Abstract

1. Smooth muscle cell (SMC) apoptosis occurs at the onset of enalapril-induced regression of aortic hypertrophy in SHR. A potential mechanism is the correction of endothelial dysfunction (ED) leading to reduced production of reactive oxygen species and enhanced bioavailability of nitric oxide (NO), a potent apoptosis inducer. Stimulants of NO include the precursor L-arginine and the NO synthase cofactor tetrahydrobiopterin (BH 4), which correct ED in several models. 2. The objective was to examine the relationships between ED and the cell growth/death balance during vascular remodeling induced by enalapril in SHR. 3. SHR, 10-week-old, received enalapril (ENA: 30 mg.kg -1.day -1 p.o.) for 1 or 2 weeks, or a cotreatment of L-arginine (2.0 g.kg -1.day -1 p.o.) and BH 4 (5.4 mg.kg -1.day -1 i.p. twice daily) administered alone (group: LB) or in combination with enalapril (ENA + LB) for 1 week. Controls received vehicle. 4. After 1 week, ED was completely corrected with LB but not affected significantly by ENA, whereas both treatments failed to induce SMC apoptosis or aortic remodeling. The correction of ED and the induction of SMC apoptosis (3.3-fold increase in TUNEL labeling) required 2 weeks of ENA treatment. The combination of LB with ENA for 1 week, however, was additive for the reduction of SMC proliferation, and synergistic for the induction of apoptosis and regression of vascular hypertrophy. These interactions were independent of blood pressure regulation. 5. Our results suggest that the correction of ED is not sufficient to induce SMC apoptosis and vascular remodeling, although it facilitates these responses during enalapril treatment.