Synergistic interaction between enalapril, L-arginine and tetrahydrobiopterin in smooth muscle cell apoptosis and aortic remodeling induction in SHR.
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. The objective was to examine the relationships between ED and the cell growth/death balance during vascular remodeling induced by enalapril in SHR. SHR, 10-week-old, received enalapril (ENA: 30 mg x kg(-1) x day(-1) p.o.) for 1 or 2 weeks, or a co-treatment of L-arginine (2.0 g x kg(-1) x day(-1) p.o.) and BH(4) (5.4 mg x kg(-1) x day(-1) i.p. twice daily) administered alone (group: LB) or in combination with enalapril (ENA+LB) for 1 week. Controls received vehicle. 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. 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.
Der Sarkissian
Shant
S
Department of Pharmacology, University of Montreal, University of Montreal Hospital (CHUM) Research Center, 3840 St. Urbain St., Room 7-132B, Montreal, Quebec, Canada H2W 1T8.
Marchand
Eve-Lyne
EL
Duguay
David
D
deBlois
Denis
D
D000109:Acetylcholine / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D017209:Apoptosis / Q000187:drug effects*; D001120:Arginine / Q000494:pharmacology*; D001708:Biopterins / Q000031:analogs & derivatives* / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D004357:Drug Synergism; D004656:Enalapril / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D020287:In Situ Nick-End Labeling; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology*; D009569:Nitric Oxide / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D017382:Reactive Oxygen Species / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology
D000806:Angiotensin-Converting Enzyme Inhibitors; D017382:Reactive Oxygen Species; D014665:Vasodilator Agents; D001708:Biopterins; D009569:Nitric Oxide; D004656:Enalapril; D001120:Arginine; C003402:sapropterin; D000109:Acetylcholine