Effects of 5 HIV protease inhibitors on vasomotor function and superoxide anion production in porcine coronary arteries.
HIV protease inhibitors (PIs) have been implicated to cause cardiovascular complications. Previous studies demonstrated that the PI ritonavir (RTV) caused endothelial dysfunction in porcine arteries. This study investigated and compared the effects of 5 commonly used PIs on vasomotor function, endothelial nitric oxide synthase (eNOS) expression, and oxidative stress in porcine coronary arteries. Vessel rings were incubated with 15 microM of RTV, amprenavir (APV), saquinavir (SQV), indinavir (IDV), or nelfinavir (NFV) for 24 hours. Vasomotor function was studied using a myograph system. The contractility of the rings was significantly reduced for RTV and SQV. In response to bradykinin at 10(-5) M, the endothelium-dependent relaxation was significantly reduced for RTV, APV, and SQV. The eNOS mRNA levels were significantly reduced for RTV, APV, and SQV. Furthermore, the superoxide anion (O(2)(-)) levels of the vessels were significantly increased for RTV and APV. It was found that nitric oxide production was decreased, whereas the level of nitrotyrosine proteins was increased in RTV-treated vessels. Furthermore, antioxidant seleno-L-methionine (SeMet) reversed RTV-induced O(2)(-) production and vasomotor dysfunction. Thus, the HIV PIs RTV, APV, and SQV at 15 microM have more potent in vitro effects on vasomotor dysfunction, eNOS downregulation, and O(2)(-) production than IDV and NFV. The antioxidant SeMet can block these adverse effects of RTV. The results suggest that antioxidant therapy may have applications for controlling PI-associated cardiovascular complications.
Chai
Hong
H
Molecular Surgeon Research Center, Division of Vascular Surgery and Endovascular Therapy, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA.
Yang
Hui
H
Yan
Shaoyu
S
Li
Min
M
Lin
Peter H
PH
Lumsden
Alan B
AB
Yao
Qizhi
Q
Chen
Changyi
C
D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D002219:Carbamates; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology*; D015536:Down-Regulation / Q000187:drug effects; D005663:Furans; D017320:HIV Protease Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D019469:Indinavir / Q000494:pharmacology; D008715:Methionine / Q000031:analogs & derivatives* / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000503:physiopathology; D009213:Myography; D019888:Nelfinavir / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D009924:Organ Culture Techniques; D012333:RNA, Messenger / Q000032:analysis; D019438:Ritonavir / Q000494:pharmacology; D019258:Saquinavir / Q000494:pharmacology; D018036:Selenium Compounds / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism*; D013552:Swine; D014666:Vasomotor System / Q000187:drug effects* / Q000503:physiopathology
D002219:Carbamates; D005663:Furans; D017320:HIV Protease Inhibitors; D012333:RNA, Messenger; D018036:Selenium Compounds; D013449:Sulfonamides; D013481:Superoxides; C095108:amprenavir; D019469:Indinavir; D008715:Methionine; D019001:Nitric Oxide Synthase; D019888:Nelfinavir; D019258:Saquinavir; D019438:Ritonavir; D001920:Bradykinin