Coxsackievirus B3 infection compromises endothelial-dependent vasodilation of coronary resistance arteries.
The mechanisms of coronary artery dysfunction in coxsackievirus B3 (CVB3)-mediated viral myocarditis are poorly understood. We used pressure myography of mouse septal coronary arteries to determine the early and late effects of CVB3 infection on vascular function. Male CD-1 mice (age 6-7 weeks) were infected with CVB3 (1.75 x 10(10) pfu, i.p.). Control mice were injected with PBS. Mice were killed at 3, 7, and 42 days post infection, and the ventricular septal artery was dissected and mounted on a pressure myograph. Pressure-induced myogenic tone was similar in CVB3-infected and sham-infected mice at 3 and 7 days post infection. However, at 42 days post infection constriction of septal arteries to pressures equal to or less than 60 mm Hg was enhanced in CVB3-infected mice compared with sham controls. Agonist-induced vasodilation, as assessed by response to acetylcholine (1 nM-3 microM), was unaltered at early time points (days 3 and 7) in CVB3-infected mice. At later time points (day 42), there was a significant decrease in ACh-induced vasodilation in CVB3-infected mice. Bosentan, an ET-1 (ETA and ETB) receptor antagonist, did not completely ameliorate the reduced ACh-induced vasodilation in 42-day infected mice, indicating that ET-1 does not contribute to vascular dysfunction. Smooth muscle function, as measured by constriction to KCl or dilation to sodium nitroprusside, was unchanged in infected mice at early and late time points. Immunohistochemistry and ET-1 immunoassay were then performed to assess ET-1 levels in CVB3- and sham-infected hearts. There were no differences in ET-1 protein localization or levels at 42 days post infection in sham- and CVB3-infected animals. Finally, in situ hybridization and TUNEL staining were performed to assess viral localization and cell death in CVB3-infected hearts. There was no detectable CVB3 or TUNEL positivity in the endothelium of coronary arteries. Therefore, late impairment of endothelial-dependent vasorelaxation of coronary resistance vessels in CVB3-induced myocarditis does not appear to involve altered ET-1 expression but may be secondary to decreased stimulated NO secretion by the endothelium.
Choy
Jonathan C
JC
UBC McDonald Research Laboratories/The iCAPTUR4E Centre, Department of Pathology and Laboratory Medicine, St. Paul's Hospital/Providence Health Care-University of British Columbia, British Columbia, Canada.
Lui
Amy H
AH
Moien-Afshari
Farzad
F
Wei
Kevin
K
Yanagawa
Bobby
B
McManus
Bruce M
BM
Laher
Ismail
I
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D000077300:Bosentan; D003331:Coronary Vessels / Q000503:physiopathology*; D003384:Coxsackievirus Infections / Q000503:physiopathology*; D019332:Endothelin-1 / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism*; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008955:Models, Cardiovascular; D009205:Myocarditis / Q000503:physiopathology*; D013449:Sulfonamides / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D000959:Antihypertensive Agents; D019332:Endothelin-1; D013449:Sulfonamides; D014665:Vasodilator Agents; D000109:Acetylcholine; D000077300:Bosentan