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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:233.)
© 2001 American Heart Association, Inc.

Vascular Biology

Flow-Induced Constriction in Arterioles of Hyperhomocysteinemic Rats Is Due to Impaired Nitric Oxide and Enhanced Thromboxane A₂ Mediation

Zsolt Bagi; Zoltan Ungvari; Lajos Szollár; Akos Koller

From the Department of Pathophysiology, Semmelweis University, Budapest, Hungary (Z.B., Z.U., L.S., A.K.); and Department of Physiology, New York Medical College, Valhalla, NY (A.K.).

Correspondence to Akos Koller, MD, PhD, Department of Physiology, New York Medical College, Valhalla, NY 10595. E-mail koller{at}nymc.edu

Abstract—Hyperhomocysteinemia (HHcy) is thought to promote arteriosclerosis and peripheral arterial disease, in part by impairing the function of endothelium. Because flow-induced dilation is mediated by the endothelium, we hypothesized that HHcy alters this response by interfering with the synthesis/action of NO and prostaglandins. Thus, changes in the diameter of isolated, pressurized (at 80 mm Hg) gracilis skeletal muscle arterioles (diameter 170 µm) from control and methionine diet–induced HHcy rats were investigated with videomicroscopy. Increases in intraluminal flow (from 0 to 25 µL/min) resulted in dilations of control arterioles (maximum, 34±4 µm). In contrast, increases in flow elicited constrictions of HHcy arterioles (-36±3 µm). In control arterioles, the NO synthase inhibitor N-nitro-L-arginine-methyl ester significantly attenuated (50%) dilation, whereas the additional administration of indomethacin, an inhibitor of cyclooxygenase, eliminated flow-induced dilation. In the arterioles of HHcy rats, flow-induced constriction was not affected by N-nitro-L-arginine-methyl ester, whereas it was abolished by indomethacin or the prostaglandin H₂/thromboxane A₂ (TXA₂) receptor antagonist SQ 29,548 or the TXA₂ synthase inhibitor CGS 13,080. Thus, in HHcy, increases in intraluminal flow elicit constrictions of skeletal muscle arterioles due to the impaired NO and enhanced TXA₂ mediation of the response, alterations that likely contribute to the development of peripheral arterial disease.

Key Words: homocysteine • arteriole • flow-induced response • endothelium • nitric oxide • thromboxane A₂

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