Flow-induced constriction in arterioles of hyperhomocysteinemic rats is due to impaired nitric oxide and enhanced thromboxane A₂ mediation

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^ω-nitro-L-argininemethyl 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^ωnitro-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.