Flow-induced constriction in arterioles of hyperhomocysteinemic rats is due to impaired nitric oxide and enhanced thromboxane A(2) 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 approximately 170 microm) from control and methionine diet-induced HHcy rats were investigated with videomicroscopy. Increases in intraluminal flow (from 0 to 25 microL/min) resulted in dilations of control arterioles (maximum, 34+/-4 microm). In contrast, increases in flow elicited constrictions of HHcy arterioles (-36+/-3 microm). In control arterioles, the NO synthase inhibitor N:(omega)-nitro-L-arginine-methyl ester significantly attenuated (approximately 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:(omega)-nitro-L-arginine-methyl ester, whereas it was abolished by indomethacin or the prostaglandin H(2)/thromboxane A(2) (TXA(2)) receptor antagonist SQ 29,548 or the TXA(2) 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 TXA(2) mediation of the response, alterations that likely contribute to the development of peripheral arterial disease.
Bagi
Z
Z
Department of Pathophysiology, Semmelweis University, Budapest, Hungary.
Ungvari
Z
Z
Szollár
L
L
Koller
A
A
D000818:Animals; D001160:Arterioles / Q000378:metabolism / Q000503:physiopathology*; D003251:Constriction, Pathologic; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism / Q000503:physiopathology; D020138:Hyperhomocysteinemia / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D013928:Thromboxane A2 / Q000378:metabolism / Q000502:physiology*
D009569:Nitric Oxide; D013928:Thromboxane A2