Increased role of prostaglandin H 2 /thromboxane A 2 (PGH 2 /TXA 2 ) in mediation of flow dependent responses of gracilis muscle venules in hyperhomocysteinemia (HHcy)

Abstract

The vasomotor function of arterial vessels is impaired in HHcy. Thus we hypothesized that HHcy alters the mediation of flow dependent responses of venules. Thus changes in diameter of pressurized venules (diameter: 250±30 μm at 10 mmHg) isolated from normal and HHcy (~5 weeks methionine diet) rats to increases in perfusate flow were measured. Increases in intraluminal flow elicited dilations of control vessels (max.: 13,4±1 %), whereas in HHcy venules flow elicited constrictions (max.: −19±6 %). The NO donor SNP elicited similar magnitude of dilations in both groups. In control venules, the PGH2/TXA2receptor antagonist SQ 29,548 augmented flow-induced dilations, whereas in HHcy venules reversed flow-induced constrictions to dilation. In the presence of SQ 29,548 the NO synthase inhibitor L-NAME significantly decreased flow-induced dilations in control venules, whereas in HHcy the “restored” dilations were not significantly affected. Presence of SOD and CAT did not significantly change flow-induced dilations in control venules, whereas abolished flow-induced constrictions in HHcy venules. Correspondingly, as compared to controls, there was an increased ethidium bromide fluorescence detected in HHcy venules, indicating substantial superoxide production. In conclusion, elevated levels of plasma homocysteine - in part - due to an increased production of reactive oxygen species, could reduce the role of NO and increase the role of PGH2/TXA2 in mediation of flow-induced responses of skeletal muscle venules. These changes may impair the regulation of blood flow and favor increased thrombus formation in venules. Supported by AHA NE Aff. 0555897T and Hungarian NSRF/OTKA-T48376 and HSC/ETT 364/2006.