Simultaneously Increased TxA 2 Activity in Isolated Arterioles and Platelets of Rats With Hyperhomocysteinemia

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Abstract
—We aimed to elucidate the effect of hyperhomocysteinemia (HHcy) on the synthesis of prostaglandins in rat skeletal muscle arterioles and platelets. Male Wistar rats were divided into 2 groups: (1) control rats, with plasma Hcy levels of 6.5±0.5 μmol/L (n=50) and (2) rats with HHcy, induced by daily intake of 1 g/kg body weight methionine in the drinking water for 4 weeks (plasma Hcy levels were 20.6±3.0 μmol/L, P−10 to 10−7 mol/L) were significantly greater in HHcy than in control rat arterioles (at 10−9 mol/L BK, changes were 11±3% in control and 41±9% in HHcy rats). The cyclooxygenase inhibitor indomethacin (10−5 mol/L), the prostaglandin H2/thromboxane A2 (PGH2/TxA2) receptor antagonist SQ 29,548 (10−6 mol/L), or the TxA2 synthase inhibitor furegrelate (5×10−6 mol/L) significantly decreased constrictions to BK in both groups but more so in HHcy arterioles, thus eliminating the difference between responses of HHcy and control arterioles. Constrictions to U46619 (a TxA2 analogue) were significantly greater in HHcy than in control arterioles (at 10−8 mol/L U46619, values for controls were 33±2% and 54±3% for HHcy). Endothelium removal or indomethacin treatment attenuated constrictions to U46619 in HHcy arterioles and eliminated the difference in responses. Also, aggregation of platelets from HHcy rats to collagen and ADP was significantly enhanced compared with controls (with 5 μg/mL collagen: controls, 23±5%; HHcy, 49±5%; with 10−7 mol/L ADP: controls, 25±3%; HHcy, 35±3%). Indomethacin or SQ 29,548 caused greater inhibition of aggregation of HHcy platelets compared with controls, thereby eliminating the differences between the 2 groups. Thus, HHcy enhances TxA2 synthesis both in the arteriolar endothelium and platelets. By promoting vascular constriction and platelet aggregation simultaneously, these alterations are likely to contribute to the atherothrombotic vascular diseases described in HHcy.