Simultaneously increased TxA(2) activity in isolated arterioles and platelets of rats with hyperhomocysteinemia

We aimed to elucidate the effect of hyperhomocysteinemia (HHcy) on the synt hesis of prostaglandins in rat skeletal muscle arterioles and platelets. Ma le Wistar rats were divided into 2 groups: (1) control rats, with plasma He y levels of 6.5+/-0.5 mu mol/L (n=50) and (2) rats with HHcy, induced by da ily intake of 1 g/kg body weight methionine in the drinking water for 3 wee ks (plasma Hey levels were 20.6+/-3.0 mu mol/L, P<0.01 versus controls; n=5 0). Arterioles (diameter approximate to 130 mu m) were isolated from the gr acilis muscle, cannulated, and pressurized (at 80 mm Hg), and changes in th eir diameters were followed by video microscopy. Constrictions to bradykini n (BK; 10(-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 (10-9 mol/L), the prostaglandin H-2/thromboxane A, (PGH(2)/TxA(2)) receptor anta gonist SQ 29,548 (10(-6) mol/L), or the TxA(2) synthase inhibitor furegrela te (5 X 10(-6) mol/L) significantly decreased constrictions to BK in both g roups but more so in HHcy arterioles, thus eliminating the difference betwe en responses of HHcy and control arterioles. Constrictions to U46619 (a TxA (2) 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 HH cy). Endothelium removal or indomethacin treatment attenuated constrictions to U46619 in HHcy arterioles and eliminated the difference in responses. A lso, aggregation of platelets from HHcy rats to collagen and ADP was signif icantly enhanced compared with controls (with 5 mu g/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 TxA(2) synthesis both in the art eriolar endothelium and platelets. By promoting vascular constriction and p latelet aggregation simultaneously, these alterations are likely to contrib ute to the atherothrombotic vascular diseases described in HHcy.