nitroarginine and Thromboembolism

It has been shown that NO and prostacyclin (prostaglandin I(2)) from cultured endothelium synergistically inhibit blood platelet aggregation in vitro. However, it is unknown whether this synergism is also effective in the inhibition of thromboembolism in vivo and, if it is, whether it differs between vessel types. Therefore, the effect of endogenous NO and prostacyclin, in combination or alone, on thromboembolism was studied in an in vivo model. Thromboembolism was induced by micropipette puncture of rabbit mesenteric arterioles and venules (diameter 18 to 40 micrometer). In addition, the influence of wall shear rate was analyzed. In arterioles, the combined inhibition of NO synthase (N(G)-nitro-L-arginine [L-NA] 0.1 mmol/L; local superfusion) and of cyclooxygenase (aspirin [ASA] 100 mg/kg IV) resulted in a pronounced, significant prolongation of embolization duration (median >600 seconds) compared with control (median 153 seconds) or treatment with either L-NA (234 seconds) or ASA (314 seconds). This combined effect of L-NA+ASA was greater than the sum of the individual effects of L-NA and ASA. In contrast, in venules L-NA+ASA had no additional effect on embolization duration (209 seconds) compared with the effect of L-NA alone (230 seconds); ASA alone had no effect (122 seconds; control 72 seconds). Interestingly, only in the L-NA+ASA arterioles did embolization correlate positively with wall shear rate (r(s)=0.687; P=0.028). In conclusion, this study indicates that in arterioles, but not in venules, endogenous NO and prostaglandins synergistically counteract ongoing thromboembolism after vessel wall injury and that the combination of endogenous NO and prostaglandins appears to protect against enhancement of arteriolar thromboembolism by wall shear rate.

Topics: Animals; Arterioles; Aspirin; Blood Flow Velocity; Cyclooxygenase Inhibitors; Female; Male; Mesentery; Nitric Oxide; Nitroarginine; Prostaglandins; Rabbits; Thromboembolism; Venules

Because nitric oxide (NO) inhibits aggregation and adhesion of blood platelets, NO may play a role in platelet-vessel wall interactions. Therefore, the purpose of this study was to investigate the involvement of endogenous NO in thromboembolic processes, as induced by wall puncture, in rabbit mesenteric arterioles and venules (diameters 20 to 43 microm). In venules, inhibition of NO synthase by superfusion of the mesentery with N omega-nitro-L-arginine (L-NA; 0.1 mmol/L) significantly increased the duration of embolization (from 50 seconds to 511 seconds) and the number of emboli produced (from 2 to 11 emboli per vessel), while the median period of time needed to produce an embolus was not influenced. On the contrary, in arterioles, L-NA had no significant effect on embolization (duration of embolization: 426 seconds in the control and 382 seconds in the L-NA group, with 20 and 12 emboli per vessel, respectively). Addition to the L-NA superfusate of L-arginine (L-ARG; 1 mmol/L), the active precursor for endogenous NO synthesis, resulted in a complete reversal of the L-NA effects in venules, while addition of the inactive D-arginine (D-ARG; 1 mmol/L) had no effect. Addition of L-ARG and D-ARG had no significant effect in arterioles. Addition to the L-NA superfusate of the exogenous NO donor sodium nitroprusside (0.1 micromol/L) also resulted in reversal of the L-NA effects in venules, while in arterioles, it slightly but significantly decreased embolization duration. The differences in effect of L-NA on embolization between arterioles and venules were not caused by differences in fluid dynamic conditions. It is concluded that the role of endogenous NO in inhibiting thromboembolic processes is more important in venules than in arterioles.

Topics: Animals; Arginine; Arterioles; Female; Male; Microscopy, Video; Nitric Oxide; Nitroarginine; Nitroprusside; Rabbits; Rupture; Thromboembolism; Venules