P37: Local and systemic hemodynamic effects of low molecular weight nitrosothiols in adult sheep

Background Low molecular weight nitrosothiols (SNOs) are potent vasodilators. The mechanisms by which SNOs effect vasodilation in vivo have been difficult to define, but are recently proposed to involve the uptake of SNO into the smooth muscle cell as S -nitroso- l -cysteine ( l -cysNO) via the l -type amino acid transporter. Therefore, we hypothesized that l -cysNO would demonstrate greater vasodilatory potency compared to its stereoisomer S -nitroso- d -cysteine ( d -cysNO) and the membrane-impermeable S -nitroso-glutathione (GSNO) following infusion into the femoral artery. Method Adult sheep were anesthetized, mechanically ventilated, and instrumented with transonic flow probes around both femoral arteries. Catheters were inserted into the brachial artery for measurement of mean arterial blood pressure (MAP), and into side-branches of the femoral arteries to enable infusion of SNOs directly into the main femoral artery. Hexamethonium was administered intravenously to block all autonomic influence on vascular tone. l -and d -cysNO and GSNO were administered into the ipsilateral femoral artery by continuous infusions. Local hemodynamic effects were assessed by comparing ipsilateral and contralateral responses. The systemic hemodynamic effects were investigated by assessing changes in MAP and the vascular conductance of the contralateral femoral artery, where SNOs had been diluted by passage through the lungs and heart. Dose responses were obtained by changing the rate (continuous infusion) or concentration (bolus injection) of the infusate. Vascular responses were correlated with plasma SNO concentrations, measured by triiodide chemiluminescence. The kinetics of SNO metabolism in blood in vitro were also characterized. Results Continuous infusion of l -cysNO caused potent local vasodilation with conductance in the ipsilateral leg exceeding that of the contralateral leg increased with infusion rate. On the contrary, neither d -cysNO nor GSNO infusion resulted in greater ipsilateral compared to contralateral conductance. All three SNOs had significant systemic effects with reduced MAP and similar increases in the vascular conductances of both legs. Kinetic studies indicated a much faster metabolism of l -cysNO ( t 1/2 = 12 min) than GSNO ( t 1/2 = 28 min) in whole blood in vitro, whereas in vivo rates of elimination of l -cysNO ( t 1/2 = 4.2 min) and GSNO ( t 1/2 = 4.0 min) were similar. The half-lives of l -cysNO and GSNO in vivo correspond well with their systemic hypotensive action duration by bolus injection. Conclusion These results support a stereoselective component of vasodilation for SNOs in the femoral artery of intact adult sheep resulting in increased potency of l -cysNO compared to other SNOs. However, the stereoselective effects of l -cysNO are lost within one circulation transit, possibly due to elimination of the l -cysNO by metabolism or transnitrosation to other endogenous thiols with different vasodilating properties. Finally, the study demonstrates that the hemodynamic effects of SNOs are correlated to their in vivo kinetics. Disclosure Nothing to disclose.