Cardiac surgery with cardiopulmonary bypass (CPB) induces a whole body inflammatory response that sometimes leads to postoperative organ dysfunction, and neutrophil activation plays an important role in this reaction. Neutrophil priming has been described as a change in neutrophil status such that neutrophils show enhanced responsiveness to a second activating stimulus. We hypothesized that neutrophil priming occurs by cardiac surgery with CPB and is temporally related to the neutrophilia after surgery. To evaluate primed circulatory neutrophil status, we measured aggregation activity stimulated by N-formyl-methyl-leucyl-phenyl-alanine (FMLP) and free radical producing activity by tumor necrosing factor (TNF) alpha in peripheral blood samples. Eleven adult patients undergoing elective cardiac surgery with CPB were studied. Blood samples were taken before surgery, at the end of bypass, 12 h after surgery, and 7 days after surgery. Aggregation activity and superoxide generation were significantly elevated 12 h after surgery when compared to presurgery values, indicating that cardiac surgery is associated with circulatory neutrophil priming. The number of neutrophils markedly increased at the end of cardiopulmonary bypass and reached a peak 12 h after surgery. The circulatory neutrophils of cardiac surgical patients become primed after surgery, coincident with the peak neutrophil count. These results suggest that circulatory neutrophils after cardiac surgery with CPB have enhanced responsiveness and are predisposed to systemic inflammation.

SUMMARY 1. The present study investigated whether rapid desensitization (tachyphylaxis) develops after exposure of human hand veins to angiotensin (Ang)II and whether pretreatment with indomethacin affects its development. 2. Venoconstrictor responses to increasing (2–256 ng/min) and constant (50 ng/min) doses of AngII and noradrenaline (NA) infusion were obtained in six healthy male subjects using the dorsal hand vein technique. After pretreatment with indomethacin and placebo, venoconstrictor responses to 50 ng/min AngII infusion were obtained in eight healthy male subjects. 3. The maximal mean (±SD) venoconstrictor response to NA (obtained with 256 ng/min NA) was 93.1±4.7%, whereas that to AngII (obtained with doses between 16 and 128 ng/min) was 43.8±12.2%. Continuous infusion of NA induced constant venoconstriction, whereas the venoconstrictor response to AngII peaked 3 min after the beginning of infusion and, thereafter, was attenuated. 4. Venoconstriction in response to constant AngII infusion after indomethacin pretreatment was significantly larger than that after placebo from 6 to 18 min after the initiation of infusion. 5. These findings show that rapid desensitization to AngII develops in human hand veins and this is compatible with the hypothesis that vasodilator prostaglandins are involved in the development of this desensitization.

These results suggest that O2- production by circulatory PMNs is augmented in SHR, but not in L-NAME and DOCA/salt hypertensive rats. This enhanced function, which is also observed in human essential hypertension, might contribute to the development of cardiovascular damage in genetically determined hypertension.

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The effect of pretreatment with FTY720 (2-amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol hydrochloride) or cyclosporin, or both, on neutrophil-mediated injury has been examined by use of a rat model of transient clamping of hepatic flow. Pretreatment with FTY720 alone or with cyclosporin induced a marked reduction of circulatory lymphocytes, whereas the use of these drugs in combination was very effective at suppressing the elevation of the number of peripheral polymorphonuclear neutrophils (PMN) after reperfusion. Pretreatment with cyclosporin, with or without FTY720, significantly reduced hepatic damage, whereas FTY720 alone tended to prolong hepatic damage. Pretreatment of cyclosporin alone, but not in combination with FTY720, significantly reduced the accumulation of PMN and led to lower myeloperoxidase levels in the damaged liver. In conclusion, pretreatment with cyclosporin, with or without FTY720, reduced hepatic damage after warm ischaemia-reperfusion, whereas pretreatment with FTY720 alone tended to prolong this damage.