A recent study in dogs suggested that erythropoietin (EPO) not only promotes the synthesis of increased numbers of reticulated platelets but that these newly produced platelets are hyperreactive compared with controls. Because of the increasing use of EPO in the perioperative setting, we characterized the effects of EPO on platelet reactivity in healthy human volunteers. In a randomized, controlled trial, we studied the effects of EPO on platelet reactivity, thrombopoiesis, and endothelial activation in circumstances similar to those of autologous blood donation. Thirty healthy male volunteers received placebo or EPO (100 or 500 U/kg of body weight given intravenously) three times a week for 2 weeks and underwent phlebotomy on days 8 and 15. Thrombin receptor–activating peptide induced expression of P-selectin, and CD63 increased 2- to 3-fold during EPO treatment. The enhanced platelet reactivity was also reflected by a 50% increase in soluble P-selectin in plasma. Plasma E-selectin levels increased in a dose-dependent fashion by more than 100% during EPO treatment, indicating substantial activation of endothelial cells. A 10% to 20% increase in platelet counts was observed in both EPO groups on day 5. In the placebo group, platelets increased only several days after the first phlebotomy. The increase in platelet counts was not reflected by changes in the amounts of reticulated platelets or circulating progenitor cells. In summary, we found that EPO markedly enhances endothelial activation and platelet reactivity, which may adversely affect patients at cardiovascular risk. However, the increased platelet reactivity could be exploited in patients with platelet dysfunction.

Aims It has been demonstrated that inhibition of endothelium derived nitric oxide with N G -monomethyl-l-arginine (l-NMMA) results in a different cardiac and peripheral vascular response. The purpose of this study was to investigate the pharmacokinetic-pharmacodynamic profile of l-NMMA and pharmacokinetic interactions with l-arginine in healthy subjects. Methods Plasma pharmacokinetics were analysed from two different studies: In study 1, 3 mg kg −1 l-NMMA was administered i.v. over 5 min and systemic haemodynamics, cardiac output (CO), fundus pulsation amplitude (FPA), and NO-exhalation (exhNO) were measured at baseline and 15, 65, 95, 155, and 305 min after start of drug administration (n=7). In study 2, 17 mg kg −1 min −1 of the physiologic substrate for nitric oxide synthase, l-arginine, was coinfused i.v. over 30 min with a primed constant infusion of 50 mg kg , drug effects over time were in good agreement with an E max model (r 2 >0.98 each), which also suggested that concentrations producing half-maximum effects were higher for FPA than for CO and exhNO. The coinfusion with l-arginine caused a nearly two-fold increase in plasma l-NMMA levels, indicating a pharmacokinetic interaction. Conclusions In the absence of a systemic hypertensive response, l-NMMA significantly decreased CO, exhNO, and FPA. The concentration calculated to produce a half maximal effect was equivalent for exhNO and CO, but markedly higher for FPA. Furthermore, measurement of FPA is susceptible to changes in l-NMMA levels at small plasma concentrations.

There is evidence that the vasodilator action of insulin is mediated by the release of nitric oxide (NO). We hypothesized that euglycemic hyperinsulinemia might increase renal and ocular blood flow, and that the vasodilator capacity of insulin might be NO-dependent. Euglycemic insulin clamps were performed in 10 healthy subjects. Sixty minutes after the start of insulin administration, an intravenous coinfusion of N-monomethyl-L-arginine (L-NMMA), an inhibitor of NO synthase, or of norepinephrine (NE), an endothelium-independent vasoconstrictor, was started. Renal plasma flow was measured by para-aminohippurate (PAH) clearance method. Ocular hemodynamics were assessed by laser interferometric measurement of fundus pulsations and Doppler sonographic measurement of blood flow velocity in the ophthalmic artery. Renal plasma flow and ocular fundus pulsations were increased by insulin. L-NMMA almost completely abolished the vasodilative effects of insulin, whereas the effects of combined infusion of insulin and NE were approximately the sum of the hemodynamic changes induced by each agent alone. The results show that during euglycemic hyperinsulinemia, renal and ocular blood flow are increased, which may be mediated either by a local vasodilator effect or a systemic increase in flow. The hemodynamic effects of insulin in the kidney and the eye are at least partially dependent on NO synthesis. Because the insulin plasma levels we obtained are in the high physiological range, it may be assumed that insulin plays a role in renal and ocular blood flow regulation.

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Animal experiments indicate that inhibition of nitric oxide synthase (NOS) influences renal hemodynamics and that this effect can be reversed by L-arginine, the precursor of NO synthesis. We have therefore studied the effects of an inhibitor of NOS, N(G)-monomethyl-L-arginine (L-NMMA), and a subsequent coinfusion with L-arginine on renal hemodynamics. In a double-blind, randomized crossover design, eight healthy volunteers (means +/- 1SD, 25.6 +/- 3.1 yr) received a primed constant infusion of L-NMMA (3 mg/kg bolus infusion over 5 min, followed by 50 microg x kg(-1) x min(-1) over 120 min) with subsequent coinfusion of L-arginine (17 mg x kg(-1) x min(-1) over 30 min). In the absence of a hypertensive response, L-NMMA decreased renal plasma flow to 79% of baseline (P < 0.005); this effect was abrogated by L-arginine. Glomerular filtration rate was not affected, NO exhalation was reduced to 30% of baseline (P < 0.005) by L-NMMA, and this effect was attenuated by L-arginine. Our results demonstrate that basal NO production maintains renal blood flow in vivo in humans. In addition, the renal vasculature is particularly sensitive to inhibition of NOS, and these pharmacodynamic effects can be reversed by excess doses of L-arginine.