Abstract
Endogenous endothelium-derived NO provides a continuous vasodilating
effect, but may also in humans have an antithrombotic effect, which is
exerted by inhibition of platelet function and by vasodilatation.
Inhalation of NO selectively relaxes the pulmonary vascular bed, without
causing systemic hypotension. The selectivity for the pulmonary
circulation is related to its short half-life in blood. Inhaled NO was
thought to have no systemic effects until it was reported that the
bleeding time increased during NO inhalation. It is of clinical
importance to know more about the effects of inhaled NO on bleeding time
and platelet function since NO is increasingly used to treat patients. A
prolonged bleeding time might be hazardous when inhaled NO is
administered to newborn babies, who have an increased risk of
intracranial bleeding, but may also be an advantage when administered to
patients with thrombo-embolic disorders.
The effect of NO inhalation on hemostasis was studied, with special
attention to bleeding time, and platelet function. We found a slight
increase of bleeding time during prolonged inhalation of NO (55 min) in a
dose of 30 ppm, but no change during inhalation of 3 0 or 80 ppm during a
shorter time period (15 min). No effect on platelet function was
demonstrated. Subsequently a randomized, double blind, placebocontrolled
crossover study in healthy volunteers was performed since the bleeding
time measurement may be influenced by the person who performs the test.
In this study, we found slight increases in bleeding time during
inhalation of both NO (30 ppm) and placebo (air) gas.
The effects of L-NMMA infusion, a nonselective NO synthesis inhibitor,
were studied after establishing a model with prolonged infusion. Infusion
of L-NMMA (13.5 mg/kg/60 min) was well tolerated and inhibited endogenous
NO production, as measured by a reduction of NO in nasal air, by
approximately 65% and increased systemic vascular resistance. NO
inhalation added during the last 30 min of infusion increased the
bleeding time similarly with L-NMMA and placebo infusion. Neither L-NMMA
nor NO inhalation had effects on circulating platelets.
Aspirin was used as a positive control in two of our studies. It was
shown to markedly increase bleeding time, and to inhibit platelet
function.
The in vitro effect of a NO donor, S-nitrosoglutathione (GSNO), on
platelet function in the presence and absence of hemoglobin was studied.
A tenfold higher concentration of GSNO was needed to inhibit platelet
function in whole blood compared to platelet rich plasma. These results
provide an explanation for the limited platelet inhibiting effects of NO
in vivo, as opposed to in vitro.
In conclusion, NO inhalation had little or no effect on bleeding time or
platelet function in healthy adult volunteers.
