Long term monitoring of immunoreactive endothelin-1 and endothelin-3 in ventricular cerebrospinal fluid, plasma, and 24-h urine of patients with subarachnoid hemorrhage.

Abstract

Endothelins (ETs), peptides that were originally isolated from endothelial cells, have extremely potent and long-lasting vasoconstricting effects on cerebral vessels in vitro and in vivo. Observations that astrocytes produce these peptides and that their ET production can be stimulated, e.g. by thrombin, and potentiated via a self-enhancing autoregulatory mechanism may have shed new light upon the pathogenesis of cerebrovasospasm (CVS). ETs are present at low levels in normal human cerebrospinal fluid (CSF). Few and contradictory reports exist on ET levels in subarachnoid hemorrhage (SAH)-associated CVS. We monitored ventricular CSF, plasma, and 24-h urine levels of immunoreactive endothelin-1 (ET-1) and endothelin-3 (ET-3) in seven patients with SAH, who did (five) or did not (two) develop CVS in the course of their disease, as well as in two patients with different conditions (acoustic neuroma/postoperative meningitis; hydro-/hematocephalus) over 7-19 days. A distinct peak of both ET-1 and ET-3 in CSF of patients with SAH coincided with clinically documented signs of CVS and was absent in CSF of patients with SAH but no CVS. CSF levels of ET-1 and ET-3 displayed a striking parallelism in all subjects. Plasma ET-1 levels were essentially in the normal range. ET-3 was not detectable in plasma under our assay conditions. The excretion profiles of ET-1 and ET-3 in 24-h urine revealed again a predominantly parallel behavior of the two peptides. Interestingly, patients with high ET levels in CSF showed simultaneous peaks in urinary ET excretion, expressed as nanograms per gram of creatinine. Our findings support an association of ETs with the pathogenic events following SAH. The well-documented effects of these peptides on cerebral vessels suggest they are mediators rather than markers of disease.