Rapid reversal of endothelin-1-induced cerebral vasoconstriction by intrathecal administration of nitric oxide donors.

Abstract

To determine the capability of donors of nitric oxide (NO) (sodium nitroprusside, nitroglycerine) to reverse endothelin-1 (ET-1)-induced cerebral vasoconstriction in vivo, when administered through the cerebrospinal fluid (CSF) to the adventitial side of the constricted blood vessel. The rabbit basilar artery was exposed through a transcervical, transclival approach and subsequently subjected to pharmacological manipulations and direct observation of effects by videomicroscopy. Specific manipulations were suffusion of ET-1 (100 nmol/L, 1 ml/min) in synthetic CSF (sCSF) to provoke vasoconstriction and then either suffusion of an NO donor in sCSF (2 mg/ml/min), or sCSF alone. The second suffusion was always made separately and begun during the period of stable maximal vasoconstriction, which occurred between 20 and 30 minutes after beginning the first suffusion. Measurements of the diameter of the artery were made using an inline video caliper. Sodium nitroprusside and nitroglycerine, both donors of NO, rapidly and completely reversed ET-1-induced vasoconstriction without causing hypotension. The average value for maximal vasoconstriction by ET-1/sCSF was 50.4% of baseline arterial diameter and occurred between 20 and 30 minutes. The rate of vasodilatory response was 100% of significantly constricted arteries. The response was complete in less than 6 minutes in all preparations, as compared to the 60 minutes required for spontaneous relaxation (sCSF suffusion alone). NO donors are effective in reversing cerebral vasoconstriction when administered intrathecally, cause no significant hemodynamic change when so administered, and may represent an important therapeutic intervention for cerebral vasospasm.