Endothelins and the Role of Endothelin Antagonists in the Management of Posttraumatic Vasospasm

Abstract

Increasing evidence implicates endothelin in the pathophysiological development of cerebral vasospasm. This review summarizes background topics such as the structures and biosynthesis of endothelins, the types of endothelin and their receptors, as well as their biological effects. Basic science and clinical observations supportive of the role of endothelins in the spasm associated with stroke and subarachnoid hemorrhage are presented. Similar basic science and clinical observations are presented regarding the role of endothelins in impaired cerebral hemodynamics following traumatic brain injury, cryogenic cortical lesion injury and fluid percussion brain injury. The role of age in the contribution of endothelin to impaired cerebral hemodynamics following fluid percussion brain injury is discussed. Finally, potential mechanisms for endothelin contributions to vasospasm following fluid percussion brain injury such as impaired K+ channel function are described.

Heat shock protein modulation of KATPand KCachannel cerebrovasodilation after brain injury

“…Additional results of the present study show that cromakalim-, CGRP-, and NS-1619-induced pial artery dilations were blunted within 60 min after FPI, consistent with previous observations (3)(4)(5)(6). However, pretreatment with HSP-70, in the same concentration used in the noninjury studies (see HSP-27 blunts whereas HSP-70 potentiates K ϩ channel agonist-induced pial artery dilation in noninjured newborn pigs), 30 min before FPI along with continued coadministration of this agent with the K ϩ channel agonists postinjury fully restored decremented pial artery dilation to cromakalim and CGRP.…”

“…Cerebral blood flow decreases and pial arteries constrict more in newborn (1-5 day old) versus juvenile (3)(4) wk old) pigs after fluid percussion brain injury (FPI), a model of concussive head injury, supporting the idea that the newborn has greater cerebral hemodynamic sensitivity to brain injury (5). With the use of pial artery dilation as an index of channel activity, it was observed that K ϩ channel impairment contributes substantially to age-dependent altered cerebral hemodynamics after FPI (5,6).…”

Endothelin-1 Is Increased in Cerebrospinal Fluid and Associated with Unfavorable Outcomes in Children after Severe Traumatic Brain Injury

“…A mismatch between CBF and metabolism has been suggested with early hypoperfusion after injury and superimposed hypermetabolism (Armstead et al, 2004;Kochanek et al, 2006;Robertson et al, 1992). Hypoperfusion of injured brain tissue after severe TBI in children is associated with unfavorable outcomes (Adelson et al, 2005).…”

“…Endothelial-derived ET-1 reduces CBF and is associated with clinical vasospasm and secondary neurological injury due to its high potency and long duration of action (Gorlach et al, 2001). In animal models of TBI, including pediatric models, brain ET-1 concentrations increase two-to threefold (Steiner et al, 2004), and are associated with prolonged vasoconstriction (Armstead, 2004). Moreover, antagonism of ET-1 partially reversed this vasoconstrictor response (Ho et al, 2001).…”

Endothelin receptors: what's new and what do we need to know?

“…An incomplete list of these diseases includes hypertension [pregnancy, pulmonary, portopulmonary, and essential systemic (11,31,65,77,86,113)], congestive heart failure (81), cancer (8,37,38,85), diabetes (50,55,60), glaucoma (17), pain (41,56), sexual dysfunction (112), fibrosis (108), renal failure (4,63,93), inflammation (4), and cerebral vasospasm (6).…”