endothelin-1 and Hematoma

Since their discovery in 1988, endothelins have attracted scientific interest because of their extremely potent and long lasting vasoconstrictive effects. In the clinical part of the study plasma and cerebrospinal fluid (CSF) concentrations of big endothelin-1, endothelin-1 and endothelin-3 in patients with aneurysmal subarachnoid hemorrhage (SAH) were measured serially for 2 weeks after the onset of SAH. Big endothelin-1 was the predominant peptide present in CSF. The CSF concentrations of big ET-1, ET-1 and ET-3 were significantly higher in older than in younger patients. In patients with cerebral vasospasm postoperative concentrations of endothelins in the CSF remained at or were increased above levels measured before surgery. The volume of hematoma in the basal cisterns was predictive of the concentrations of endothelins in CSF. In the experimental study the efficacy of the orally active endothelin-receptor-antagonist RO 47-0203 for the prevention of cerebral vasospasm after experimental SAH, using the canine two-hemorrhage model, was investigated. Twenty-eight beagle dogs were used in this laboratory experiment. Fourteen animals each were assigned to the treatment and to the control group. In the treatment group each dog received two single doses of 30 mg/kg RO 47-0203 orally per day. The diameter of the basilar artery decreased from 1.36 +/- 0.17 mm at day 1 to 1.19 +/- 0.23 mm at day 8 in the treatment group while in the control group the vessel diameter decreased from 1.48 +/- 0.19 mm at day 1 to 1.02 +/- 0.22 mm at day 8. These results corresponded to a decrease of vessel diameter of 13.1% +/- 11.2% in the treatment group and a decrease of vessel diameter of 30.7% +/- 12.4% in the control group (p < 0.001). Concentrations of endothelin-1 in CSF significantly increased with time after SAH. These results underline the important role of endothelin in the development of cerebral vasospasm, and gives for the first time evidence that prevention of cerebral vasospasm can be achieved by the endothelin-receptor-antagonist RO 47-0203.

Topics: Adolescent; Adult; Aged; Aging; Animals; Bosentan; Dogs; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-3; Endothelins; Female; Hematoma; Humans; Ischemic Attack, Transient; Male; Middle Aged; Protein Precursors; Sulfonamides

To determine the effects of minimally invasive surgery (MIS) at various stages after intracerebral hemorrhage (ICH) on perihematomal endothelin (ET)-1 levels and neurological functioning.. Sixty rabbits were randomly distributed into a model control group (MC group, 30 rabbits) or a MIS group (MI group, 30 rabbits). An ICH model was established in all animals. In the MI group, ICH was evacuated by MIS at 6, 12, 18, 24, and 48 hours (six rabbits at each time point) after the ICH was established. The animals in the MC group underwent the same procedures for ICH evacuation, but with a sham operation without hematoma aspiration. All the animals were sacrificed 7 days after the ICH was established. Neurological deficit scores were determined, and the perihematomal brain tissue was removed to determine the ET-1 levels, blood-brain barrier (BBB) permeability, and brain water content (BWC).. The neurological deficit scores, perihematomal ET-1 levels, BBB permeability, and BWC all decreased significantly in the MI group compared to the MC group. Performing the MIS for evacuating the ICH at 6 hours resulted in the most remarkable decreases in these indices, followed by a significant difference observed at 12 hours within the MI subgroups.. Performing MIS at 6-12 hours after ICH resulted in the most significant decreases in neurological deficit scores, ET-1 levels, BBB permeability, and brain edema. The optimal time window for performing MIS for ICH evacuation might be within 6-12 hours after hemorrhage.

Topics: Animals; Blood-Brain Barrier; Brain; Brain Edema; Cerebral Hemorrhage; Disease Models, Animal; Endothelin-1; Hematoma; Male; Minimally Invasive Surgical Procedures; Neurosurgical Procedures; Permeability; Rabbits; Recovery of Function; RNA, Messenger

Cerebral hematoma increases cerebrospinal fluid (CSF) endothelin-1 (ET-1). Inhibitors of ET-1 synthesis prevent this increment and hematoma-induced modification of cerebral arteriolar reactivity. We hypothesized that intrathecal ET-1 injection could 1) modify pial arteriolar reactivity similarly to hematoma; 2) increase CSF lysophosphatidic acid (LPA), a potential contributor to altered cerebrovascular reactivity; and 3) reduce the level of adenosine 3',5'-cyclic monophosphate (cAMP) in the CSF. Either ET-1 (10(-7) M) or artificial CSF was injected over the left parietal cortex of newborn pigs. Four days later, cranial windows were implanted. CSF ET was increased from a basal level of 11 fmol/ml to 18 fmol/ml 4 days after ET-1 injection, whereas CSF cAMP was reduced from 2,700 to 950 fmol/ml. The mean diameter of pial arterioles was reduced 31%. In control animals, 10(-12) M ET caused dilation, and higher concentrations induced vasoconstriction. Four days after ET-1 injection topical ET-1 caused constriction instead of dilation at 10(-12) M, and constrictions at higher doses were enhanced. Norepinephrine-induced constrictions were potentiated in the ET-1-injected group. Dilations to cAMP-dependent (but not independent) vasodilators were attenuated after ET-1. The concentration of the vasoconstrictor lipid mediator LPA increased approximately fourfold. Thus intrathecal injection of ET-1 mimics hematoma-induced modification of cerebral vascular reactivity and increase in LPA production. The mechanism(s) of ET-1- and hematoma-induced modifications may involve LPA, which is known to contribute to the loss of dilator responses by inhibition of cAMP product on. The present study further suggests that ET-1 together with LPA could be causing changes in cerebrovascular reactivity following cerebral hemorrhage. ET-1 stimulates the release of LPA from brain parenchyma independent of serum so that LPA could serve as a secondary mediator.

Topics: Animals; Animals, Newborn; Arterioles; Cerebral Hemorrhage; Cerebrovascular Circulation; Cyclic AMP; Endothelin-1; Endothelins; Hematoma; Lysophospholipids; Microcirculation; Swine; Vasoconstriction; Vasodilator Agents

Endothelin-1 (ET-1) has been implicated in hematoma-induced cerebral vasoconstriction and modification of cerebral microvascular reactivity, particularly attenuation of vasodilation to cAMP-dependent dilators and enhanced vasoconstriction to ET-1. We examined effects of the ET-1 antagonist, BQ-123, on hematoma-induced modification of pial arteriolar responses to ET-1 and iloprost, a cAMP-dependent dilator, in vivo, plus the effects of such treatment on the cortical CSF cAMP. Closed cranial windows were implanted in alpha-chloralose anesthetized piglets 4 days following cortical subarachnoid injection of: (1) artificial cerebrospinal fluid (aCSF); (2) autologous blood; (3) BQ-123 alone; or (4) BQ-123 in combination with blood. ET-1 in CSF was significantly elevated from 3 in control to 45 fmol/ml 6 h following hematoma, dropping to 24 fmol/ml at 24 h but remaining above control 4 days later (14 fmol/ml). The mean diameters of pial arterioles were reduced 30% 4 days following blood injection. This reduction was prevented by pretreatment with BQ-123. In the control piglets, pial arterioles dose-dependently dilated to topical application of iloprost with increases in diameter of 10%, 16% and 21% at 10(-12) M, 10(-10) M and 10(-8) M, respectively. Iloprost-induced dilation was attenuated by hematoma to 4%, 9% and 14% at 10(-12) M, 10(-10) M and 10(-8) M, respectively. Treating piglets with BQ-123 along with hematoma on day 1 prevented the hematoma-induced attenuation of pial arteriolar dilation to iloprost on day 4 (14%, 21% and 29% at 10(-12) M, 10(-10) M and 10(-8) M, respectively). Conversely, dilation to sodium nitroprusside (SNP) was not different among the groups. Topical ET-1 dilated pial arterioles at 10(-12) M and produced dose-dependent constriction at higher doses in the control piglets. The dilation at 10(-12) M ET-1 was reversed to constriction 4 days following hematoma and constrictions to higher doses were enhanced. BQ-123 treatment along with hematoma prevented both the loss of low dose dilation and the enhanced vasoconstriction to ET-1. Treatment with BQ-123 alone on day 1 did not affect the dilation to iloprost or constriction to ET-1, 4 days later. The cortical CSF level of cAMP was significantly reduced from 1637 fmol/ml in controls to 294 fmol/ml in piglets with hematoma. Treatment with BQ-123 along with hematoma blocked the reduction in cAMP (3369 fmol/ml). Initial elevation of ET-1 and the subsequent activation of ETA, receptor may play

Topics: Animals; Animals, Newborn; Blood Vessels; Cerebral Arteries; Cerebral Hemorrhage; Cerebrovascular Circulation; Cyclic AMP; Endothelin-1; Hematoma; Iloprost; Nitroprusside; Peptides, Cyclic; Pia Mater; Swine; Time Factors; Vasoconstriction; Vasodilation; Vasodilator Agents