Role of endothelin-1 in cerebral hematoma-induced modification of cerebral vascular reactivity in piglets.
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 an important role in hematoma-induced alterations of cerebral vascular reactivity and prolonged cerebral vasoconstriction that occur 4 days later. Thus, cerebral hematoma appears to attenuate iloprost-induced dilation and reduce basal cAMP level 4 days following hematoma via release that involves ET-1 of substance(s) on day 1 of hematoma. This substance(s) may act by inhibiting adenylyl cyclase. These results suggest that ET-1 plays an important role in the blood-induced prolonged cerebral vasoconstriction and altered vasoreactivity that follows cerebral hemorrhage via stimulation of ETA receptor.
Department of Physiology and Biophysics, University of Tennessee, Memphis 38163, USA.
M A
MA
Yakubu
C W
CW
Leffler
D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D001808:Blood Vessels / Q000378:metabolism / Q000503:physiopathology; D002536:Cerebral Arteries / Q000187:drug effects; D002543:Cerebral Hemorrhage / Q000378:metabolism / Q000503:physiopathology*; D002560:Cerebrovascular Circulation; D000242:Cyclic AMP / Q000096:biosynthesis; D019332:Endothelin-1 / Q000378:metabolism / Q000502:physiology*; D006406:Hematoma / Q000378:metabolism / Q000503:physiopathology*; D016285:Iloprost / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010841:Pia Mater / Q000098:blood supply; D013552:Swine; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D019332:Endothelin-1; D010456:Peptides, Cyclic; D014665:Vasodilator Agents; D009599:Nitroprusside; D000242:Cyclic AMP; D016285:Iloprost; C072247:cyclo(Trp-Asp-Pro-Val-Leu)