ET-1 induces cortical spreading depression via activation of the ET_Areceptor/phospholipase C pathway in vivo

Abstract

. ET-1 induces cortical spreading depression via activation of the ETA receptor/phospholipase C pathway in vivo. Am J Physiol Heart Circ Physiol 286: H1339-H1346, 2004. First published December 4, 2003 10.1152 10. /ajpheart.00227.2003 has been shown that brain topical superfusion of endothelin (ET)-1 at concentrations around 100 nM induces repetitive cortical spreading depressions (CSDs) in vivo. It has remained unclear whether this effect of ET-1 is related to a primary neuronal/astroglial effect, such as an increase in neuronal excitability or induction of interastroglial calcium waves, or a penumbra-like condition after vasoconstriction. In vitro, ET-1 regulates interastroglial communication via combined activation of ETA and ETB receptors, whereas it induces vasoconstriction via single activation of ETA receptors. We have determined the ET receptor profile and intracellular signaling pathway of ET-1-induced CSDs in vivo. In contrast to the ETB receptor antagonist BQ-788 and concentration dependently, the ETA receptor antagonist BQ-123 completely blocked the occurrence of ET-1-induced CSDs. The ETB receptor antagonist did not increase the efficacy of the ETA receptor antagonist. Direct stimulation of ETB receptors with the selective ETB agonist BQ-3020 did not trigger CSDs. The phospholipase C (PLC) antagonist U-73122 inhibited CSD occurrence in contrast to the protein kinase C inhibitor Gö-6983. Our findings indicate that ET-1 induces CSDs through ETA receptor and PLC activation. We conclude that the induction of interastroglial calcium waves is unlikely the primary cause of ET-1-induced CSDs. On the basis of the receptor profile, likely primary targets of ET-1 mediating CSD are either neurons or vascular smooth muscle cells.endothelin-1; endothelin receptor antagonists; interastroglial calcium waves; gap junction communication; protein kinase C inhibition; arachidonic acid; cortical spreading depression ENDOTHELIN (ET)-1 was initially believed to influence brain functions only indirectly through regulation of cerebral perfusion due to its vasoconstrictor activity. However, over the past few years, evidence has accumulated that ET-1 may fulfill a wider range of physiological actions within the central nervous system (CNS), which has also led to its recognition as a neuropeptide (for reviews, see Refs. 33 and 36). Beside neurons, astrocytes represent a major ET target. Several studies have shown that ET-1 affects numerous cell functions of cultured astrocytes such as control of ion channel activity (5), glutamate efflux (52) and uptake (41), glucose utilization (58), permeability of gap junction communications (3, 16), and calcium signaling (3, 64). In turn, astrocytes are a major source of ET-1 (12, 13) and seem to play an important role in the regulation of ET-1 levels within the CNS (14,24,25).In contrast to the cerebrovascular system, in which ET A receptors are the major receptor subtype, astrocytes predominantly express the ET B receptor subtype (26,38). However, at least in cultured astrocytes, there ...

Spreading Depolarization, A Pathophysiological Mechanism of Stroke and Migraine Aura

“…This is observed in animals in the brain topical model of the vasoconstrictor ET-1 for example [55,70,71], or in response to microemboli [72].…”

A Small-Molecule-Inducible Nrf2-Mediated Antioxidant Response Provides Effective Prophylaxis against Cerebral IschemiaIn Vivo

“…For example, brain glucose levels decrease concurrently with an increase in lactate, suggesting metabolic inhibition (Gramsbergen et al, 2004). Furthermore, extracellular glutamate and dopamine levels accumulate (Bogaert et al, 2000), and peri-infarct depolarizations occur (Kleeberg et al, 2004). ET-1-induced ischemic injury can also be attenuated by strategies known to be protective during intraluminal suture MCAO, such as blockade of NMDA receptors (MK801 [(ϩ)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate]) (Sharkey et al, 1994), voltage-gated sodium channels (AM-36) (Callaway et al, 2004), and voltage-gated calcium channels (nimodipine) (Bogaert et al, 2001), as well as by free radical scavengers (ebselen and coenzyme Q10) (Dawson et al, 1995;Ostrowski et al, 1998), and hypothermia (Van Hemelrijck et al, 2003).…”

Blockade of endothelin B receptor improves the efficacy of levetiracetam in chronic epileptic rats

“…ET-1 is a potent vasoactive 21-amino acid peptide that binds to the ET A and ET B receptors. ET A receptor activation induces vasoconstriction [6], while ET B receptor activation results in vasodilation via nitric oxide (NO) production [7][8][9][10]. In addition, ET-1 regulates PGP expression and transport activity in isolated, intact rat brain capillaries, but not in rat brain capillary endothelial cell lines [11][12][13][14][15].…”