Faraci, Frank M., and Donald D. Heistad. Regulation of the Cerebral Circulation: Role of Endothelium and Potassium Channels. Physiol. Rev. 78: 53–97, 1998. — Several new concepts have emerged in re...

Regulation of the Cerebral Circulation: Role of Endothelium and Potassium Channels

Organization of the gene encoding the human endothelin-converting enzyme (ECE-1).

Molecular Pharmacology and Pathophysiological Significance of Endothelin

Recently, scientists interested in diseases of the human brain have paid much attention to the endothelin group of peptides. Under normal conditions they are found in some types of neurons and in endothelial cells of microvessels but not in glial cells. This review focuses on the endothelin peptides and their involvement in various brain diseases. Particular attention is paid to their expression in reactive astrocytes seen in many pathological conditions of the human brain. Endothelin-1 is a very potent vasoconstrictor which may be involved in the vasospasm occurring in subarachnoid haemorrhage. Intracerebral injection or application to cerebral arteries in animals will cause a focal necrosis, apparently due to severe vasoconstriction. Reactive astrocytes occurring in cases with infarcts, lacunae, Alzheimer's disease, progressive multifocal leukoencephalopathy (PML) and subacute sclerosing panencephalitis (SSPE) express endothelin-like immunoreactivity. Astrocytes in vitro may produce, store and release endothelins. To some extent astrocytes grown in vitro mimic reactive astrocytes in vivo since in cultures astrocytes are removed from their natural environment which may trigger reactive responses. Therefore, in vivo reactive astrocytes may produce, store and release endothelins just as in vitro. If endothelins are released from reactive astrocytes they may act as mitogens and may influence microcirculation by inducing vasoconstriction of intracerebral arterioles. In such ways endothelins may contribute to the final lesions seen in cases with infarcts, lacunae, traumatic conditions, Alzheimer's disease and inflammatory diseases of the brain.

Endothelin peptides in brain diseases.

These studies tested the hypothesis that the cerebral vasospasm that follows subarachnoid hemorrhage (SAH) is due to alterations in endothelin (ET) and ET receptor expression. Eight monkeys underwent cerebral angiography and induction of SAH. Angiography was repeated 7 days later to confirm the presence of cerebral vasospasm, and animals were killed. RNA was isolated from right (vasospastic) and left (control) side middle cerebral arteries and surrounding cerebral cortex. The levels of prepro (PP) ET-1 (ppET-1) and ppET-3 and ET A and ET B receptor mRNAs were determined using a quantitative reverse transcriptase polymerase chain reaction-based assay. ET-1 peptide was also measured in CSF at baseline and after 7 days. Specific agonist binding to ET A and ET B receptors in both middle cerebral arteries and in surrounding brain cortex was measured in three animals by autoradiographic binding assays. Levels of ET B receptor mRNA were 3.4 ± 2.2-fold higher in the right than in the left cerebral arteries (p < 0.01). There were no significant differences in the levels of ppET-1, ppET-3, or ET A receptor mRNA in cerebral arteries. ET-1 peptide was not elevated in CSF. Levels of ET A and ET B receptor mRNAs were 2.6 ± 1.1- and 2.1 ± 1.3-fold higher, respectively, in the right than in the left cerebral cortex, while the level of ppET-3 mRNA was 2.1 ± 1.0-fold lower. There were no differences in ppET-1 mRNA levels between right and left cerebral cortex. Binding to ET A and ET B receptors in cerebral arteries and cortex did not differ significantly between right and left sides. These results do not support the hypothesis that overexpression of ET-1 is the principal cause of vasospasm, but rather they suggest that SAH causes complex changes in the ET system that together are responsible for the cellular response to SAH.

http://jcb.sagepub.com/content/16/4/688.full.pdf

Increased expression of endothelin B receptor mRNA following subarachnoid hemorrhage in monkeys.

(+/-)-SB 209670, a potent nonpeptide endothelin (ET) receptor antagonist, was used to investigate the potential role of ET in cerebral vasospasm associated with subarachnoid hemorrhage.

The effects of (+/-)-SB 209670 were evaluated in isolated segments of canine posterior cerebral arteries in vitro, vascular smooth muscle cells in culture, and in the canine two-hemorrhage model of delayed cerebral vasospasm in vivo.

In the canine basilar and anterior spinal arteries, (+/-)-SB 209670 caused a dose-related inhibition of contractile responses mediated by ET (KB = 4.6 nmol/L and apparent KB = 2.7 nmol/L, respectively). The effects of (+/-)-SB 209670 were mediated by inhibition of ETA receptors since the ETB selective agonist sarafotoxin 6c did not contract these posterior cerebral vessels. (+/-)-SB 209670 also produced a concentration-dependent inhibition (IC50 = 1 nmol/L) of the mitogenic response induced by ET-1 in vascular smooth muscle cell culture. In the canine model of delayed cerebral vasospasm, animals received intracisternal vehicle (saline) or (+/-)-SB 209670 (360 +/- 10 micrograms/d) via osmotic minipump for 7 days. On day 7, the cross-sectional areas in the (+/-)-SB 209670 group were significantly greater than those in the vehicle group in both the basilar artery (68% versus 27%) and anterior spinal artery (78% versus 38%). No differences in blood pressure or heart rate were noted in the two groups, and the vasospasm in the vehicle group did not differ from that of historic controls in this model.

The results suggest that ET plays a significant role in the development of delayed cerebral vasospasm via an interaction with ETA receptors. Furthermore, ETA receptor antagonists may represent a novel therapeutic approach to the treatment of subarachnoid hemorrhage.

https://www.ahajournals.org/doi/pdf/10.1161/01.STR.25.12.2450

Nonpeptide endothelin antagonist. Cerebrovascular characterization and effects on delayed cerebral vasospasm.

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Nonpeptide endothelin antagonist. Cerebrovascular characterization and effects on delayed cerebral vasospasm.