Katsutoshi Goto

Endothelin-1 Acts in Cerebral Arteries from the Adventitial but Not from the Luminal Side

Summary The in vivo vasoconstrictor effect of endothelin-1 (ET-1) was investigated on feline and canine basilar arteries. The basilar artery caliber was angiographically measured after either vertebral artery perfusion or asternal injection of the peptide. In both cats and dogs, ET-1 (5–500 pmol) induced a dose-dependent basilar artery contraction in vivo when applied intracisternally. The vasoconstriction was extremely long lasting; no significant recovery of vessel caliber was observed up to 12 h after injection. In contrast, bolus injection of ET-1 up to 3 nmol into the vertebral artery had no appreciable effect on the basilar artery caliber. These observations suggest that ET-1 acts in cerebral vessels from the adventitial but not from the luminal side, possibly due to the presence of the blood-brain barrier. The long-lasting nature of the ET-1-induced constriction of the cerebral arteries in vivo suggests that the peptide might be involved in the pathogenesis of cerebral vasospasm.

Essential Role of p38 Mitogen-activated Protein Kinase in Contact Hypersensitivity

The present study was designed to elucidate the role of p38 mitogen-activated protein kinase (p38) in the pathogenesis of inflammation, using a mouse contact hypersensitivity (CHS) model induced by 2,4-dinitro-1-fluorobenzene (DNFB). Ear swelling was induced by challenge with DNFB, accompanied by infiltration of mononuclear cells, neutrophils, and eosinophils and a marked increase in mRNA levels of cytokines such as interleukin (IL)-2, interferon (IFN)-γ, IL-4, IL-5, IL-1β, IL-18, and tumor necrosis factor-α in the challenged ear skin. Both ear swelling and the number of infiltrated cells in DNFB-challenged ear skin were significantly inhibited by treatment with SB202190, a p38 inhibitor. Furthermore, the DNFB-induced expression of all cytokines except IL-4 was significantly inhibited by treatment with SB202190. Ribonuclease protection assay revealed that the mRNA levels of chemokines such as IP-10 and MCP-1 in ear skin were markedly increased at 24 h after challenge with DNFB. The induction of these chemokines was significantly inhibited by treatment with SB202190. In p38α +/− mice, both ear swelling and infiltration of cells induced by DNFB were reduced compared with those in wild-type mice. However, induction of cytokines by DNFB was also observed in p38α +/− mice, although the induction of IFN-γ, IL-5, and IL-18 was typically reduced compared with that in wild-type mice. Challenge with DNFB slightly induced IP-10 and MCP-1 mRNA in p38α +/− mice, with weaker signals than those in SB202190-treated wild-type mice. These results suggest that p38 plays a key role in CHS and is an important target for the treatment of CHS.

Possible role of endothelin in the pathogenesis of cerebral vasospasm.

Since the discovery of endothelin-1 (ET-1), its involvement in cerebral vasospasm after subarachnoid hemorrhage (SAH) has been suspected. We performed various experiments, first to demonstrate the presence of ET in both patients and dogs with SAH, and second to examine the effects of ET synthesis inhibition in experimental vasospasm. Here we report that ET was present in both plasma and cerebrospinal fluid (CSF) in SAH, but did not correlate with vasospasm. However, ET was locally expressed in the vascular endothelium in vasospasm. Several therapeutic approaches causing the inhibition of ET synthesis were effective in preventing the development of vasospasm. Such approaches utilized drugs that inhibited RNA and DNA synthesis. Among them, actinomycin D treatment was most effective. We also utilized phosphoramidon, a recently found conversion inhibitor of big ET to ET. However, this product failed to ameliorate the development of vasospasm. Therefore, although we cannot yet conclude that ET is the main cause of cerebral vasospasm, it may, at least, act as one of the modifying factors in cerebral vasospasm.