Importance of MAPK and PKC in cerebrovascular endothelin receptor changes

Sammanfattning: Endothelin is a vasoactive peptide that exerts its effect through two receptors; the endothelin type A (ETA) and type B (ETB) receptor. The contractile ETA receptor is localized on smooth muscle cells in the vascular wall, while the ETB receptors are mainly situated on endothelial cells, mediating vasodilatation. The endothelin system is involved in several pathophysiological conditions, such as atherosclerosis and ischemic stroke. Previous studies have shown an upregulation of contractile ETB receptors in the ipsilateral middle cerebral artery (MCA) after experimental focal ischemia and a similar upregulation is also seen after organ culture of MCA. Furthermore, studies have shown an involvement of protein kinase C (PKC) and extracellular signal-regulated kinases (ERK) 1/2 in ischemia. The aim of this thesis was to further elucidate the mechanisms underlying this receptor upregulation process, both in experimental ischemia and in organ culture of rat MCA. The results from the organ culture studies (paper I-III) show that the ETB receptor upregulation is time-dependent, reaching a maximum after 24 hours of organ culture. By adding inhibitors of PKC and ERK1/2 pathways to the culture medium, the ETB receptor upregulation was attenuated. In the experimental model of ischemia (paper IV-V), we administered PKC and ERK1/2 inhibitors to the rats in conjuction with the ischemic insult. Both inhibitors diminished the ETB receptor responses, as well as decreasing brain damage and improving neurological function. In conclusion, the results of this thesis may provide a new perspective on possible mechanisms of actions of PKC and ERK in cerebral ischemia.