Novel mechanism by which hemoglobin induces constriction of cerebral arteries

Since oxyhemoglobin (OxyHb) is implicated in the pathogenesis of cerebral v asospasm, we have investigated the role of protein tyrosine phosphorylation in OxyHb-mediated signalling in canine cerebral arteries and cultured cani ne cerebrovascular smooth muscle cells. OxyHb produced a contraction of bas ilar artery preparations, which was reversed by genistein, an inhibitor of tyrosine kinases, and PD098059, an inhibitor of mitogen-activated protein k inase. In cerebrovascular smooth muscle cells, OxyHb induced tyrosine phosp horylation of 42, 46, 54-60 and 80-100 kDa proteins with a time-course whic h paralleled the contractile action of OxyHb, suggesting that these events might be functionally linked. The 42 and 60 kDa proteins were immunological ly related to the mitogen-activated protein kinase, extracellular signal re gulated protein kinase (ERK2), and to p60(c-Src) (c-Src), respectively. The increase in protein tyrosine phosphorylation was attenuated by genistein, and the phosphorylation of the 42 kDa protein (ERK2) was inhibited by PD098 059. These results suggest that OxyHb-mediated signalling utilizes a protei n tyrosine kinase-based mechanism. (C) 1998 Elsevier Science B.V. All right s reserved.