Novel mechanism by which hemoglobin induces constriction of cerebral arteries.
Since oxyhemoglobin (OxyHb) is implicated in the pathogenesis of cerebral vasospasm, we have investigated the role of protein tyrosine phosphorylation in OxyHb-mediated signalling in canine cerebral arteries and cultured canine cerebrovascular smooth muscle cells. OxyHb produced a contraction of basilar artery preparations, which was reversed by genistein, an inhibitor of tyrosine kinases, and PD098059, an inhibitor of mitogen-activated protein kinase. In cerebrovascular smooth muscle cells, OxyHb induced tyrosine phosphorylation of 42, 46, 54-60 and 80-100 kDa proteins with a time-course which paralleled the contractile action of OxyHb, suggesting that these events might be functionally linked. The 42 and 60 kDa proteins were immunologically related to the mitogen-activated protein kinase, extracellular signal regulated protein kinase (ERK2), and to p60c-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 PD098059. These results suggest that OxyHb-mediated signalling utilizes a protein tyrosine kinase-based mechanism.
Vollrath
B
B
Department of Pharmacology, University of Alberta, Edmonton, Canada. bozena.vollrath@ualberta.ca
Cook
D
D
Megyesi
J
J
Findlay
J M
JM
Ohkuma
H
H
D000818:Animals; D002536:Cerebral Arteries / Q000502:physiology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006454:Hemoglobins / Q000502:physiology*; D008297:Male; D010108:Oxyhemoglobins / Q000378:metabolism / Q000494:pharmacology; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D013997:Time Factors; D014443:Tyrosine / Q000378:metabolism; D014661:Vasoconstriction
D006454:Hemoglobins; D010108:Oxyhemoglobins; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases