MITOGEN-ACTIVATED PROTEIN-KINASE ACTIVATION - AN ALTERNATE SIGNALING PATHWAY FOR SUSTAINED VASCULAR SMOOTH-MUSCLE CONTRACTION

Purpose: The vascular smooth muscle determines the dynamic caliber of the blood vessel and hence is the final effector cell in modulating va somotor tone. Although considerable information is available regarding the physiologic agonists that induce contraction, less is known about the cellular signaling events that lead to long-lasting contractions or vasospasm. We examined the hypothesis that activation of mitogen-ac tivated protein (MAP) kinase may be associated with sustained smooth m uscle contractions. Methods: Physiologic contractile responses were de termined in intact bovine carotid artery smooth muscles in a muscle ba th. Corresponding signaling events were determined with immunoblots us ing antiphosphotyrosine antibodies or immunoprecipitation of whole cel l phosphorylated strips of muscle. Results: The tyrosine kinase inhibi tor, genestein, significantly inhibited the magnitude of contractions induced by phorbol ester, endothelin, angiotensin, and serotonin. In a ddition, genestein inhibited the sustained phase of contractions induc ed by serotonin. Serotonin induced vascular smooth muscle contractions were temporally associated with an increase in the phosphorylation of MAP kinase. Conclusions. These data suggest that the activation of MA P kinase is associated with sustained vascular smooth muscle contracti ons. Pharmacologic manipulation of MAP kinase activation may lead to n ew approaches to treat pathologic circumstances of increased vasomotor tone such as vasospasm.