CANINE PULMONARY VASOREACTIVITY TO SEROTONIN - ROLE OF PROTEIN-KINASE-C AND TYROSINE KINASE

The role of protein kinase C- and protein tyrosine kinase-mediated sig nal transduction in the canine pulmonary vascular response to serotoni n (5-HT) was determined in the isolated blood-perfused dog lung. Pulmo nary vascular resistances and compliances were measured with vascular occlusion techniques. 5-HT (10(-5) M) significantly increased precapil lary resistance by similar to 150% and postcapillary resistance twofol d and significantly decreased total vascular compliance to similar to 50% of control values by decreasing large-vessel compliance and middle -compartment compliance. The 5-HT2-receptor blocker ketanserin (10(-7) M), the protein kinase C inhibitor staurosporine (10(-7) M), the volt age-dependent Ca2+-channel blocker verapamil (10(-5) M), and the speci fic protein tyrosine kinase inhibitors genistein (5 x 10(-4) M) and ty rphostin 25 (5 x 10(-4) M) completely inhibited the presser response t o 5-HT, whereas the 5-HT1-receptor antagonist (-)pindolol (10(-7) M) h ad no significant effect on the serotonergic response. These results i ndicate that the canine pulmonary vascular response to 5-HT involves a ctivation of 5-HT2 receptors and suggests that this receptor signal tr ansduction pathway involves protein kinase C and tyrosine kinase and t he activation of voltage-dependent Ca2+ channels.