Canine pulmonary vasoreactivity to serotonin: Role of protein kinase C and tyrosine kinase

The role of protein kinase C- and protein tyrosine kinase-mediated signal transduction in the canine pulmonary vascular response to serotonin (5-HT) was determined in the isolated blood-perfused dog lung. Pulmonary vascular resistances and compliances were measured with vascular occlusion techniques. 5-HT (10^-5 M) significantly increased precapillary resistance by ~150% and postcapillary resistance twofold and significantly decreased total vascular compliance 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 voltage-dependent Ca²⁺-channel blocker verapamil (10^-5 M), and the specific protein tyrosine kinase inhibitors genistein (5 x 10^{- 4} M) and tyrphostin 25 (5 x 10^-4 M) completely inhibited the pressor response to 5-HT, whereas the 5-HT₁-receptor antagonist (-)pindolol (10^-7 M) had no significant effect on the serotonergic response. These results indicate that the canine pulmonary vascular response to 5-HT involves activation of 5-HT₂ receptors and suggests that this receptor signal transduction pathway involves protein kinase C and tyrosine kinase and the activation of voltage-dependent Ca²⁺ channels.