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 approximately 150% and postcapillary resistance twofold and significantly decreased total vascular compliance to approximately 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.
Barman
S A
SA
Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta 30912, USA.
Pauly
J R
JR
Isales
C M
CM
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D011652:Pulmonary Circulation / Q000187:drug effects*; D012701:Serotonin / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D014655:Vascular Resistance / Q000187:drug effects; D014666:Vasomotor System / Q000187:drug effects*; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D012702:Serotonin Antagonists; D012701:Serotonin; D014700:Verapamil; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C