Vanadate stimulation of adenylyl cyclase: an index of tyrosine kinase vascular effects.
BACKGROUND
Beyond their mitogenic effects, hormones such as insulin, which activate receptor tyrosine kinases, regulate vascular tone. Further, we have demonstrated that receptor tyrosine kinase activation enhances adenylyl cyclase activation, a prominent mechanism that mediates vasodilation. However, whether tyrosine kinase-mediated human vascular responses parallel tyrosine kinase-mediated cellular effects on adenylyl cyclase activity is unknown.


RESULTS
To assess tyrosine kinase-mediated vascular responses, vascular sensitivity to insulin was assessed with the dorsal hand vein linear variable differential transformer technique. Insulin infusion resulted in a dose-dependent relaxation in all subjects. Cellular responses were assessed by means of the insulinomimetic vanadate-mediated sensitization of vascular adenylyl cyclase activity. Vanadate stimulated a tyrosine kinase-dependent enhancement of adenylyl cyclase function in human and rat aortic vascular smooth muscle cells, human lymphocytes, and human aortic endothelial cells. Further, maximal insulin-mediated vasodilation was significantly positively correlated with maximal vanadate-mediated enhancement of human lymphocyte adenylyl cyclase activity.


CONCLUSIONS
Insulin-mediated vasodilation is positively correlated with vanadate-mediated enhancement of adenylyl cyclase activity. Vanadate-mediated enhancement of adenylyl cyclase activity in lymphocytes may represent an index of tyrosine kinase-mediated vascular effects.
Tan
C M
CM
Department of Pharmacology, University of Western Ontario, John P. Robarts Research Institute, London, Canada.
McDonald
C G
CG
Chorazyczewski
J
J
Burry
A F
AF
Feldman
R D
RD
Macdonald
C J
CJ
D000262:Adenylyl Cyclases / Q000187:drug effects / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005576:Colforsin / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism; D006225:Hand / Q000098:blood supply; D006801:Humans; D007262:Infusions, Intravenous; D007328:Insulin / Q000008:administration & dosage; D008214:Lymphocytes / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D011505:Protein-Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism*; D014638:Vanadates / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000008:administration & dosage
D007328:Insulin; D014665:Vasodilator Agents; D005576:Colforsin; D014638:Vanadates; D000242:Cyclic AMP; D011505:Protein-Tyrosine Kinases; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases