Tyrosine kinase inhibitors suppress agonist-induced contraction in smooth muscle.
Because tyrosine kinases participate in diverse signalling pathways, we suspected that these enzymes might also participate in regulation of signal transduction in smooth muscle. Therefore, we studied the effects of geldanomycin, tyrphostin, and genistein, three structurally unrelated tyrosine kinase inhibitors, on receptor-mediated and depolarization-mediated contraction in three different types of smooth muscle. Contraction elicited by stimulation of muscarinic receptors with carbachol, or by stimulation of alpha-adrenergic receptors with norepinephrine or phenylephrine were markedly (> 80%) and reversibly inhibited by tyrosine-kinase inhibitors. In contrast, only slight inhibition (20%) occurred in contractions elicited by K(+)-induced depolorization. Moreover, tyrphostin did not inhibit direct Ca(2+)-mediated activation of the contractile apparatus in preparations permeabilized with beta-escin. These results suggest the novel hypothesis that tyrosine kinases participate in regulation of signal transduction that is associated with receptor-mediated contraction of smooth muscle.
Di Salvo
J
J
Department of Medical and Molecular Physiology, University of Minnesota-Duluth 55812.
Steusloff
A
A
Semenchuk
L
L
Satoh
S
S
Kolquist
K
K
Pfitzer
G
G
D000818:Animals; D016227:Benzoquinones; D002217:Carbachol / Q000494:pharmacology; D002396:Catechols / Q000494:pharmacology; D004285:Dogs; D019833:Genistein; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007529:Isoflavones / Q000494:pharmacology; D047029:Lactams, Macrocyclic; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects*; D009570:Nitriles / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D011809:Quinones / Q000494:pharmacology; D015398:Signal Transduction; D020032:Tyrphostins
D016227:Benzoquinones; D002396:Catechols; D007529:Isoflavones; D047029:Lactams, Macrocyclic; D009570:Nitriles; D011809:Quinones; D020032:Tyrphostins; C060152:tyrphostin 47; D010656:Phenylephrine; D002217:Carbachol; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D011188:Potassium; C001277:geldanamycin