Tyrosine kinase inhibitors block calcium channel currents in vascular smooth muscle cells.
Selective inhibitors of tyrosine kinases, tyrphostin 23 and genistein, produced concentration-dependent inhibition of voltage-operated calcium channel currents in vascular smooth muscle cells isolated from rabbit ear artery. The potency of these two structurally dissimilar inhibitors was similar to that reported for their action as inhibitors of tyrosine kinases. Daidzein, an inactive analogue of genistein, had little inhibitory effect on calcium channel currents at concentrations below 300 microM consistent with an action of these agents at a tyrosine kinase. However, tyrphostin 1, a reportedly less active tyrphostin derivative, also inhibited calcium channel currents with a potency similar to tyrphostin 23. These findings suggest that voltage-operated calcium channels in vascular smooth muscle may be modulated by endogenous tyrosine kinase(s) which display different sensitivities to inhibitors compared with the epidermal growth factor (EGF) receptor. Alternatively the possibility of direct blocking actions of these inhibitors at voltage-operated calcium channels cannot be excluded.
Wijetunge
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S
Department of Clinical Pharmacology, St. Mary's Hospital Medical School, Imperial College of Science, Technology and Medicine, London, UK.
Aalkjaer
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Schachter
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M
Hughes
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AD
D000818:Animals; D001158:Arteries / Q000502:physiology*; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology*; D002396:Catechols / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004423:Ear / Q000098:blood supply; D005071:Evoked Potentials / Q000187:drug effects; D019833:Genistein; D066298:In Vitro Techniques; D007529:Isoflavones / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D009570:Nitriles / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011817:Rabbits; D020032:Tyrphostins
D015220:Calcium Channels; D002396:Catechols; D007529:Isoflavones; D009570:Nitriles; D020032:Tyrphostins; C004742:daidzein; D019833:Genistein; D011505:Protein-Tyrosine Kinases; C060641:tyrphostin A23