Activation of L-type calcium channels by tolazoline derivatives

Role of isothiocyanate moiety

L. P. Lei, P. L. Vaghy, J. De Los Angeles, Duane Miller, D. R. Feller

Research output: Contribution to journalArticle

Abstract

The mechanism of action for the isothiocyanato (NCS) affinity label of tolazoline, 2-(4′-isothiocyanatobenzyl)-imidazoline [IBI], was evaluated for interactions with imidazoline preferring receptors (IPRs), α-adrenoceptors (α-ARs) and calcium channels in cardiovascular muscle systems. IBI produced an irreversible, slow-onset and sustained contraction of rat aorta with an EC50 = 5 μM and a maximal contractile effect (116%) which was greater than phenylephrine (100%) and tolazoline (59%). The contractions to IBI were blocked by verapamil, nifedipine, (+)-Bay K 8644, and removal of extracellular calcium, but not affected by the presence of α-AR and IPR ligands such as phenoxybenzamine, cirazoline, efaroxan, moxonidine or idazoxan. IBI inhibited the binding of dihydropyridine (DHP) radioligands, [3H]-PN 200-110 and [3H]-(-)-Bay K 8644, to calcium channel sites in rabbit skeletal t-tubules. Unlike nifedipine, IBI and isothiocyanato derivatives (NCS nifedipine and NCS naphazoline) partially displaced (50-88%) the binding of these radioligands. IBI and NCS nifedipine exhibited positive cooperativity (nH = 1.37-1.46) in binding to DHP sites whereas nifedipine displaced specific binding in a noncooperative manner (nH = 0.97). The binding data indicate that NCS derivatives bind allosterically to L-type calcium channels. Binding of the NCS group to specific nucleophilic protein sites of the calcium channel may be responsible for the contractile responses to IBI.

Original languageEnglish (US)
JournalFASEB Journal
Volume12
Issue number5
StatePublished - Mar 20 1998

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Tolazoline
Imidazolines
L-Type Calcium Channels
calcium channels
isothiocyanates
Nifedipine
chemical derivatives
Chemical activation
Derivatives
Calcium Channels
Imidazoline Receptors
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester
efaroxan
moxonidine
phenoxybenzamine
receptors
phenylephrine
verapamil
adrenergic receptors
aorta

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Lei, L. P., Vaghy, P. L., De Los Angeles, J., Miller, D., & Feller, D. R. (1998). Activation of L-type calcium channels by tolazoline derivatives: Role of isothiocyanate moiety. FASEB Journal, 12(5).

Activation of L-type calcium channels by tolazoline derivatives : Role of isothiocyanate moiety. / Lei, L. P.; Vaghy, P. L.; De Los Angeles, J.; Miller, Duane; Feller, D. R.

In: FASEB Journal, Vol. 12, No. 5, 20.03.1998.

Research output: Contribution to journalArticle

Lei, L. P. ; Vaghy, P. L. ; De Los Angeles, J. ; Miller, Duane ; Feller, D. R. / Activation of L-type calcium channels by tolazoline derivatives : Role of isothiocyanate moiety. In: FASEB Journal. 1998 ; Vol. 12, No. 5.
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