Aluminum fluoride induces a reversible Ca2+ sensitization in alpha-toxin-permeabilized vascular smooth muscle.
The mechanism of aluminumfloride (AlF)-induced Ca2+ sensitization was explored in alpha-toxin-permeabilized rabbit mesenteric artery. In the presence of 0.18 microM Ca2+ and deferoxamine, a strong chelator of aluminum (Al3+), fluoride (F-; applied in the form of NaF) induced very slow tension development, while in the presence of tracer levels of Al3+ tension developed rapidly possibly due to formation of Al-F complexes (especially AlF4-). As a result, AlF significantly shifted the relationship between tension development and free Ca2+ concentration in the Ca(2+)-EGTA buffer (pCa-tension curve) to the left. The rate of the tension development also depended on the EGTA concentration: increasing the EGTA concentration from 0.5 to 10 mM markedly decreased the maximal rate of contraction ((dT/dt)max), probably due to chelation of Al3+ by EGTA, without effect on the maximal tension (delta Tmax). The AlF-induced Ca2+ sensitization could be reversed by extensive washing with relaxing solution (pCa greater than 8), in contrast to the contractions induced by guanosine 5'-[gamma-thio]triphosphate (GTP gamma s; a non-hydrolyzable GTP analogue) or phorbol 12,13-dibutyrate (PDBu) which were irreversible. However, the action of all the compounds appeared to be mediated through a H-7 (1-[5-isoquinolinesulfonyl]-2-methylpiperazine dihydrochloride)-sensitive pathway, and no additive effects among them were observed. In addition, GDP increased (dT/dt)max due to AlF without changing delta Tmax, whereas guanosine 5'-[beta-thio]diphosphate (GDP beta s; a non-hydolyzable GDP analogue) decreased both parameters. These findings suggest that AlF acts on G-proteins to enhance Ca2+ sensitivity of contractile elements through a H-7-sensitive pathway.
Kawase
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T
Department of Pharmacology, University of Miami School of Medicine, FL 33101.
Van Breemen
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C
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000535:Aluminum / Q000494:pharmacology*; D017607:Aluminum Compounds; D000818:Animals; D001427:Bacterial Toxins / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology*; D004533:Egtazic Acid / Q000494:pharmacology; D005459:Fluorides / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000502:physiology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D006460:Hemolysin Proteins; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology; D011817:Rabbits; D014661:Vasoconstriction / Q000187:drug effects
D017607:Aluminum Compounds; D001427:Bacterial Toxins; D006460:Hemolysin Proteins; D007546:Isoquinolines; D010879:Piperazines; C021091:staphylococcal alpha-toxin; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D004533:Egtazic Acid; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000535:Aluminum; D019204:GTP-Binding Proteins; D005459:Fluorides; D002118:Calcium; C032311:aluminum fluoride