Selectivity of the imidazoline alpha-adrenoceptor agonists (oxymetazoline and cirazoline) for human cloned alpha 1-adrenoceptor subtypes.
- Document Type:
- Reference
- Product Catalog Number:
- Multiple
- Product Catalog Name:
- Multiple
imidazolines
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Selectivity of the imidazoline alpha-adrenoceptor agonists (oxymetazoline and cirazoline) for human cloned alpha 1-adrenoceptor subtypes.
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Effects of the imidazoline ligands efaroxan and KU14R on blood glucose homeostasis in the mouse.
- The putative imidazoline I(3) receptor antagonist 2-(2-ethyl-2,3-dihydrobenzo[b]furan-2-yl)-1H-imidazole (KU14R) has been shown to block the effects of the atypical I(3) agonist efaroxan at the level of the ATP-sensitive K(+) (K(ATP)) channel in isolated pancreatic islet beta cells, but its effects in vivo are not known. We have therefore investigated the effects of KU14R on blood glucose and insulin level in vivo. When KU14R was administered before or after a hypoglycaemic dose of efaroxan, the fall in blood glucose was at least additive. When the antihyperglycaemic imidazoline ligand S22068 was administered after a dose of KU14R, it did not alter the hypoglycaemic response. In the mouse isolated vas deferens preparation, neither rauwolscine (at concentrations which competitively antagonised the inhibitory response to 5-bromo-6-(2-imidazolin-2-ylamino)-quinoxaline (UK14304)) nor KU14R affected inhibition produced by S22068. At 10(-4) M, KU14R had weak alpha(2)-adrenoceptor antagonist activity. We conclude that KU14R does not act as an antagonist of either efaroxan or S22068 at an imidazoline site in vivo.
- Document Type:
- Reference
- Product Catalog Number:
- SRI-13K
- Product Catalog Name:
- Sensitive Rat Insulin RIA
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Phentolamine inhibits exocytosis of glucagon by Gi2 protein-dependent activation of calcineurin in rat pancreatic alpha -cells.
- Capacitance measurements were used to investigate the molecular mechanisms by which imidazoline compounds inhibit glucagon release in rat pancreatic alpha-cells. The imidazoline compound phentolamine reversibly decreased depolarization-evoked exocytosis >80% without affecting the whole-cell Ca(2+) current. During intracellular application through the recording pipette, phentolamine produced a concentration-dependent decrease in the rate of exocytosis (IC(50) = 9.7 microm). Another imidazoline compound, RX871024, exhibited similar effects on exocytosis (IC(50) = 13 microm). These actions were dependent on activation of pertussis toxin-sensitive G(i2) proteins but were not associated with stimulation of ATP-sensitive K(+) channels or adenylate cyclase activity. The inhibitory effect of phentolamine on exocytosis resulted from activation of the protein phosphatase calcineurin and was abolished by cyclosporin A and deltamethrin. Exocytosis was not affected by intracellular application of specific alpha(2), I(1), and I(2) ligands. Phentolamine reduced glucagon release (IC(50) = 1.2 microm) from intact islets by 40%, an effect abolished by pertussis toxin, cyclosporin A, and deltamethrin. These data suggest that imidazoline compounds inhibit glucagon secretion via G(i2)-dependent activation of calcineurin in the pancreatic alpha-cell. The imidazoline binding site is likely to be localized intracellularly and probably closely associated with the secretory granules.
- Document Type:
- Reference
- Product Catalog Number:
- GL-32K
- Product Catalog Name:
- Glucagon RIA
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SB 203580 is a specific inhibitor of a MAP kinase homologue which is stimulated by cellular stresses and interleukin-1.
- A class of pyridinyl imidazoles inhibit the MAP kinase homologue, termed here reactivating kinase (RK) [Lee et al. (1994) Nature 372, 739-746]. We now show that one of these compounds (SB 203580) inhibits RK in vitro (IC50 = 0.6 microM), suppresses the activation of MAPKAP kinase-2 and prevents the phosphorylation of heat shock protein (HSP) 27 in response to interleukin-1, cellular stresses and bacterial endotoxin in vivo. These results establish that MAPKAP kinase-2 is a physiological RK substrate, and that HSP27 is phosphorylated by MAPKAP kinase-2 in vivo. The specificity of SB 203580 was indicated by its failure to inhibit 12 other protein kinases in vitro, and by its lack of effect on the activation of RK kinase and other MAP kinase cascades in vivo. We suggest that SB 203580 will be useful for identifying other physiological roles and targets of RK and MAPKAP kinase-2.
- Document Type:
- Reference
- Product Catalog Number:
- Multiple
- Product Catalog Name:
- Multiple