title: Binding and effects of P1075, an opener of ATP-sensitive K+ channels, in the aorta from streptozotocin-treated diabetic rats.
abstract: Diabetes mellitus is associated with major vascular complications. It was the aim of this study to examine the function of the ATP-sensitive K+ channel (K(ATP) channel) in aortic rings prepared from diabetic rats and from age-matched controls. Diabetes was induced by injection of streptozotocin (60 mg/kg i.p.) and the animals were sacrificed 10 weeks after treatment. The binding of the K(ATP) channel opener, P1075 (N-cyano-N'-(1,1dimethylpropyl)-N"-3-pyridylguanidine), as well as the vasorelaxant and 86Rb+ efflux stimulating effects of the drug were measured. In endothelium-denuded rings from diabetic rats, the maximum contraction and sensitivity to noradrenaline were increased; in rings with intact endothelium, the acetylcholine-induced (endothelium-dependent) relaxation was similar in the two groups. In rings from diabetic rats the relaxation-concentration curve of the K(ATP) channel opener P1075 against noradrenaline was shifted rightwards by a factor of 1.3 and the maximum relaxation was reduced from 81 to 71% of initial tension (P <0.01). However, specific binding of 3H-P1075 was increased by 20% without a change in affinity, indicating that the number of binding sites for the opener was increased as a consequence of diabetes. In addition, P1075-induced 86Rb+ efflux, a qualitative measure of K(ATP) channel opening, was augmented by 50%. The data show that in the aorta from diabetic rats the K+ channel opening response to P1075 is markedly increased; however, the vasorelaxant effect to the K(ATP) channel opener is slightly impaired. A possible explanation of these findings is that the vasorelaxant mechanisms (which are in part independent of plasmalemmal K(ATP) channel opening) may be altered; alternatively, the link between membrane potential and smooth muscle tone may be changed in this model of insulin-dependent diabetes mellitus.
authors.affiliation: Department of Pharmacology, Medical Faculty, University of Tübingen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Glocker
authors.forename: U
authors.initials: U
authors.lastname: Quast
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D006146:Guanidines / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012414:Rubidium Radioisotopes / Q000378:metabolism; D014316:Tritium; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D006146:Guanidines; D015221:Potassium Channels; D011725:Pyridines; D012414:Rubidium Radioisotopes; D014665:Vasodilator Agents; D014316:Tritium; C073896:N-cyano-N'-(1,1-dimethylpropyl)-N''-(3-pyridinyl)guanidine; D009638:Norepinephrine