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 (60mg/kg i.p.) and the animals were sacrificed 10 weeks after treatment. The binding of the K_ATP channel opener, P1075 (N-cyano-N’-(1,1-dimethylpropyl)-N’’-3-pyridylguanidine), as well as the vasorelaxant and ⁸⁶Rb⁺ efflux stimulating effects of the drug were measured.

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%.

+

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.