Vasodilative Response to Hypoxia and Simulated Ischemia Is Mediated by ATP-Sensitive K + Channels in Guinea Pig Thoracic Aorta

Abstract

Local vasodilation in response to hypoxia or ischemia improves perfusion and O₂ supply of the affected tissue. This local vasodilation thus constitutes the most important mechanism in the prevention of ischemic cell injury. The regula tion of vascular tone has mainly been attributed to changes of cytoplasmatic Ca²⁺ ((Ca²⁺)_i) concentrations in vascular smooth muscle cells. The mechanism underlying these changes has not, however, been elucidated so far.

Using aortic strips of guinea pigs (transversally cut in spirals; normal Tyrode, in mM: NaCl 150, KCI 4.5, MgCl₂ 2, CaCl₂ 2.5, glucose 10; buffered with 10 mM HEPES at pH 7.4; equilibrated with 100% O₂ at 31°C) the authors could show that metabolic blockade (glucose replaced by 10 mM 2-deoyglucose (DOG) led to a relaxation of the preparation.

Thus, in four experiments, resting tension decreased from 0.75 g by 27% ± 12% within two hours (% of maximal contractile force developed by each prepa ration when depolarized with 43 mM KCI and 101.5 mM NaCl). When the same experiment was carried out in the presence of 1 mM tolbutamide (a known blocker of ATP-dependent K⁺ channels) in vascular smooth muscle no such re laxation could be seen (n = 4).

Furthermore, in the same type of preparation, similar results have been obtained upon hypoxic relaxation (100% O₂ replaced by 100% N₂), where 1 mM tolbutamide also prevented vasodilation.

Thus, hypoxic/ischemic vasodilation in response to glycolytic inhibition (DOG) and hypoxia (N₂) is based upon the opening of K⁺ _ATP channels and hence can be prevented by sulfonylureas (the opening of K⁺ _ATP channels would lead to hyperpolarization (increased K⁺ conductance, Goldmann equation), thus di minishing the open probability of voltage-gated Ca²⁺ channels with subsequent vasodilation).

This inhibition by sulfonylureas of vasodilative response to ischemia may also constitute the so far unknown cause of the increased cardiovascular mortal ity seen under sulfonylurea treatment.