K(ATP)-channel inhibition improves hemodynamics and cellular energetics in hemorrhagic shock

Abstract

We tested whether activation of K(ATP) channels contributes to vasodilatation and end-organ hypoperfusion in severe hemorrhagic shock (HS). Anesthetized juvenile pigs were hemorrhaged to a portal blood flow of 45% of baseline for 45 min and then resuscitated with Ringer lactate (RL; 100% volume of shed blood; n = 10) or RL in combination with the K(ATP)-channel antagonist glibenclamide (10 mg/kg iv bolus injection; n = 10). Addition of glibenclamide to the resuscitation fluid caused a sustained recovery of systemic blood pressure, cardiac index, portal blood flow, renal blood flow, renal cortical ATP concentration, and ileal mucosal P(CO2). Treatment with RL alone caused only a partial and transient hemodynamic and metabolic benefit. Glibenclamide treatment of sham-shocked control pigs (n = 6) transiently increased mesenteric and systemic vascular resistance. Inhibition of K(ATP)-channel activity in HS, which effectively and safely restores systemic hemodynamics, regional perfusion, and tissue metabolism, is a potentially novel therapeutic approach to the management of severe HS.

Parenteral administration of glipizide sodium salt, an inhibitor of adenosine triphosphate-sensitive potassium channels, prolongs short-term survival after severe controlled hemorrhage in rats*

“…These situations require a rapidly administrable drug that can be injected by nonmedical personnel with the ultimate goal to extend the time until definitive medical intervention ("golden hour") (1). Although the present study evaluated parenteral therapy with glipizide sodium salt only under conditions of controlled hemorrhage without determining long-term survival, the results are consistent with the notion that inhibition of K ATP channels might be a potentially effective pharmacologic intervention in the previously mentioned situations (4,5,14). All vehicle-treated rats died, whereas 30% of the animals that received higher doses of the drug were alive as long as 9 hrs after the 40 mm Hg hemorrhage.…”

“…In a preliminary study in a rodent model of lethal pressure-controlled HS, we have demonstrated that an intravenous administration of glibenclamide and tolazamide caused an increase in mean arterial pressure (MAP) and reduced early mortality (4). In anesthetized pigs subjected to pressure-controlled hemorrhage, combined resuscitation with glibenclamide and lactated Ringer's solution also improved systemic and regional hemodynamics and metabolism (5). Furthermore, intravenously injected glibenclamide increased MAP, attenuated acute renal failure, and improved survival in sheep subjected to severe uncontrolled aortal bleeding (14).…”

Inotropes and Vasopressors

“…A vasopressin-modulated increase in vascular sensitivity to norepinephrine further augments its pressor effects. The agent may also directly influence mechanisms involved in the pathogenesis of vasodilation, through inhibition of ATP-activated potassium channels, 19 attenuation of nitric oxide production, 20 and reversal of adrenergic receptor downregulation. 21 The pressor effects of vasopressin are relatively preserved during hypoxic and acidotic conditions, which commonly develop during shock of any origin.…”

Caveolae Localize Protein Kinase A Signaling to Arterial ATP-Sensitive Potassium Channels

“…7,8 Furthermore, pathological activation of K ATP channels has been implicated in the catastrophic vasodilation of septic and hemorrhagic shock. 4,9,10 Many endogenous vasodilators, including calcitonin gene-related peptide (CGRP) and adenosine, act at receptors coupled to the G protein Gs to elevate K ATP channel activity via activation of cAMP-dependent protein kinase A (PKA). 3 Upstream of PKA, the formation of cAMP is catalyzed by the Gs-stimulated enzyme adenylyl cyclase.…”