HMR1402, a potassium ATP channel blocker during hyperdynamic porcine endotoxemia: effects on hepato-splanchnic oxygen exchange and metabolism

Abstract

The short-term beneficial hemodynamic effects of KATP channel blockers have to be weighted with the detrimental effect on mitochondrial respiration.

Inhibition of potassium channels in critical illness

“…Similar increases in systemic vascular resistance and arterial blood pressure have been reported after bolus injection of the sulfonylurea glipizide in sheep with hyperdynamic endotoxemia [32]. Likewise, infusion of the K ATP channel blocker HMR1402 increased mean arterial pressure in hyperdynamic porcine endotoxemia [31]. Of note, sulfonylurea agents had no [6,34], or only slight, hemodynamic effects [32] when given to healthy control animals, suggesting that K ATP channels 106 Intensive care Figure 1 Cartoons illustrating the cellular mechanism of increased K ATP channel activation in vascular smooth muscle cells and channel inhibition by sulfonylurea drugs (a) K ATP channels can be activated by decreases in cytosolic ATP concentration and pH or increases in ADP concentration, leading to increased K þ efflux and hyperpolarization of the plasma membrane.…”

“…Nonetheless, bolus administration of sulfonylureas or continuous infusion of HMR1402 resulted in only transient increases in blood pressure, lasting 20-60 min [6,31,32,34]. In contrast to this, continuous administration of the sulfonylurea glipizide entirely reversed the endotoxemia-induced hypotensive-hyperdynamic circulation in sheep during the 3-h infusion period [36 ].…”

“…There is increasing evidence from experimental in vivo studies that K ATP channels are critically involved in the development of systemic vasodilation and vascular hyporesponsiveness noticed in endotoxemia and sepsis [6,[31][32][33][34]. In rats [35], dogs [6], and pigs [34] intravenous bolus infusion of the sulfonylurea glibenclamide immediately reversed endotoxin-induced systemic hypotension owing to significant increases in systemic vascular resistance.…”

“…Although most studies reported that sulfonylureas increase vascular resistance without affecting cardiac output [6,34], continuous infusion of a sulfonylurea drug or HMR1402 resulted in significant reductions of cardiac index [31,36 ]. Furthermore, K ATP channel blockade with HMR1402 caused hyperlactatemia in arterial, hepatic venous, and portal venous blood and significantly increased lactate/pyruvate ratios, possibly indicating impaired cytosolic redox status owing to inhibition of mitochondrial K ATP channels [31].…”

Adenosine triphosphate–magnesium chloride: relevance for intensive care

“…In fact, it has been underscored that therapies of septic shock be investigated in animal models that mimick the features of human sepsis, for example, a hyperdynamic circulatory state associated with hypermetabolism [81]. Therefore we infused ATP-MgCl 2 during long-term hyperdynamic porcine endotoxemia characterized by a sustained increase in cardiac output [82]. ATP-MgCl 2 further increased systemic blood flow and thereby hepatosplanchnic perfusion while preserving the hepatic arterial buffer response, which is normally ablated by endotoxin.…”