Different mechanism of LPS‐induced vasodilation in resistance and conductance arteries from SHR and normotensive rats

Abstract

1 The direct and endothelium-dependent e ects of lipopolysaccharide (LPS) were investigated on resistance and conductance arteries from normotensive Wistar (NWR) and spontaneously hypertensive (SHR) rats. 2 In both NWR and SHR, LPS induced dose-dependent relaxations of the mesenteric vascular bed, which were inhibited by L-NNA in SHR but not in NWR. Iberiotoxin (IBTX) inhibited the responses to LPS in both groups, indicating the participation of high conductance Ca 2+ -dependent K + channels. 3 In mesenteric artery rings, the resting membrane potentials and the hyperpolarizing responses of NWR to LPS did not di er in endothelized and denuded preparations but L-NNA inhibited the responses only in endothelized rings. These responses were reduced by bosentan, suggesting that endothelin release may mask a possible hyperpolarizing response to LPS. The hyperpolarizing responses to LPS were blocked by IBTX in both endothelized and de-endothelized NWR rings. In the SHR only intact rings showed hyperpolarization to LPS, which was inhibited by IBTX and by L-NNA. 4 In SHR aortic endothelized or denuded rings, LPS induced hyperpolarizing responses which, in endothelized rings, were partially blocked by L-NNA, by IBTX or by glibenclamide, but totally abolished by IBTX plus glibenclamide. No response to LPS was observed in NWR aortic rings. 5 Our results indicate that LPS activates large conductance Ca 2+ -sensitive K + channels located in the smooth muscle cell membrane both directly and indirectly, through NO release from the endothelium in NWR, whereas NO is the major mediator of the LPS responses in SHR resistance vessels.

Vascular BK Channel Deficiency Exacerbates Organ Damage and Mortality in Endotoxemic Mice

“…7,8 Blockade of BK channels improves arterial reactivity to NE in humans and survival in endotoxemic mice, 9,10 and inhibits sepsis-induced arterial relaxation in vitro. 11,12,13 These data suggest that BK channels contribute to sepsis-induced vasodilation. Theoretically, BK channel blockers should protect against sepsis-induced vascular hypocontractility and prolonged hypotension.…”

Lactic Acid Inhibits Lipopolysaccharide-Induced Mast Cell Function by Limiting Glycolysis and ATP Availability

“…We postulate that these clinical phenotypes are at least partly immune independent. LPS and lactic acid have been shown to have overlapping effects on endothelial cells, increasing NO production, vascular permeability, and vasodilation (62)(63)(64)(65)(66)(67)(68)(69)(70). In mice, low-dose infusions of HCl have been reported to drop blood pH to 7.13, increase endothelial NO, reduce blood pressure, and reduce temperature (66).…”

In Vivo Evidence for Nitric Oxide–Mediated Calcium-Activated Potassium-Channel Activation During Human Endotoxemia

“…This observation is in accordance with various in vitro studies that demonstrate involvement of the K Ca channel, and not the K ATP channel, with the use of TEA 8,9 or highly specific K Ca channel blockers like charybdotoxin 8,9 and iberiotoxin. 29 The absence of a potentiating effect of quinine may well be explained by its rather poor specificity because quinine also acts as an ␣-adrenergic blocking agent. 30 The fact that the vasoconstrictor response to various agonists (norepinephrine, angiotensin II, vasopressin) is attenuated during endotoxemia 17 supports the idea that the final common pathway is affected (influx of calcium and an increase in intracellular calcium), and not the specific receptors or specific signaling pathways for the aforementioned vasoconstrictor substances.…”