Activation of GPR75 Signaling Pathway Contributes to the Effect of a 20-HETE Mimetic, 5,14-HEDGE, to Prevent Hypotensive and Tachycardic Responses to Lipopolysaccharide in a Rat Model of Septic Shock

Abstract

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Turn Up the HETE on Septic Shock

“…Reduced cardiac output in conjunction with peripheral vasodilation causes severe refractory hypotension and tissue hypoperfusion leading to multiorgan dysfunction, especially in the liver, kidney, heart, and gastrointestinal tract. Further details regarding the downstream GPR75/20-HETE signaling pathways can be found in the current study of Tunctan et al 1 and previous studies by others. 20,21…”

“…In rat aortic VSMCs, GPR75 activation was associated with Gαq/11/PKC and Src-mediated phosphorylation of the K Ca channel and enhanced the response of rat renal interlobar arteries to phenylephrine. 20,21 The present study by Tunctan et al 1 investigated whether the activation of GPR75-mediated signaling in various vascular beds is responsible for the ability of 5,14-HEDGE to prevent vascular hyporeactivity, hypotension, and tachycardia in the LPS-induced rat model of septic shock. Recent studies have shown that GPR75 is highly expressed in the brain, cerebral arterioles, and pericytes, 23,24 but very little is currently known about its expression in the aorta and other vessels throughout the rest of the body.…”

“…However, human clinical trials failed to establish any significant benefit of nonsteroidal anti-inflammatory drugs in sepsis. 25 Nevertheless, the current study of Tunctan et al 1 is a significant step forward and provides a very compelling case for the further development of 20-HETE mimetics in clinical trials for the treatment of septic shock.…”

“…Given the importance of 20-HETE in the control of vascular tone and that it contributes to the vasodilator effects of NO in the microcirculation, a group from the Mersin University in Turkey, headed by Bahar Tunctan, published a remarkable series of studies to determine if preventing the fall in 20-HETE levels prevents septic shock in rats and mice. 1,4,[17][18][19] They first demonstrated that administration of LPS to rats produces a fall in MAP and increased heart rate (HR) over a 4-hour course of their experiments. 18 This was associated with an increase in iNOS expression and a decrease in plasma 20-HETE levels.…”

“…Sepsis is life-threatening organ dysfunction caused by a dysregulated response to infection. 1 Annually, sepsis affects 1.7 million adults in the United States and is responsible for 270,000 deaths. 2–4 The global burden exceeds 19 million cases/yr and 5 million deaths.…”