Pannexin 1 Channels Control the Hemodynamic Response to Hypoxia by Regulating O<sub>2</sub>-Sensitive Extracellular ATP in Blood.

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2021-01-15

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Abstract

Pannexin1 (Panx1) channels export ATP and may contribute to increased concentration of the vasodilator ATP in plasma during hypoxia in vivo. We hypothesized that Panx1 channels and associated ATP export contributes to hypoxic vasodilation, a mechanism that facilitates the matching of oxygen delivery to tissue metabolic demand. Male and female mice devoid of Panx1 (Panx1-/-) and wild-type controls (WT) were anesthetized, mechanically ventilated, and instrumented with a carotid artery catheter or femoral artery flow transducer for hemodynamic and plasma ATP monitoring during inhalation of 21% (normoxia) or 10% oxygen (hypoxia). ATP export from WT vs. Panx1-/- erythrocytes (RBC) was determined ex vivo via tonometer experimentation across progressive deoxygenation. Mean arterial pressure (MAP) was similar in Panx1-/- (N=6) and WT (N=6) mice in normoxia, but the decrease in MAP in hypoxia seen in WT was attenuated in Panx1-/- mice (-16±9% vs -2±8%; P<0.05). Hindlimb blood flow (HBF) was significantly lower in Panx1-/- (N=6) vs. WT (N=6) basally, and increased in WT but not Panx1-/- mice during hypoxia (8±6% vs -10±13%; P<0.05). Estimation of hindlimb vascular conductance using data from the MAP and HBF experiments showed an average response of 28% for WT vs -9% for Panx1-/- mice. Mean venous plasma ATP during hypoxia was 57% lower in Panx1-/- (N=6) vs WT mice (N=6) (P<0.05). Mean hypoxia-induced ATP export from RBCs from Panx1-/- mice (N=8) was 82% lower than from WT (N=8) ( P<0.05). Panx1 channels participate in hemodynamic responses consistent with hypoxic vasodilation by regulating hypoxia-sensitive extracellular ATP levels in blood.

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10.1152/ajpheart.00651.2020

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Kirby, Brett S, Matthew A Sparks, Eduardo R Lazarowski, Denise A Lopez Domowicz, Hongmei Zhu and Timothy J McMahon (2021). Pannexin 1 Channels Control the Hemodynamic Response to Hypoxia by Regulating O2-Sensitive Extracellular ATP in Blood. American journal of physiology. Heart and circulatory physiology. 10.1152/ajpheart.00651.2020 Retrieved from https://hdl.handle.net/10161/22272.

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Scholars@Duke

Sparks

Matthew A. Sparks

Associate Professor of Medicine

I serve as the Program Director for the Nephrology Fellowship Program. My goal is to work with each fellow to ensure they develop a successful career in whatever direction they choose. I am the lead for the newly established Society for Early Education Scholars (SEEDS) in the Department of Medicine. The SEEDS Program is a year-long mentored education program designed for fellows planning careers as clinician educators or education scholars.

Nephrology Fellowship Program

My interest is in finding ways to promote medical education. My focus is on leveraging social media to enhance learning in nephrology. I serve as the associate director for the Nephrology Social Media Collective (NSMC) internship and member of the board of directors of nephrology journal club (NephJC), a non-profit organization dedicated to enhancing free online medical education in nephrology. I am also co-founder and advisory board member of the first nephrology blog associated with a journal- AJKD blog, the official blog of the American Journal of Kidney Diseases. Co-creator of the popular educational project NephMadness. Past deputy editor of Renal Fellow Network where I continue to remain as faculty lead. I am currently a member of the Nephrology Board of the American Board of Internal Medicine, the Scientific and Clinical Education Lifelong learning Committee Chair, Kidney in Cardiovascular Disease Council of the American Heart Association and am a fellow of the American Society of Nephrology, the American Heart Association, and the National Kidney Foundation. 


Listen to my podcast "The Nephron Segment"

@Nephro_Sparks on X

McMahon

Timothy Joseph McMahon

Professor of Medicine

The McMahon Lab at Duke University and Durham VA Medical Center is investigating novel roles of the red blood cell (RBC) in the circulation. The regulated release of the vasodilator SNO (a form of NO, nitric oxide) by RBCs within the respiratory cycle in mammals optimizes nutrient delivery at multiple levels, especially in the lung (gas exchange) and the peripheral microcirculation (O2 transport to tissues). Deficiency of RBC SNO bioactivity (as in human RBCs banked for transfusion), for example, appears to contribute to the serious lung and circulatory problems associated with RBC transfusion in some settings. We have also demonstrated benefit in the use of treatments that exploit RBCs as a vehicle for delivery of SNOs, in both human patients and in model animals.

RBCs also release ATP in response to stimuli including deformation and hypoxia, and the exported ATP also participates in the maintenance of a healthy circulation, according to mechanisms that we are now unraveling.

We use basic and translational approaches to understand the molecular mechanisms by which these RBC-derived signals effect circulatory changes in human health and disease, particularly in the lung. Disease states driving this research include acute and chronic lung diseases such as sepsis (severe infection, such as COVID-19), transfusion-related respiratory problems, sickle cell disease, and pulmonary hypertension of adults and newborns.

Funding: VA and NIH.


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