Kir1.1 and SUR1 are not implicated as subunits of an adenosine triphosphate-sensitive potassium channel involved in diazoxide cardioprotectionCentral MessagePerspective

Jie Wang, MD; Kyriakos Papanicolaou, PhD; Robert Tryon, PhD; Janelle Sangalang, BA; Ben Salazar, BS; Alejandro Suarez-Pierre, MD; Jie Dong, MD; Anson Lee, BS, BA; Emily Larson, BS; Sari Holmes, PhD; Brian O’Rourke, PhD; Colin Nichols, PhD; Jennifer Lawton, MD

JTCVS Open (Sep 2023)

Kir1.1 and SUR1 are not implicated as subunits of an adenosine triphosphate-sensitive potassium channel involved in diazoxide cardioprotectionCentral MessagePerspective

Jie Wang, MD,
Kyriakos Papanicolaou, PhD,
Robert Tryon, PhD,
Janelle Sangalang, BA,
Ben Salazar, BS,
Alejandro Suarez-Pierre, MD,
Jie Dong, MD,
Anson Lee, BS, BA,
Emily Larson, BS,
Sari Holmes, PhD,
Brian O’Rourke, PhD,
Colin Nichols, PhD,
Jennifer Lawton, MD

Affiliations

Jie Wang, MD: Division of Cardiac Surgery, Department of Surgery, Johns Hopkins University, Baltimore, Md
Kyriakos Papanicolaou, PhD: Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, Md
Robert Tryon, PhD: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Mo
Janelle Sangalang, BA: Division of Cardiac Surgery, Department of Surgery, Johns Hopkins University, Baltimore, Md
Ben Salazar, BS: Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, Md
Alejandro Suarez-Pierre, MD: Department of Surgery, University of Colorado School of Medicine, Aurora, Colo
Jie Dong, MD: Division of Cardiac Surgery, Department of Surgery, Johns Hopkins University, Baltimore, Md
Anson Lee, BS, BA: Division of Cardiac Surgery, Department of Surgery, Johns Hopkins University, Baltimore, Md
Emily Larson, BS: Division of Cardiac Surgery, Department of Surgery, Johns Hopkins University, Baltimore, Md
Sari Holmes, PhD: Division of Cardiac Surgery, Department of Surgery, Johns Hopkins University, Baltimore, Md
Brian O’Rourke, PhD: Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, Md
Colin Nichols, PhD: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Mo
Jennifer Lawton, MD: Division of Cardiac Surgery, Department of Surgery, Johns Hopkins University, Baltimore, Md; Address for reprints: Jennifer Lawton, MD, 1800 Orleans St, Zayed 7107, Baltimore, MD 21287.

Journal volume & issue: Vol. 15
pp. 231 – 241

Abstract

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Objective: The adenosine triphosphate-sensitive potassium channel opener diazoxide mimics ischemic preconditioning and is cardioprotective. Clarification of diazoxide's site and mechanism of action could lead to targeted pharmacologic therapies for patients undergoing cardiac surgery. Several mitochondrial candidate proteins have been investigated as potential adenosine triphosphate-sensitive potassium channel components. Renal outer medullary potassium (Kir1.1) and sulfonylurea sensitive regulatory subunit 1 have been suggested as subunits of a mitochondrial adenosine triphosphate-sensitive potassium channel. We hypothesized that pharmacologic blockade or genetic deletion (knockout) of renal outer medullary potassium and sensitive regulatory subunit 1 would result in loss of diazoxide cardioprotection in models of global ischemia with cardioplegia. Methods: Myocyte volume and contractility were compared after Tyrode's physiologic solution (20 minutes), stress (hyperkalemic cardioplegia ± diazoxide, ± VU591 (Kir1.1 inhibitor), N = 9 to 23 each, 20 min), and Tyrode's (20 minutes). Isolated mouse (wild-type, sensitive regulatory subunit 1 [−/−], and cardiac knockout renal outer medullary potassium) hearts were given cardioplegia ± diazoxide (N = 9-16 each) before global ischemia (90 minutes) and 30 minutes reperfusion. Left ventricular pressures were compared before and after ischemia. Results: Stress (cardioplegia) was associated with reduced myocyte contractility that was prevented by diazoxide. Isolated myocytes were not responsive to diazoxide in the presence of VU591. In isolated hearts, diazoxide improved left ventricular function after prolonged ischemia compared with cardioplegia alone in wild-type and knockout (sensitive regulatory subunit 1 [−/−] and cardiac knockout renal outer medullary potassium) mice. Conclusions: Isolated myocyte and heart models may measure independent and separate actions of diazoxide. By definitive genetic deletion, these data indicate that sensitive regulatory subunit 1 and renal outer medullary potassium are not implicated in cardioprotection by diazoxide.

Published in JTCVS Open

ISSN: 2666-2736 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine: Diseases of the circulatory (Cardiovascular) system; Medicine: Surgery
Website: https://www.journals.elsevier.com/jtcvs-open

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