Defects in myoglobin oxygenation in K(ATP)-deficient mouse hearts under normal and stress conditions characterized by near infrared spectroscopy and imaging.

BACKGROUND Disruption of ATP-sensitive potassium (K(ATP)) channel activity results in the development of dilated cardiomyopathy in response to different forms of stress, likely due to the underlying metabolic defects. To further understand the role of Kir6.2-containing channels in the development of cardiac disease, we analysed the left ventricular (LV) wall oxygenation and the physiologic responses induced by acute stress in non-dilated Kir6.2(-/-) hearts. METHODS Control (C57BL6) and Kir6.2(-/-) mouse hearts were perfused in constant flow Langendorff mode with Krebs-Henseleit buffer. Myocardial oxygenation was evaluated using a newly developed technique, near infrared spectroscopic imaging (NIRSI) of the myoglobin (Mb) oxygen saturation parameter (OSP, ratio of oxy- to total Mb). RESULTS 2,4-dinitrophenol (DNP, 50-µM) and isoproterenol (0.1-µM) failed to produce a transient vasodilatory response and caused a significant diastolic pressure increase in Kir6.2(-/-) hearts. DNP strongly suppressed contractile function in both groups and induced severe mean OSP decreases in Kir6.2(-/-) hearts. Isoproterenol-induced decreases in OSP were similar despite the lack of contractile function stimulation in the Kir6.2(-/-) group. The index of OSP spatial heterogeneity (relative dispersion, RD) was lower by 15% in the Kir6.2(-/-) group at the baseline conditions. Recovery after stress caused reduction of RD values by 20% (DNP) and 8% (isoproterenol) in controls; however, these values did not change in the Kir6.2(-/-) group. CONCLUSIONS 1) NIRSI can be used to analyse 2-D dynamics of LV oxygenation in rodent models of cardiomyopathy; 2) Kir6.2-containing K(ATP) channels play an important role in maintaining myocardial oxygenation balance under acute stress conditions and in post-stress recovery.

[1]  P. Light,et al.  Current status of the E23K Kir6.2 polymorphism: implications for type-2 diabetes , 2005, Human Genetics.

[2]  J R Wilson,et al.  Value of Peak Exercise Oxygen Consumption for Optimal Timing of Cardiac Transplantation in Ambulatory Patients With Heart Failure , 1991, Circulation.

[3]  M. Artman,et al.  Immunolocalization of KATP channel subunits in mouse and rat cardiac myocytes and the coronary vasculature , 2005, BMC Physiology.

[4]  S. Nighswander-Rempel,et al.  Assessment of optical path length in tissue using neodymium and water absorptions for application to near-infrared spectroscopy. , 2005, Journal of biomedical optics.

[5]  A. Coats,et al.  Ethical authorship and publishing. , 2009, International journal of cardiology.

[6]  T. Kita,et al.  Real-Time 2-Photon Imaging of Mitochondrial Function in Perfused Rat Hearts Subjected to Ischemia/Reperfusion , 2006, Circulation.

[7]  D. K. Arrell,et al.  Proteomic profiling of KATP channel‐deficient hypertensive heart maps risk for maladaptive cardiomyopathic outcome , 2009, Proteomics.

[8]  S. Nighswander-Rempel,et al.  Mapping regional oxygenation and flow in pig hearts in vivo using near-infrared spectroscopic imaging. , 2004, Journal of molecular and cellular cardiology.

[9]  A. Terzic,et al.  KATP channel knockout worsens myocardial calcium stress load in vivo and impairs recovery in stunned heart. , 2007, American journal of physiology. Heart and circulatory physiology.

[10]  L Bolinger,et al.  Validation of near-infrared spectroscopy in humans. , 1994, Journal of applied physiology.

[11]  Mark Hewko,et al.  Regional variations in myocardial tissue oxygenation mapped by near-infrared spectroscopic imaging. , 2002, Journal of molecular and cellular cardiology.

[12]  J. Dilger,et al.  Transport of protons across membranes by weak acids. , 1980, Physiological reviews.

[13]  Visser Fc Imaging of cardiac metabolism using radiolabelled glucose, fatty acids and acetate. , 2001 .

[14]  R. Karch,et al.  The spatial pattern of coronary capillaries in patients with dilated, ischemic, or inflammatory cardiomyopathy. , 2005, Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology.

[15]  J. Schipke The heterogeneities of the heart. , 2001, Basic research in cardiology.

[16]  V. Kupriyanov,et al.  Potassium fluxes, energy metabolism, and oxygenation in intact diabetic rat hearts under normal and stress conditions. , 2008, Canadian journal of physiology and pharmacology.

[17]  Z. Wei,et al.  KATP Channels Are an Important Component of the Shear‐Sensing Mechanism in the Pulmonary Microvasculature , 2006, Microcirculation.

[18]  J. Rendell,et al.  K+ transport and energetics in Kir6.2(-/-) mouse hearts assessed by 87Rb and 31P magnetic resonance and optical spectroscopy. , 2006, Journal of molecular and cellular cardiology.

[19]  R. Tsien,et al.  Mechanisms of calcium channel modulation by beta-adrenergic agents and dihydropyridine calcium agonists. , 1986, Journal of molecular and cellular cardiology.

[20]  H. Weiss,et al.  Dependence of spatial heterogeneity of myocardial blood flow on mean blood flow rate in the rabbit heart. , 1985, Cardiovascular research.

[21]  D L Farkas,et al.  Calcium measurements in perfused mouse heart: quantitating fluorescence and absorbance of Rhod-2 by application of photon migration theory. , 2001, Biophysical journal.

[22]  S. Nighswander-Rempel,et al.  Regional cardiac tissue oxygenation as a function of blood flow and pO2: A near-infrared spectroscopic imaging study. , 2006, Journal of biomedical optics.

[23]  A. Terzic,et al.  Kir6.2 is required for adaptation to stress , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[24]  R. Balaban,et al.  Function, metabolic, and flow heterogeneity of the heart: the view is getting better. , 2001, Circulation research.

[25]  S. Edgar,et al.  Microvascular involvement in cardiac pathology. , 1998, Journal of molecular and cellular cardiology.

[26]  R. Moreno-Sánchez,et al.  Heart metabolic disturbances in cardiovascular diseases. , 2003, Archives of medical research.

[27]  D. Loiselle Exchange of oxygen across the epicardial surface distorts estimates of myocardial oxygen consumption , 1989, The Journal of general physiology.

[28]  Bruce D. Johnson,et al.  KATP channel Kir6.2 E23K variant overrepresented in human heart failure is associated with impaired exercise stress response , 2009, Human Genetics.

[29]  M. Sowa,et al.  Near‐Infrared In Vivo Spectroscopic Imaging: Biomedical Research and Clinical Applications , 2011 .

[30]  V. Kupriyanov,et al.  Hemoglobin plus myoglobin concentrations and near infrared light pathlength in phantom and pig hearts determined by diffuse reflectance spectroscopy. , 2008, Analytical biochemistry.

[31]  J. Schipke Editorial: The heterogeneities of the heart , 2001, Basic Research in Cardiology.

[32]  E. Takahashi,et al.  Impact of diffusional oxygen transport on oxidative metabolism in the heart. , 1998, The Japanese journal of physiology.

[33]  F. Kajiya,et al.  Pattern differences between distributions of microregional myocardial flows in crystalloid- and blood-perfused rat hearts. , 2004, American journal of physiology. Heart and circulatory physiology.

[34]  B. Chance,et al.  Heterogeneity of the Hypoxic State in Perfused Rat Heart , 1977, Circulation research.

[35]  J. Miyazaki,et al.  Defective insulin secretion and enhanced insulin action in KATP channel-deficient mice. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[36]  A. Terzic,et al.  KCNJ11 gene knockout of the Kir6.2 KATP channel causes maladaptive remodeling and heart failure in hypertension. , 2006, Human molecular genetics.

[37]  J B Bassingthwaighte,et al.  Validity of microsphere depositions for regional myocardial flows. , 1987, The American journal of physiology.

[38]  D. R. Marble,et al.  Optical Spectroscopic Method for in vivo Measurement of Cardiac Myoglobin Oxygen Saturation , 1999 .

[39]  R. Arena,et al.  The clinical and research applications of aerobic capacity and ventilatory efficiency in heart failure: an evidence-based review , 2008, Heart Failure Reviews.

[40]  J. Rossen,et al.  Abnormal microvascular function in diabetes: relationship to diabetic cardiomyopathy. , 1996, Coronary artery disease.

[41]  Georg Ertl,et al.  Fast High-Resolution Magnetic Resonance Imaging Demonstrates Fractality of Myocardial Perfusion in Microscopic Dimensions , 2001, Circulation research.

[42]  B. Chance,et al.  Oxygen dependence of energy state and cardiac work in the perfused rat heart. , 1990, Advances in experimental medicine and biology.

[43]  T. Iwanaga,et al.  Diverse roles of K(ATP) channels learned from Kir6.2 genetically engineered mice. , 2000, Diabetes.

[44]  Xinli Hu,et al.  Disruption of Sarcolemmal ATP-Sensitive Potassium Channel Activity Impairs the Cardiac Response to Systolic Overload , 2008, Circulation research.