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INTRACELLULAR POTASSIUM OR INTRAMOLECULAR K-DEPENDENT FUNCTION

INTRACELLULAR POTASSIUM OR INTRAMOLECULAR K-DEPENDENT FUNCTION NEW PHYSIOLOGICAL APROACH FOR DRUG DEVELOMENT IN XXI CENTURY. Prof. Antonio Delgado-Almeida A, MD, FAHA, FACC American Physiological Society, CV Section American Chemical Society

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INTRACELLULAR POTASSIUM OR INTRAMOLECULAR K-DEPENDENT FUNCTION

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  1. INTRACELLULAR POTASSIUM OR INTRAMOLECULAR K-DEPENDENT FUNCTION NEW PHYSIOLOGICAL APROACH FOR DRUG DEVELOMENT IN XXI CENTURY Prof. Antonio Delgado-Almeida A, MD, FAHA, FACC American Physiological Society, CV Section American Chemical Society delgado_almeida@hypertensresearch.org, med_documentos@hotmail.com Clinical Research Unit & Ion Transport Laboratory, University of Carabobo Medical School, Valencia, Venezuela

  2. Body K Physiology Body Potassium Distribution • Humans (70-Kg man) Total body K (TBK) 3700- 3800 mmol 150 mmol/L of cell water 109 ± 6 mmol/Kg of cell (AJP 2003) 96 -103 mmol/l RBC 5 mmol/l extracellular water 1 mmol/Kg W for 24-h urinary excretion Intracellular K 98 % of TBK Skeletal Muscle K (77 %), Liver (8 %) and RBC (8%), the major body K stores Extracellular K 2 % of TBK Plasma (< 0.5 %) – total K space (< 2.0 %)

  3. Body K Physiology Cell Potassium Homeostasis Factors Involved • Dietary Intake (Proteins, K, Mg, and Ca content) • Gender, Age and Ethnicity • Skeletal muscle activity • Inter-organ regulation (GI and Kidney) • Insulin, Catecholamine (Cell K uptake) • Aldosterone (Body K regulation/renal excretion • Arterial pH (Bohr’s Effect, 1905) • Pharmacological Effects Steroids, Loop Diuretics, NSAID, Potassium-Proton Pump Inhibitors, β-blockers, Cytotastic drugs and others (*)

  4. Body K Physiology Human Potassium Undefined Facts Plasma K Regulation Enteral K Absorption Body K Homeostasis

  5. RBC K and blood pH RBC K and blood pH (cell Na 6.2±1.2 mmol/l cell ) New Methods Trapped Plasma (0.8 ± 0.07%) Delgado-Almeida, Antonio Intracellular Potassium: New Concept on the Physiology and Pathophysiology of Potassium. QV277D4533, 1986: 1-71 pages. University of Carabobo Health Science Central Library (Spanish).

  6. RBC K and K Excretion RBC K and tubular K excretion following IV furosemide in Healthy Subjects Inter-Organ K Transport Delgado Almeida, Antonio. Intracellular Potassium: New Concept on the Physiology and Pathophysiology of Potassium. QV277D4533, 1986: 1-71 pages. University of Carabobo Health Science Central Library

  7. RBC K in Hypertension Bimodal Distribution on BP and RBC K MC Delgado, A Delgado Almeida. Nutr Metab and Cardiovasc Diseases. 2002 ; 12:112-116 MC Delgado, A Delgado Almeida. J Hum Hypertens. 2006; 19: 432-436

  8. RBC K in Hypertension RBC K could be a marker of K changes in other cells involved in blood pressure regulation MC Delgado, A Delgado Almeida. J Hum Hypertens. 2006; 19: 432-436 8

  9. Clinical RBC K Physiology in HT Delgado-Almeida A. Am J Hypertension. 2006; 19: 432-436

  10. Hereditable Defect in RBC K Uptake Ion Transport Studies Non-Invasive Aortic PW 248 ms 122 ms Bimodal PW Reflection in Healthy Subjects Clinical Research Unit, 2006-2012

  11. Hereditable Defect in RBC K Uptake Family Co-segregation 1992 2008 MC Delgado, A Delgado-Almeida. Abnormal Potassium. In: Advanced Therapy in Hypertension and Cardiovascular Medicine, 2006: Chapter 35

  12. Drug testing addressing Erythrocytes K Content Although many drugs were tested in our laboratory the most promising compound was 3,5-diamino-N-(diaminomethylene)-6-chloropyrazinecarboxamide hydrochloride dihydrate, amiloride hydrochloride Delgado-Almeida A. Recent Patent on Cardiovasc. Drug Discovery. 2010;5: 227.238

  13. Pharmacology Approach for RBC K transport in HT Basal Treatment 1-Month Treatment + amiloride Aortic PWA recording and analysis DynaPulse Technology, PulseMetric Inc, CA USA- 2000-2011

  14. Pharmacology Approach of Amiloride in CHD RBC K AND THE TREATMENT OF CHD Novel Physiological Approach for Reversion of Angina, ST-T Alterations and Electrical Regeneration of the Heart Delgado-Almeida A. Recent Patent on Cardiovasc. Drug Discovery.2010:5:227-238 Delgado-Almeida A, et al. Circulation 2010;122: A15761

  15. Proceeding Book Article and Online Conference 2011 Erythrocyte K t and Hb-O2 binding: a novel drug discovery for reversion of angina, ST-T alterations and the electrical regeneration of the heart in CHD Antonio Delgado-Almeida, FAHA , FACC, APS. ACS

  16. Pharmacology Approach of Amiloride in CHD AMILORIDE TIAL in Hypertension with Extensive AMI 1 2 3 4 ECG with extensive AMI and before amiloride(1). After amiloride , rapid improved ECG at 6-month (2), 1-year (3), and virtually normal at 1½ year (4)

  17. Pharmacology Approach for RBC K in CHD Improving RBC K Transport and Hemoglobin O2-binding by Amiloride: A Novel Therapeutic Approach www.Clinicaltrial.gov (NCT01228214, NCT01231165

  18. RBC Hb-K Binding In Vitro Venous Blood Oxygenation Delgado-Almeida A. From Bohr Effect to the Electrical Regeneration of the Heart FASEB J. March 29, 2012; 26:1126.7. Experimental Biology2012, April 25, 2012) Table

  19. Physiology 2009, Ellsworth ML (*) Erythrocytes(*) Oxygen Sensors and O2 delivery via ATP release for Vascular Control in CHD, Stroke, DM Erythrocytes (¶) K-Oxygen binding by Human hemoglobin Rapid pH regulation and Cell K Transport Renal K Excretion Delgado-Almeida, A (¶) “...the erythrocyte could be a novel target for the development of drugs for the treatment of vascular insufficiency"

  20. Enzyme K-binding Crystal Structure of Na+, K+ Pump K First crystal structures of Na+,K+-ATPase: new light on the oldest ion pump. Toyoshima C, et al. Structure. 2011 19(12):1732-8

  21. Potassium binding (spheres, purple); Water (red) Diagram Unrelated to Na+ exchanges First crystal structures of Na+,K+-ATPase: new light on the oldest ion pump. Toyoshima C, et al. Structure. 2011 19(12):1732-8

  22. anti-coagulant Coagulant Effects of K and Na activation of Human Thrombin Chimera

  23. New Ideas for the future David Miller, Jan 2006 I think the physiologist's experimental situation, which (usually) comprises a small piece of tissue in a large volume of bathing solution, can easily trick us (the non-clinicians like me at least) into this way of thinking. It requires special effort to bear in mind that, for most cells in most tissues, the ECF is actually a small volume surrounded by a large volume of more-or-less leaky cells! Reader in Physiology & former Director of the Graduate SchoolInstitute of Biomedical & Life SciencesUniversity of Glasgow 23

  24. THANKS YOU Prof. Delgado-Almeida A, MD FACC, FAHA, APS, ACS Prof. Antonio Javier Delgado, MD Dr. Carlos Luis Delgado-León, MD Clinical Research Unit & Ion Transport Laboratory University of Carabobo Medical School Northern Metropolitan Hospital Venezuelan Foundation of Heart Failure delgado_almeida@hypertensresearch.org med_documentos@hotmail.com

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