András Sikter*

Municipal Clinic of Szentendre, Internal Medicine, Szentendre, Hungary

*Corresponding Author: András Sikter, Municipal Clinic of Szentendre, Internal Medicine, Szentendre, Hungary.

Received: March 15, 2022; Published: April 22, 2022

Abstract

The author presents a new model for age-associated diseases through a hypothesized pathogenesis of hypertension. Preservation or restoration of the constancy of each original cell-specific intracellular ion-pattern is essential for upholding cellular identity and integrity. The ageing background is intracellular acidosis: low-grade respiratory acidosis elevates the intracellular HCO₃^-/Cl^- gradient and induces metabolic syndrome, while low-grade metabolic acidosis causes exhausting buffer syndrome (EBS) with a decreased intracellular HCO₃^-/Cl^- rate. The former elicits higher aldosterone levels to restore the original ion-pattern by NHE-1 (natrium-hydrogen exchange) mechanism located in the membrane of vascular smooth muscle cells (VSMCs) and by retaining NaCl. The fault of ion-status restoration leads to Salt-sensitive hypertension through cascades of events. The ion-pattern changes in EBS elicit angiotensin II levels elevation through the renin-angiotensin system, which tries to eliminate intracellular changes via NBCn1 (natrium-bicarbonate cotransporter). However, it leads to a dead-end, and Salt-resistant hypertension develops. Hypertension occurs because restoring the original intracellular ion-pattern in VSMCs by aldosterone and angiotensin II fails. These hormonal counter-regulations lead to Na⁺ retention and alkaline overcompensation in the VSMCs. There may be several explanations for the failure, but hypertension would not develop if the intracellular ion-milieu were initially neutral or slightly alkaline. Regulated breathing could overcome hypertension.

Keywords: Age-associated Diseases; Exhausting Buffer Syndrome (EBS); Hypertension; Intracellular pH Homeostasis; Metabolic Syndrome; Signalling by Intracellular Ion-pattern

References

1. Bruton A and Holgate ST. “Hypocapnia and asthma: a mechanism for breathing retraining?”. Chest 5 (2005): 1808-1811.
2. Sikter A., et al. "New aspects in the pathomechanism of diseases of civilization, particularly psychosomatic disorders. Part 1. Theoretical background of a hypothesis”. Neuropsychopharmacologia Hungarica2 (2017): 95-105.
3. Hayflick L. “Entropy explains aging, genetic determinism explains longevity, and undefined terminology explains misunderstanding both”. (Editorial) PLoS Genetics12 (2007): e220.
4. Goldstein DS and Kopin IJ. “Evolution of concept of stress”. Stress 10 (2007): 109-120.
5. Bitman-Lotan E and Orian A. “Nuclear organization and regulation of the differentiated state”. Cellular and Molecular Life Sciences 7 (2021): 3141-3158.
6. Fisher AG. “Cellular identity and lineage choice”. Nature Reviews Immunology12 (2002): 977-982.
7. Orlov SN and Hamet P. “Intracellular monovalent ions as second messengers”. The Journal of Membrane Biology 3 (2006): 161-172.
8. Newton AC., et al. "Second messengers”. Cold Spring Harbor Perspectives in Biology8 (2016): a005926.
9. Sikter A. “Psychosomatic molecular mechanisms of metabolic syndrome and type 2 diabetes. Part 1. A theory for modelizing the cytoplasm and diseases”. Acta Scientific Medical Sciences1 (2020): 124-140.
10. McEwen BS and Stellar E. “Stress, adaptation and the individual. Mechanisms leading to disease”. Archives of Internal Medicine 153 (1993): 2093-2101.
11. Brouillard C., et al. "Long-lasting bradypnea by repeated social defeat”. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 311 (2016): R352-364.
12. Sikter A., et al. "New aspects in the pathomechanism of diseases of civilization, particularly psychosomatic disorders. Part 2. Chronic hypocapnia and hypercapnia in the medical practice”. Neuropsychopharmacologia Hungarica3 (2017): 159-169.
13. Relman AS. “Metabolic consequences of acid-base disorders”. Kidney International 1 (1972): 347-359.
14. Sikter A. “Hypocapnia and mental stress can trigger vicious circles in critically ill patients due to energy imbalance: a hypothesis presented through cardiogenic pulmonary oedema”. Neuropsychopharmacologia Hungarica2 (2018): 65-74.
15. Panel M., et al. “Mitochondria and aging: A role for the mitochondrial transition pore?”. Aging Cell4 (2018): e12793.
16. Peuhkurinen KJ. “Ischemic heart disease at the cellular level”. IJBEM 1 (2000): 1-9.
17. Deprez MA., et al. "pH homeostasis links the nutrient sensing PKA/TORC1/Sch9 ménage-à-trois to stress tolerance and longevity”. Microbial Cell3 (2018): 119-136.
18. Laffey JG., et al. "Therapeutic hypercapnia reduces pulmonary and systemic injury following In Vivo lung reperfusion”. American Journal of Respiratory and Critical Care Medicine 162 (2000): 2287-2294.
19. Jaul E and Barron J. “Age-related diseases and clinical and public health implications for the 85 years old and over population”. Frontiers in Public Health 5 (2017): 335.
20. Osanai T., et al. "Intracellular protons accelerate aging and switch on aging hallmarks in mice”. Journal of Cellular Biochemistry 12 (2018): 9825-9837.
21. Sikter A and Sonne C. “Is the Primary Aetiology of Hypertension Unknown? Novel Views on Previous Assumptions”. Acta Scientific Medical Sciences8 (2021): 47-53.
22. Anderson DE and Brady JV. “Preavoidance blood pressure elevations accompanied by heart rate decreases in the dog”. Science3983 (1971): 595-597.
23. Anderson DE., et al. "Racial differences in resting end-tidal CO2 and circulating sodium pump inhibitor”. American Journal of Hypertension 14 (2001): 761-767.
24. Anderson DE., et al. "Capnometric feedback training decreases 24-h blood pressure in hypertensive postmenopausal women”. BMC Cardiovascular Disorder1 (2021): 447.
25. Rosskopf D., et al. "Membrane sodium-proton exchange and primary hypertension”. Hypertension 21 (1993): 607-617.
26. Chipperfield AR and Harper AA. “Chloride in smooth muscle”. Progress in Biophysics and Molecular Biology 3-5 (2006): 175-221.
27. Schwartz WB., et al. "Effects of chronic hypercapnia on electrolyte and acid-base equilibrium. II. Recovery, with special reference to the influence of chloride intake”. Journal of Clinical Investigation7 (1961): 1238-1249.
28. Grollman A., et al. "Sodium restriction in the diet for hypertension”. JAMA8 (1945): 533-537.
29. McCallum L., et al. "The hidden hand of chloride in hypertension”. Pflugers Arch3 (2015): 595-603.
30. Rosendorff C. “The renin-angiotensin system and vascular hypertrophy”. JACC4 (1996): 803-812.
31. Ghike SM. “Metabolic syndrome - A truly psychosomatic disorder? A global hypothesis”. Medical Hypotheses 97 (2016): 46-53.
32. Santos MA., et al. "Emotional stress evaluation of patients with moderate and severe sleep apnea syndrome”. International Archives of Otorhinolaryngology 1 (2017): 28-32.
33. Resnick LM., et al. "Intracellular pH in human and experimental hypertension”. Proceedings of the National Academy of Sciences of the United States of America 21 (1987): 7663-7667.
34. Aryal D., et al. "Chronic metabolic acidosis elicits hypertension via upregulation of intrarenal angiotensin II and induction of oxidative stress”. Antioxidants (Basel)1 (2021): 2.
35. Frassetto L and Sebastian A. “Age and systemic acid-base equilibrium: analysis of published data”. Journals of Gerontology, Series A: Biological Sciences and Medical Sciences 1 (1996): B91-99.
36. Adeva MM and Souto G. “Diet-induced metabolic acidosis”. Clinical Nutrition4 (2011): 416-421.
37. Sikter A and Sonne C. “A new hypothesis on vascular calcification: the exhausting buffer syndrome (EBS)”. Neuropsychopharmacologia Hungarica1 (2021): 215-220.
38. Wagner CA. “Effect of Mineralocorticoids on Acid-Base Balance”. Nephron Physiology 128 (2014): 26-34.
39. Zhou Y., et al. "Effects of angiotensin II on the CO2 dependence of HCO3- reabsorption by the rabbit S2 renal proximal tubule”. American Journal of Physiology - Renal Physiology3 (2006): F666-673.
40. Wakabayashi I., et al. "Intracellular pH as a determinant of vascular smooth muscle function”. Journal of Vascular Research3 (2006): 238-250.
41. Melamed ML and Raphael KL. “Metabolic Acidosis in CKD: A Review of Recent Findings”. Kidney Medicine2 (2021): 267-277.
42. Wesson DE. “Is NaHCO3 an antiaging elixir?” American Journal of Physiology - Renal Physiology 311 (2016): F182-F183.
43. Di Iorio BR., et al. "Treatment of metabolic acidosis with sodium bicarbonate delays progression of chronic kidney disease: the UBI Study”. Journal of Nephrology6 (2019): 989-1001.
44. Leibrock CB., et al. "Bicarbonate-sensitive calcification and lifespan of klotho-deficient mice”. American Journal of Physiology - Renal Physiology 310 (2016): F102-F108.
45. Forni LG., et al. "The Janus faces of bicarbonate therapy in the ICU: not sure!” Intensive Care Medicine3 (2020): 522-524.
46. Navaneethan SD., et al. "Effects of treatment of metabolic acidosis in CKD: A systematic review and meta-analysis”. Clinical Journal of the American Society of Nephrology 7 (2019): 1011-1020.
47. Neubauer B., et al. "Angiotensin II short-loop feedback: Is there a role of Ang II for the regulation of the renin system in vivo?” Hypertension 71 (2018): 1075-1082.
48. Meyer DJ., et al. "Na/K pump mutations associated with primary hyperaldosteronism cause loss of function”. Biochemistry13 (2019): 1774-1785.
49. Jean-Louis G., et al. "Cardiovascular disease risk reduction with sleep apnea treatment”. Expert Review of Cardiovascular Therapy 7 (2010): 995-1005.
50. Iftikhar IH., et al. "Effects of continuous positive airway pressure on blood pressure in patients with resistant hypertension and obstructive sleep apnea: a meta-analysis”. Journal of Hypertens12 (2014): 2341-2350.

Citation

Citation: András Sikter. “Hypertension and the Interior Ion-milieu. Can we Overcome Hypertension with Regulated Breathing?”.Acta Scientific Medical Sciences 6.5 (2022): 155-164.

Copyright

Copyright: © 2022 András Sikter. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.