Skip to main content

Advertisement

Log in

Hypotension in hereditary cardiomyopathy

  • Molecular and cellular mechanisms of disease
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

It is well accepted that hypertension may lead to the development of heart failure (HF). However, little is known about the development of hypotension that may contribute to the onset of hereditary cardiomyopathy (HCM), thus promoting heart failure and early death. The purpose of this study is to verify whether a decrease in blood pressure takes place during different phases of HCM (asymptomatic, necrosis, hypertrophy, and heart failure). Using the well-known animal model, the UM-X7.1 hamster strain of HCM (HCMH), our results showed the absence of a change in mean arterial pressure (MAP) during the asymptomatic phase preceding the development of necrosis in HCMHs when compared to age-matched normal hamster (NH). However, there was a progressive decrease in MAP that reached its lowest level during the heart failure phase. The MAP during the development of the necrosis phase of HCM was accompanied by a significant increase in the level of the sodium–hydrogen exchanger, NHE1. Treatments with the potent NHE1 inhibitor, EMD 87580 (rimeporide), did not affect MAP of NH. However, treatments with EMD 87580 during the three phases of the development of HCM significantly reversed the hypotension associated with HCM.

Our results showed that the development of HCM is associated with hypotension. These results suggest that a decrease in blood pressure could be a biomarker signal for HCM leading to HF and early death. Since the blockade of NHE1 significantly but partially prevented the reduction in MAP, this suggests that other mechanisms can contribute to the development of hypotension in HCM.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Artamonov MV, Sonkusare SK, Good ME et al. (2018) RSK2 contributes to myogenic vasoconstriction of resistance arteries by activating smooth muscle myosin and the Na(+)/H(+) exchanger. Sci Signal 11:

  2. Avedanian L, Jacques D, Bkaily G (2011) Presence of tubular and reticular structures in the nucleus of human vascular smooth muscle cells. J Mol Cell Cardiol 50:175–186

    Article  CAS  PubMed  Google Scholar 

  3. Bkaily G, Avedanian L, Al-Khoury J et al (2011) Nuclear membrane receptors for ET-1 in cardiovascular function. Am J Physiol Regul Integr Comp Physiol 300:R251–R263

    Article  CAS  PubMed  Google Scholar 

  4. Bkaily G, Avedanian L, Jacques D (2009) Nuclear membrane receptors and channels as targets for drug development in cardiovascular diseases. Can J Physiol Pharmacol 87:108–119

    Article  CAS  PubMed  Google Scholar 

  5. Bkaily G, Chahine M, Al-Khoury J et al (2015) Na(+)-H(+) exchanger inhibitor prevents early death in hereditary cardiomyopathy. Can J Physiol Pharmacol 93:923–934

    Article  CAS  PubMed  Google Scholar 

  6. Bkaily G, Jacques D (2017) Na+-H+ exchanger and proton channel in heart failure associated with Becker and Duchenne muscular dystrophies. Can J Physiol Pharmacol 95:1213–1223

    Article  CAS  PubMed  Google Scholar 

  7. Bkaily G, Jacques D, Pothier P (1999) Use of confocal microscopy to investigate cell structure and function. Methods Enzymol 307:119–135

    Article  CAS  PubMed  Google Scholar 

  8. Bkaily G, Nader M, Avedanian L et al (2006) G-protein-coupled receptors, channels, and Na+-H+ exchanger in nuclear membranes of heart, hepatic, vascular endothelial, and smooth muscle cells. Can J Physiol Pharmacol 84:431–441

    Article  CAS  PubMed  Google Scholar 

  9. Bkaily G, Nader M, Avedanian L et al (2004) Immunofluorescence revealed the presence of NHE-1 in the nuclear membranes of rat cardiomyocytes and isolated nuclei of human, rabbit, and rat aortic and liver tissues. Can J Physiol Pharmacol 82:805–811

    Article  CAS  PubMed  Google Scholar 

  10. Bkaily G, Najibeddine W, Jacques D (2019) Increase of NOX3 in heart failure of hereditary cardiomyopathy. Can J Physiol Pharmacol

  11. Bkaily G, Pothier P, D'Orleans-Juste P et al (1997) The use of confocal microscopy in the investigation of cell structure and function in the heart, vascular endothelium and smooth muscle cells. Mol Cell Biochem 172:171–194

    Article  CAS  PubMed  Google Scholar 

  12. Bkaily G, Sleiman S, Stephan J et al (2003) Angiotensin II AT1 receptor internalization, translocation and de novo synthesis modulate cytosolic and nuclear calcium in human vascular smooth muscle cells. Can J Physiol Pharmacol 81:274–287

    Article  CAS  PubMed  Google Scholar 

  13. Boedtkjer E, Aalkjaer C (2009) Insulin inhibits Na+/H+ exchange in vascular smooth muscle and endothelial cells in situ: involvement of H2O2 and tyrosine phosphatase SHP-2. Am J Physiol Heart Circ Physiol 296:247–255

    Article  CAS  Google Scholar 

  14. Boedtkjer E, Aalkjaer C (2012) Intracellular pH in the resistance vasculature: regulation and functional implications. J Vasc Res 49:479–496

    Article  CAS  PubMed  Google Scholar 

  15. Boedtkjer E, Damkier HH, Aalkjaer C (2012) NHE1 knockout reduces blood pressure and arterial media/lumen ratio with no effect on resting pH(i) in the vascular wall. J Physiol 590:1895–1906

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Campbell R, Morris-Thurgood JA, Frenneaux MP (2004) Disturbed vascular control in hypertrophic cardiomyopathy: mechanisms and clinical significance. In: Maron BJ (ed) Diagnosis and management of hypertrophic cardiomyopathy. Blackwell Futura, Massachusetts, pp:132-146

  17. Cecchi F, Sgalambro A, Baldi M et al (2009) Microvascular dysfunction, myocardial ischemia, and progression to heart failure in patients with hypertrophic cardiomyopathy. J Cardiovasc Transl Res 2:452–461

    Article  PubMed  Google Scholar 

  18. Chahine M, Bkaily G, Nader M et al (2005) NHE-1-dependent intracellular sodium overload in hypertrophic hereditary cardiomyopathy: prevention by NHE-1 inhibitor. J Mol Cell Cardiol 38:571–582

    Article  CAS  PubMed  Google Scholar 

  19. Chamoun M, Jacques D, Bkaily G (2019) Extracellular and intracellular tumor necrosis factor alpha modulates cytosolic and nuclear calcium in human cardiovascular cells (1). Can J Physiol Pharmacol1-9

  20. de Dios ST, Hannan KM, Dilley RJ et al (2001) Troglitazone, but not rosiglitazone, inhibits Na/H exchange activity and proliferation of macrovascular endothelial cells. J Diabetes Complications 15:120–127

    Article  PubMed  Google Scholar 

  21. Dixon DD and Muldowney JAS, III (2020) Management of neurogenic orthostatic hypotension in the heart failure patient. Auton Neurosci 227:102691-

  22. Dumont EC, Lambert C, Lamontagne D (1996) Modification of aortic contractility in the cardiomyopathic hamster. Br J Pharmacol 118:1141–1146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Factor SM, Minase T, Cho S et al (1982) Microvascular spasm in the cardiomyopathic Syrian hamster: a preventable cause of focal myocardial necrosis. Circulation 66:342–354

    Article  CAS  PubMed  Google Scholar 

  24. Factor SM, Sonnenblick EH (1982) Hypothesis: is congestive cardiomyopathy caused by a hyperreactive myocardial microcirculation (microvascular spasm)? Am J Cardiol 50:1149–1152

    Article  CAS  PubMed  Google Scholar 

  25. Fang XY, Lin NY, Li YG (2010) The effects of amiloride, a Na+-H+ exchange inhibitor, on iliac artery stenosis after balloon injury in rabbits. Biochem Cell Biol 88:665–670

    Article  CAS  PubMed  Google Scholar 

  26. Fliegel L (2019) Structural and functional changes in the Na(+)/H(+) exchanger isoform 1, induced by Erk1/2 phosphorylation. Int J Mol Sci 20:

  27. Goineau S, Pape D, Guillo P et al (2001) Increased sensitivity of vascular smooth muscle to nitric oxide in dilated cardiomyopathy of Syrian hamsters (Bio TO-2 strain). J Cardiovasc Pharmacol 37:290–300

    Article  CAS  PubMed  Google Scholar 

  28. Hanselmann A, Veltmann C, Bauersachs J et al. (2020) Dilated cardiomyopathies and non-compaction cardiomyopathy. Herz

  29. Honore JC, Carrier E, Fecteau MH et al (2008) Nonselective ETA/ETB-receptor blockade increases systemic blood pressure of Bio 14.6 cardiomyopathic hamsters. Can J Physiol Pharmacol 86:394–401

    Article  CAS  PubMed  Google Scholar 

  30. Honore JC, Fecteau MH, Wessale JL et al (2004) Effects of selective and non-selective endothelin receptor blockade on ET-1-induced pressor response in the hamster. J Cardiovasc Pharmacol 44(Suppl 1):S68–S71

    Article  CAS  PubMed  Google Scholar 

  31. Huetsch J, Shimoda LA (2015) Na(+)/H(+) exchange and hypoxic pulmonary hypertension. Pulm Circ 5:228–243

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Huetsch JC, Jiang H, Larrain C et al. (2016) The Na+/H+ exchanger contributes to increased smooth muscle proliferation and migration in a rat model of pulmonary arterial hypertension. Physiol Rep 4:

  33. Huetsch JC, Walker J, Undem C et al. (2018) Rho kinase and Na(+)/H(+) exchanger mediate endothelin-1-induced pulmonary arterial smooth muscle cell proliferation and migration. Physiol Rep 6:e13698-

  34. Hunter EG, Elbrink J (1983) Increased contractility in vascular smooth muscle of dystrophic hamsters. Can J Physiol Pharmacol 61:182–185

    Article  CAS  PubMed  Google Scholar 

  35. Jacques D, Bkaily G, Jasmin G et al (2003) Isradipine prevents the development of spontaneously occurring cardiac necrosis in cardiomyopathic hamster. Can J Physiol Pharmacol 81:120–124

    Article  CAS  PubMed  Google Scholar 

  36. Jacques D, Sader S, Perreault C et al (2003) Presence of neuropeptide Y and the Y1 receptor in the plasma membrane and nuclear envelope of human endocardial endothelial cells: modulation of intracellular calcium. Can J Physiol Pharmacol 81:288–300

    Article  CAS  PubMed  Google Scholar 

  37. Jasmin G, Proschek L (1984) Calcium and myocardial cell injury. An appraisal in the cardiomyopathic hamster. Can J Physiol Pharmacol 62:891–898

    Article  CAS  PubMed  Google Scholar 

  38. Jasmin G and Proschek L (1994) Hamster cardiomyopathy: new insights in the pathogenesis of this hereditary disease. In: Bkaily G (ed) Membrane Physiopathology. Kluwer, Boston MA, pp:1-11

  39. Karmazyn M (2013) NHE-1: still a viable therapeutic target. J Mol Cell Cardiol 61:77–82

    Article  CAS  PubMed  Google Scholar 

  40. Li JF, Chen S, Feng JD et al (2014) Probucol via inhibition of NHE1 attenuates LPS-accelerated atherosclerosis and promotes plaque stability in vivo. Exp Mol Pathol 96:250–256

    Article  CAS  PubMed  Google Scholar 

  41. Lim PO, Morris-Thurgood JA, Frenneaux MP (2002) Vascular mechanisms of sudden death in hypertrophic cardiomyopathy, including blood pressure responses to exercise. Cardiol Rev 10:15–23

    Article  PubMed  Google Scholar 

  42. Loh SH, Lee CY, Chen GS et al (2015) The effect and underlying mechanism of ethanol on intracellular H(+)-equivalent membrane transporters in human aorta smooth muscle cells. Alcohol Clin Exp Res 39:2302–2312

    Article  CAS  PubMed  Google Scholar 

  43. Loh SH, Lee CY, Tsai YT et al. (2014) Intracellular acid-extruding regulators and the effect of lipopolysaccharide in cultured human renal artery smooth muscle cells. PLoS One 9:e90273-

  44. Madonna R, Montebello E, Lazzerini G et al (2010) NA+/H+ exchanger 1- and aquaporin-1-dependent hyperosmolarity changes decrease nitric oxide production and induce VCAM-1 expression in endothelial cells exposed to high glucose. Int J Immunopathol Pharmacol 23:755–765

    Article  CAS  PubMed  Google Scholar 

  45. Martin-Perez M, Michel A, Ma M et al. (2019) Development of hypotension in patients newly diagnosed with heart failure in UK general practice: retrospective cohort and nested case-control analyses. BMJ Open 9:e028750-

  46. McKenna WJ, Maron BJ, Thiene G (2017) Classification, epidemiology, and global burden of cardiomyopathies. Circ Res 121:722–730

    Article  CAS  PubMed  Google Scholar 

  47. Mikhail M, Vachon PH, D'Orleans-Juste P et al (2017) Role of endothelin-1 and its receptors, ETA and ETB, in the survival of human vascular endothelial cells. Can J Physiol Pharmacol 95:1298–1305

    Article  CAS  PubMed  Google Scholar 

  48. Mokgokong R, Wang S, Taylor CJ et al (2014) Ion transporters in brain endothelial cells that contribute to formation of brain interstitial fluid. Pflugers Arch 466:887–901

    Article  CAS  PubMed  Google Scholar 

  49. Orlov SN, Adarichev VA, Devlin AM et al (2000) Increased Na(+)/H(+) exchanger isoform 1 activity in spontaneously hypertensive rats: lack of mutations within the coding region of NHE1. Biochim Biophys Acta 1500:169–180

    Article  CAS  PubMed  Google Scholar 

  50. Pedersen AK, Mendes Lopes de MJ, Morup N et al. (2017) Tumor microenvironment conditions alter Akt and Na(+)/H(+) exchanger NHE1 expression in endothelial cells more than hypoxia alone: implications for endothelial cell function in cancer. BMC Cancer 17:542-

  51. Pedersen SF, Counillon L (2019) The SLC9A-C mammalian Na(+)/H(+) exchanger family: molecules, mechanisms, and physiology. Physiol Rev 99:2015–2113

    Article  CAS  PubMed  Google Scholar 

  52. Prasad K, Williams L, Campbell R et al (2008) Episodic syncope in hypertrophic cardiomyopathy: evidence for inappropriate vasodilation. Heart 94:1312–1317

    Article  CAS  PubMed  Google Scholar 

  53. Quinn PA, Ng LL (2001) Potassium and activity of the sodium hydrogen exchanger isoform 1 in vascular smooth muscle of hypertensive rats. Metabolism 50:778–782

    Article  CAS  PubMed  Google Scholar 

  54. Sasahara T, Yayama K, Matsuzaki T et al (2013) Na(+)/H(+) exchanger inhibitor induces vasorelaxation through nitric oxide production in endothelial cells via intracellular acidification-associated Ca2(+) mobilization. Vascul Pharmacol 58:319–325

    Article  CAS  PubMed  Google Scholar 

  55. Selthofer-Relatic K, Mihalj M, Kibel A et al (2017) Coronary microcirculatory dysfunction in human cardiomyopathies: a pathologic and pathophysiologic review. Cardiol Rev 25:165–178

    Article  PubMed  Google Scholar 

  56. Soloveva A, Fedorova D, Villevalde S et al (2020) Addressing orthostatic hypotension in heart failure: pathophysiology, clinical implications and perspectives. J Cardiovasc Transl Res 13:549–569

    Article  PubMed  Google Scholar 

  57. Sonnenblick EH, Fein F, Capasso JM et al (1985) Microvascular spasm as a cause of cardiomyopathies and the calcium-blocking agent verapamil as potential primary therapy. Am J Cardiol 55:179B–184B

    Article  CAS  PubMed  Google Scholar 

  58. Undem C, Rios EJ, Maylor J et al. (2012) Endothelin-1 augments Na(+)/H(+) exchange activity in murine pulmonary arterial smooth muscle cells via Rho kinase. PLoS One 7:e46303-

  59. Wakabayashi S, Hisamitsu T, Nakamura TY (2013) Regulation of the cardiac Na(+)/H(+) exchanger in health and disease. J Mol Cell Cardiol 61:68–76

    Article  CAS  PubMed  Google Scholar 

  60. Walker J, Undem C, Yun X et al. (2016) Role of Rho kinase and Na+/H+ exchange in hypoxia-induced pulmonary arterial smooth muscle cell proliferation and migration. Physiol Rep 4:

  61. Wu S, Yang Q, Liu Q et al (2013) Cariporide, a specific Na/H(+) exchanger 1 blocker, inhibits neointimal proliferation induced by advanced glycation end products in a balloon injury rat model. Pharmacology 91:123–130

    Article  CAS  PubMed  Google Scholar 

  62. Young K, Luni FK, Yoon Y (2016) Toxic shock syndrome: an unsual organism. Am J Med Sci 352:86–90

    Article  PubMed  Google Scholar 

  63. Yuen N, Lam TI, Wallace BK et al (2014) Ischemic factor-induced increases in cerebral microvascular endothelial cell Na/H exchange activity and abundance: evidence for involvement of ERK1/2 MAP kinase. Am J Physiol Cell Physiol 306:C931–C942

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Zhao Y, Cui G, Zhang N et al (2012) Lipopolysaccharide induces endothelial cell apoptosis via activation of Na(+)/H(+) exchanger 1 and calpain-dependent degradation of Bcl-2. Biochem Biophys Res Commun 427:125–132

    Article  CAS  PubMed  Google Scholar 

  65. Zhu ML, Wang G, Wang H et al (2019) Amorphous nano-selenium quantum dots improve endothelial dysfunction in rats and prevent atherosclerosis in mice through Na(+)/H(+) exchanger 1 inhibition. Vascul Pharmacol 115:26–32

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by a grant from the Canadian Institutes of Health Research (CIHR) and the Natural Sciences and Engineering Research Council of Canada (NSERC).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ghassan Bkaily.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Al-Khoury, J., Jacques, D. & Bkaily, G. Hypotension in hereditary cardiomyopathy. Pflugers Arch - Eur J Physiol 474, 517–527 (2022). https://doi.org/10.1007/s00424-022-02669-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00424-022-02669-9

Keywords

Navigation