Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Cooperation of augmented calcium sensitization and increased calcium entry contributes to high blood pressure in salt-sensitive Dahl rats

Abstract

Salt hypertensive Dahl rats are characterized by sympathoexcitation and relative NO deficiency. We tested the hypothesis that the increased blood pressure (BP) response to fasudil in salt hypertensive Dahl rats is due to augmented calcium sensitization in the salt-sensitive strain and/or due to their decreased baroreflex efficiency. BP reduction after acute administration of nifedipine (an L-type voltage-dependent calcium channel blocker) or fasudil (a Rho kinase inhibitor) was studied in conscious intact rats and in rats subjected to acute NO synthase inhibition or combined blockade of the renin–angiotensin system (captopril), sympathetic nervous system (pentolinium), and NO synthase (L-NAME). Intact salt-sensitive (SS) Dahl rats fed a low-salt diet had greater BP responses to nifedipine (−31 ± 6 mmHg) or fasudil (−34 ± 7 mmHg) than salt-resistant (SR) Dahl rats (−16 ± 4 and −17 ± 2 mmHg, respectively), and a high-salt intake augmented the BP response only in SS rats. These BP responses were doubled after acute NO synthase inhibition, indicating that endogenous NO attenuates both calcium entry and calcium sensitization. Additional pentolinium administration, which minimized sympathetic compensation for the drug-induced BP reduction, magnified the BP responses to nifedipine or fasudil in all groups except for salt hypertensive SS rats due to their lower baroreflex efficiency. The BP response to the calcium channel blocker nifedipine can distinguish SS and SR rats even after calcium sensitization inhibition by fasudil, which was not seen when fasudil was administered to nifedipine-pretreated rats. Thus, enhanced calcium entry (potentiated by sympathoexcitation) in salt hypertensive Dahl rats is the abnormality that is essential for their BP increase, which was further augmented by increased calcium sensitization in salt-sensitive Dahl rats.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

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

References

  1. 1.

    Somlyo AP, Somlyo AV. Signal transduction by G-proteins, Rho-kinase and protein phosphatase to smooth muscle and non-muscle myosin II. J Physiol. 2000;522:177–85.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  2. 2.

    Kimura K, Ito M, Amano M, Chihara K, Fukata Y, Nakafuku M, et al. Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase). Science. 1996;273:245–8.

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Loirand G. Rho kinases in health and disease: from basic science to translational research. Pharmacol Rev. 2015;67:1074–95.

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Sauzeau V, Le Jeune H, Cario-Toumaniantz C, Smolenski A, Lohmann SM, Bertoglio J, et al. Cyclic GMP-dependent protein kinase signaling pathway inhibits RhoA-induced Ca2+ sensitization of contraction in vascular smooth muscle. J Biol Chem. 2000;275:21722–9.

    CAS  PubMed  Article  Google Scholar 

  5. 5.

    Chitaley K, Webb RC. Nitric oxide induces dilation of rat aorta via inhibition of Rho-kinase signaling. Hypertension. 2002;39:438–42.

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Jin L, Ying Z, Hilgers RH, Yin J, Zhao X, Imig JD, et al. Increased RhoA/Rho-kinase signaling mediates spontaneous tone in aorta from angiotensin II-induced hypertensive rats. J Pharmacol Exp Ther. 2006;318:288–95.

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Hilgers RH, Todd J Jr, Webb RC. Increased PDZ-RhoGEF/RhoA/Rho kinase signaling in small mesenteric arteries of angiotensin II-induced hypertensive rats. J Hypertens. 2007;25:1687–97.

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Zicha J, Behuliak M, Pintérová M, Bencze M, Kuneš J, Vaněčková I. The interaction of calcium entry and calcium sensitization in the control of vascular tone and blood pressure of normotensive and hypertensive rats. Physiol Res. 2014;63 Suppl 1:S19–27.

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Behuliak M, Pintérová M, Bencze M, Petrová M, Líšková S, Karen P, et al. Ca2+ sensitization and Ca2+ entry in the control of blood pressure and adrenergic vasoconstriction in conscious Wistar-Kyoto and spontaneously hypertensive rats. J Hypertens. 2013;31:2025–35.

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    Behuliak M, Bencze M, Vaněčková I, Kuneš J, Zicha J. Basal and activated calcium sensitization mediated by Rhoa/Rho kinase pathway in rats with genetic and salt hypertension. Biomed Res Int. 2017;2017:8029728.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  11. 11.

    Vaněčková I, Behuliak M, Hojná S, Kopkan L, Kadlecová M, Zicha J. Exaggerated blood pressure response to fasudil or nifedipine in hypertensive Ren-2 transgenic rats: role of altered baroreflex. Hypertens Res. 2019;42:145–54.

    PubMed  Article  CAS  Google Scholar 

  12. 12.

    Löhn M, Steioff K, Bleich M, Busch AE, Ivashchenko Y. Inhibition of Rho-kinase stimulates nitric oxide-independent vasorelaxation. Eur J Pharm. 2005;507:179–86.

    Article  CAS  Google Scholar 

  13. 13.

    Dhaliwal JS, Casey DB, Greco AJ, Badejo AM Jr, Gallen TB, Murthy SN, et al. Rho kinase and Ca2+ entry mediate increased pulmonary and systemic vascular resistance in L-NAME-treated rats. Am J Physiol Lung Cell Mol Physiol. 2007;293:L1306–13.

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Brunová A, Bencze M, Behuliak M, Zicha J. Acute and chronic role of nitric oxide, renin-angiotensin system and sympathetic nervous system in the modulation of calcium sensitization in Wistar rats. Physiol Res. 2015;64:447–57.

    PubMed  Article  Google Scholar 

  15. 15.

    Uehata M, Ishizaki T, Satoh H, Ono T, Kawahara T, Morishita T, et al. Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension. Nature. 1997;389:990–4.

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Zicha J, Dobešová Z, Vokurková M, Rauchová H, Hojná S, Kadlecová M, et al. Age-dependent salt hypertension in Dahl rats: fifty years of research. Physiol Res. 2012;61 Suppl 1:S35–87.

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Mark AL. Sympathetic neural contribution to salt-induced hypertension in Dahl rats. Hypertension. 1991;17 Suppl I:I86–90.

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Huang BS, Leenen FH. Both brain angiotensin II and “ouabain” contribute to sympathoexcitation and hypertension in Dahl S rats on high salt intake. Hypertension. 1998;32:1028–33.

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    Dobešová Z, Kuneš J, Zicha J. The altered balance between sympathetic nervous system and nitric oxide in salt hypertensive Dahl rats: ontogenetic and F2 hybrid studies. J Hypertens. 2002;20:945–55.

    PubMed  Article  Google Scholar 

  20. 20.

    Gordon FJ, Matsuguchi H, Mark AL. Abnormal baroreflex control of heart rate in prehypertensive and hypertensive Dahl genetically salt-sensitive rats. Hypertension. 1981;3 Suppl I:I135–41.

    CAS  PubMed  Google Scholar 

  21. 21.

    Miyajima E, Buñag RD. Exacerbation of central baroreflex impairment in Dahl rats by high-salt diets. Am J Physiol. 1987;252:H402–9.

    CAS  PubMed  Google Scholar 

  22. 22.

    Garthoff B, Kazda S, Knorr A, Thomas G. Factors involved in the antihypertensive action of calcium antagonists. Hypertension. 1983;5:II34–8.

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Kazda S, Garthoff B, Luckhaus G. Calcium and malignant hypertension in animal experiment: effects of experimental manipulation of calcium influx. Am J Nephrol. 1986;6 Suppl 1:145–50.

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Boegehold MA. Reduced influence of nitric oxide on arteriolar tone in hypertensive Dahl rats. Hypertension. 1992;19:290–5.

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Rudd MA, Trolliet M, Hope S, Scribner AW, Daumerie G, Toolan G, et al. Salt-induced hypertension in Dahl salt-resistant and salt-sensitive rats with NOS II inhibition. Am J Physiol. 1999;277:H732–9.

    CAS  PubMed  Google Scholar 

  26. 26.

    Tan DY, Meng S, Manning RD Jr. Role of neuronal nitric oxide synthase in Dahl salt-sensitive hypertension. Hypertension. 1999;33:456–61.

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    Sharma JN, Fernandez PG, Laher I, Triggle CR. Differential sensitivity of Dahl salt-sensitive and Dahl salt-resistant rats to the hypotensive action of acute nifedipine administration. Can J Physiol Pharmacol. 1984;62:241–3.

    CAS  PubMed  Article  Google Scholar 

  28. 28.

    Kuneš J, Hojná S, Kadlecová M, Dobešová Z, Rauchová H, Vokurková M, et al. Altered balance of vasoactive systems in experimental hypertension: the role of relative NO deficiency. Physiol Res. 2004;53 Suppl 1:S23–34.

    PubMed  Google Scholar 

  29. 29.

    Zicha J, Dobešová Z, Behuliak M, Kuneš J, Vaněčková I. Preventive dietary potassium supplementation in young salt-sensitive Dahl rats attenuates development of salt hypertension by decreasing sympathetic vasoconstriction. Acta Physiol. 2011;202:29–38.

    CAS  Article  Google Scholar 

  30. 30.

    Zicha J, Dobešová Z, Kuneš J. Relative deficiency of nitric oxide-dependent vasodilation in salt-hypertensive Dahl rats: the possible role of superoxide anions. J Hypertens. 2001;19:247–54.

    CAS  PubMed  Article  Google Scholar 

  31. 31.

    Williams JM, Johnson AC, Stelloh C, Dreisbach AW, Franceschini N, Regner KR, et al. Genetic variants in Arhgef11 are associated with kidney injury in the Dahl salt-sensitive rat. Hypertension. 2012;60:1157–68.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. 32.

    Johnson AC, Wu W, Attipoe EM, Sasser JM, Taylor EB, Showmaker KC, et al. Loss of Arhgef11 in the Dahl salt-sensitive rat protects against hypertension-induced renal injury. Hypertension. 2020;75:1012–24.

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Nedvídek J, Zicha J. Baroreflex control of heart rate in young and adult salt hypertensive inbred Dahl rats. Physiol Res. 2000;49:323–30.

    PubMed  Google Scholar 

  34. 34.

    Ferrari AU, Mark AL. Sensitization of aortic baroreceptors by high salt diet in Dahl salt-resistant rats. Hypertension. 1987;10:55–60.

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Paulis L, Líšková S, Pintérová M, Dobešová Z, Kuneš J, Zicha J. Nifedipine-sensitive noradrenergic vasoconstriction is enhanced in spontaneously hypertensive rats: the influence of chronic captopril treatment. Acta Physiol. 2007;191:255–66.

    CAS  Article  Google Scholar 

  36. 36.

    Pintérová M, Líšková S, Dobešová Z, Behuliak M, Kuneš J, Zicha J. Impaired control of L-type voltage-dependent calcium channels in experimental hypertension. Physiol Res. 2009;58 Suppl 2:S43–54.

    PubMed  Article  Google Scholar 

  37. 37.

    Zicha J, Dobešová Z, Behuliak M, Pintérová M, Kuneš J, Vaněčková I. Nifedipine-sensitive blood pressure component in hypertensive models characterized by high activity of either sympathetic nervous system or renin-angiotensin system. Physiol Res. 2014;63:13–26.

    CAS  PubMed  Article  Google Scholar 

  38. 38.

    Fujita M, Ando K, Nagae A, Fujita T. Sympathoexcitation by oxidative stress in the brain mediates arterial pressure elevation in salt-sensitive hypertension. Hypertension. 2007;50:360–7.

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    Morisawa N, Kitada K, Fujisawa Y, Nakano D, Yamazaki D, Kobuchi S, et al. Renal sympathetic nerve activity regulates cardiovascular energy expenditure in rats fed high salt. Hypertens Res. 2020;43:482–91.

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Van Meel JC, Timmermans PB, Van Zwieten PA. Hypotensive activity of calcium entry blockers in rats. Relationship with depression of alpha 2-adrenoceptor-mediated vasopressor responses. Eur J Pharmacol. 1983;92:27–34.

    PubMed  Article  Google Scholar 

  41. 41.

    Nelson MT, Standen NB, Brayden JE, Worley JF. Noradrenaline contracts arteries by activating voltage-dependent calcium channels. Nature. 1988;336:382–5.

    CAS  PubMed  Article  Google Scholar 

  42. 42.

    Lewis SJ, Bhopatkar MY, Walton TM, Bates JN. Role of voltage-sensitive calcium-channels in nitric oxide-mediated vasodilation in spontaneously hypertensive rats. Eur J Pharmacol. 2005;528:144–9.

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Pintérová M, Karen P, Kuneš J, Zicha J. Role of nifedipine-sensitive sympathetic vasoconstriction in maintenance of high blood pressure in spontaneously hypertensive rats: effect of Gi-protein inactivation by pertusis toxin. J Hypertens. 2010;28:969–78.

    PubMed  Article  CAS  Google Scholar 

  44. 44.

    Manning RD Jr, Meng S, Tian N. Renal and vascular oxidative stress and salt-sensitivity of arterial pressure. Acta Physiol Scand. 2003;179:243–50.

    CAS  PubMed  Article  Google Scholar 

  45. 45.

    Vaněčková I, Vokurková M, Rauchová H, Dobešová Z, Pecháňová O, Kuneš J, et al. Chronic antioxidant therapy lowers blood pressure in adult but not in young Dahl salt hypertensive rats: the role of sympathetic nervous system. Acta Physiol. 2013;208:340–9.

    Article  CAS  Google Scholar 

  46. 46.

    Zheng X, Chen M, Li X, Yang P, Zhao X, Ouyang Y, et al. Insufficient fumarase contributes to hypertension by an imbalance of redox metabolism in Dahl salt-sensitive rats. Hypertens Res. 2019;42:1672–82.

    CAS  PubMed  Article  Google Scholar 

  47. 47.

    Fleckenstein A, Frey M, Zorn J, Fleckenstein-Grün G. Amlodipine, a new 1,4-dihydropyridine calcium antagonist with a particularly strong antihypertensive profile. Am J Cardiol. 1989;64:21I–34I.

    CAS  PubMed  Article  Google Scholar 

  48. 48.

    Nagasu H, Satoh M, Fujimoto S, Tomita N, Sasaki T, Kashihara N. Azelnidipine attenuates glomerular damage in Dahl salt-sensitive rats by suppressing sympathetic nerve activity. Hypertens Res. 2012;35:348–55.

    CAS  PubMed  Article  Google Scholar 

  49. 49.

    Nishikimi T, Akimoto K, Wang X, Mori Y, Tadokoro K, Ishikawa Y, et al. Fasudil, a Rho-kinase inhibitor, attenuates glomerulosclerosis in Dahl salt-sensitive rats. J Hypertens. 2004;22:1787–96.

    CAS  PubMed  Article  Google Scholar 

  50. 50.

    Fukui S, Fukumoto Y, Suzuki J, Saji K, Nawata J, Tawara S, et al. Long-term inhibition of Rho-kinase ameliorates diastolic heart failure in hypertensive rats. J Cardiovasc Pharmacol. 2008;51:317–26.

    CAS  PubMed  Article  Google Scholar 

  51. 51.

    Behuliak M, Vavřínová A, Bencze M, Polgárová K, Ergang P, Kuneš J, et al. Ontogenetic changes in contribution of calcium sensitization and calcium entry to blood pressure maintenance of Wistar-Kyoto and spontaneously hypertensive rats. J Hypertens. 2015;33:2443–54.

    CAS  PubMed  Article  Google Scholar 

  52. 52.

    Wirth A, Benyó Z, Lukasova M, Leutgeb B, Wettschureck N, Gorbey S, et al. G12-G13-LARG-mediated signaling in vascular smooth muscle is required for salt-induced hypertension. Nat Med. 2008;14:64–8.

    CAS  PubMed  Article  Google Scholar 

  53. 53.

    Wiciński M, Szadujkis-Szadurska K, Węclewicz MM, Malinowski B, Matusiak G, Walczak M, et al. The role of Rho-kinase and calcium ions in constriction triggered by ET-1. Microvasc Res. 2018;119:84–90.

    PubMed  Article  CAS  Google Scholar 

  54. 54.

    Ferland DJ, Mullick AE, Watts SW. Chemerin as a driver of hypertension: a consideration. Am J Hypertens. 2020;33:975–86.

    PubMed  PubMed Central  Article  Google Scholar 

Download references

Acknowledgements

Technical assistance of Zdeňka Kopecká is highly appreciated. This study was supported by the Institute of Physiology, Czech Academy of Sciences (grant No. RVO 67985823), the Ministry of Health of the Czech Republic (grant no. 15–25396A) and the Joint Project of GACR and MOST, Taiwan (grant no. 19–08260J).

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Josef Zicha or Ivana Vaněčková.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

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

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Zicha, J., Behuliak, M., Vavřínová, A. et al. Cooperation of augmented calcium sensitization and increased calcium entry contributes to high blood pressure in salt-sensitive Dahl rats. Hypertens Res (2021). https://doi.org/10.1038/s41440-021-00659-5

Download citation

Keywords

  • Rho kinase
  • Fasudil
  • Voltage-dependent calcium channels
  • Nifedipine
  • Nitric oxide
  • Sympathetic tone
  • Baroreflex efficiency

Search

Quick links