Skip to main content
SpringerLink
Log in

Impact of vitamin D3 on cardiovascular responses to glucocorticoid excess

  • Original paper
  • Published:
Journal of Physiology and Biochemistry Aims and scope Submit manuscript

Abstract

Although the cardiovascular system is not a classical target for 1,25-dihydroxyvitamin D3, both cardiac myocytes and vascular smooth muscle cells respond to this hormone. The present study aimed to elucidate the effect of active vitamin D3 on cardiovascular functions in rats exposed to glucocorticoid excess. Adult male Wistar rats were allocated into three groups: control group, dexamethasone (Dex)-treated group receiving Dex (200 μg/kg) subcutaneously for 12 days, and vitamin D3-Dex-treated group receiving 1,25-(OH)2D3 (100 ng/kg) and Dex (200 μg/kg) subcutaneously for 12 days. Rats were subjected to measurement of systolic (SBP), diastolic (DBP), and mean arterial (MAP) blood pressures and heart rate. Rate pressure product (RPP) was calculated. Rats’ isolated hearts were perfused in Langendorff preparation and studied for basal activities (heart rate, peaked developed tension, time to peak tension, half relaxation time, and myocardial flow rate) and their responses to isoproterenol infusion. Blood samples were collected for determination of plasma level of nitrite, nitric oxide surrogate. Dex-treated group showed significant increase in SBP, DBP, MAP, and RPP, as well as cardiac hypertrophy and enhancement of basal cardiac performance evidenced by increased heart rate, rapid and increased contractility, and accelerated lusitropy, together with impaired contractile and myocardial flow rate responsiveness to beta-adrenergic activation and depressed inotropic and coronary vascular reserves. Such alterations were accompanied by low plasma nitrite. These changes were markedly improved by vitamin D3 treatment. In conclusion, vitamin D3 is an efficacious modulator of the deleterious cardiovascular responses induced by glucocorticoid excess, probably via accentuation of nitric oxide.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Akaza I, Yoshimoto T, Tsuchiya K, Hirata Y (2010) Endothelial dysfunction associated with hypercortisolism is reversible in Cushing’s syndrome. Endocr J 57(3):245–252

    PubMed  Google Scholar 

  2. Arnaldi G, Angeli A, Atkinson AB, Bertagna X, Cavagnini F, Chrousos GP, Fava GA, Findling JW, Gaillard RC, Grossman AB, Kola B, Lacroix A, Mancini T, Mantero F, Newell-Price J, Nieman LK, Sonino N, Vance ML, Giustina A, Boscaro M (2003) Diagnosis and complications of Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab 88:5593–5602

    PubMed  CAS  Google Scholar 

  3. Ayobe MH, Tarazi RC (1983) Beta-receptors and contractile reserve in left ventricular hypertrophy. Hypertension 5:192–197

    CAS  Google Scholar 

  4. Beato M, Truss M, Chávez S (1996) Control of transcription by steroid hormones. Ann NY Acad Sci 784:93–123

    PubMed  CAS  Google Scholar 

  5. Bechtold AG, Patel G, Hochhaus G, Scheuer DA (2009) Chronic blockade of hindbrain glucocorticoid receptors reduces blood pressure responses to novel stress and attenuates adaptation to repeated stress. Am J Physiol 296(5):R1445–R1454

    CAS  Google Scholar 

  6. Berne RM, Levy MN, Koeppen MB, Stanton BA (2004) Fisiologia, 5ªth edn. Elsevier, Rio de Janeiro

    Google Scholar 

  7. Esler M, Eikelis N, Schlaich M, Lambert G, Alvarenga M, Kaye D, El-Osta A, Guo L, Barton D, Pier C, Brenchley C, Dawood T, Jennings G, Lambert E (2008) Human sympathetic nerve biology. Parallel influences of stress and epigenetics in essential hypertension and panic disorder. Ann NY Acad Sci 1148:338–348

    PubMed  CAS  Google Scholar 

  8. Green JJ, Robinson DA, Wilson GE, Simpson RU, Westfall MV (2006) Calcitriol modulation of cardiac contractile performance via protein kinase C. J Mol Cell Cardiol 41:350–359

    PubMed  CAS  Google Scholar 

  9. Janzewski AM, Spurgeon HA, Stern MD, Lakatta EG (1995) Effects of sarcoplasmic reticulum Ca2+load on the gain function of Ca2+ release by Ca2+ current in cardiac cells. Am J Physiol Heart Circ Physiol 268:H916–H920

    Google Scholar 

  10. Kim HW, Park CW, Shin YS, Kim YS, Shin SJ, Kim YS, Choi EJ, Chang YS, Bang BK (2006) Calcitriol regresses cardiac hypertrophy and QT dispersion in secondary hyperparathyroidism on hemodialysis. Nephron Clin Pract 102:c21–c29

    PubMed  Google Scholar 

  11. Lefer AM (1968) Influence of glucocorticoids on the mechanical performance of isolated rat papillary muscle. Am J Physiol 214:518–524

    PubMed  CAS  Google Scholar 

  12. Mancuso P, Rahman A, Hershey SD, Dandu L, Nibbelink KA, Simpson RU (2008) 1,25-Dihydroxyvitamin-D3 treatment reduces cardiac hypertrophy and left ventricular diameter in spontaneously hypertensive heart failure-prone (cp/+) rats independent of changes in serum leptin. J Cardiovasc Pharmacol 51(6):559–564

    PubMed  CAS  Google Scholar 

  13. Mangos GJ, Whitworth JA, Williamson PM, Kelly JJ (2003) Glucocorticoids and the kidney. Nephrol (Carlton) 8:267–273

    CAS  Google Scholar 

  14. Merke J, Hofmann W, Goldschmidt D, Ritz E (1987) Demonstration of 1,25 (OH)2 vitamin D3 receptors and actions in vascular smooth muscle cells in vitro. Calcif Tissue Int 41:112–114

    PubMed  CAS  Google Scholar 

  15. Mitchell BM, Dorrance AM, Mack EA, Webb RC (2004) Glucocorticoids decrease GTP cyclohydrolase and tetrahydrobiopterin-dependent vasorelaxation through glucocorticoid receptors. J Cardiovasc Pharmacol 43:8–13

    PubMed  CAS  Google Scholar 

  16. Molinari C, Uberti F, Grossini E, Vacca G, Carda S, Invernizzi M, Cisari C (2011) 1α,25-dihydroxycholecalciferol induces nitric oxide production in cultured endothelial cells. Cell Physiol Biochem 27(6):661–668

    PubMed  CAS  Google Scholar 

  17. Møller S, Laigaard F, Olgaard K, Hemmingsen C (2007) Effect of 1,25-dihydroxy-vitamin D3 in experimental sepsis. Int J Med Sci 4:190–195

    PubMed  Google Scholar 

  18. Moncada S, Higgs A (1993) The L-arginine-nitric oxide pathway. N Eng J Med 329:2002–2012

    CAS  Google Scholar 

  19. Montgomery HAC, Dymock JF (1961) The determination of nitrite in water. Analyst 86:414–416

    CAS  Google Scholar 

  20. Muiesan ML, Lupia M, Salvetti M, Grigoletto C, Sonino N, Boscaro M, Rosei EA, Mantero F, Fallo F (2003) Left ventricular structural and functional characteristics in Cushing’s syndrome. J Am Coll Cardiol 41:2275–2279

    PubMed  Google Scholar 

  21. Newell-Price J, Bertagna X, Grossman AB, Nieman LK (2006) Cushing’s syndrome. Lancet 367:1605–1617

    PubMed  CAS  Google Scholar 

  22. O’Connell TD, Simpson RU (1996) Immunochemical identification of the 1,25-dihydroxyvitamin D3 receptor protein in human heart. Cell Biol Int 20:621–624

    PubMed  Google Scholar 

  23. Penefsky ZJ, Kahn M (1971) Inotropic effects of dexamethasone in mammalian heart muscle. Eur J Pharmacol 15:259–266

    PubMed  CAS  Google Scholar 

  24. Pinheiro CH, Sousa Filho WM, Oliveira Neto J, Marinho Mde J, Motta Neto R, Smith MM, Silva CA (2009) Exercise prevents cardiometabolic alterations induced by chronic use of glucocorticoids. Arq Bras Cardiol 93(4):400–408

    PubMed  Google Scholar 

  25. Przybylski R, McCune S, Hollis B, Simpson RU (2010) Vitamin D deficiency in the spontaneously hypertensive heart failure [SHHF] prone rat. Nutr Metab Cardiovasc Dis 20(9):641–646

    PubMed  CAS  Google Scholar 

  26. Rossier MF, Lenglet S, Vetterli L, Python M, Maturana A (2008) Corticosteroids and redox potential modulate spontaneous contractions in isolated rat ventricular cardiomyocytes. Hypertension 52(4):721–728

    PubMed  CAS  Google Scholar 

  27. Scragg RK, Camargo CAJ, Simpson RU (2010) Relation of serum 25-hydroxyvitamin D to heart rate and cardiac work (from the National Health and Nutrition Examination Surveys). Am J Cardiol 105(1):122–128

    PubMed  CAS  Google Scholar 

  28. Shi H, Norman AW, Okamura WH, Sen A, Zemel MB (2001) 1α, 25-dihyroxyvitamin D3 modulates human adipocyte metabolism via non-genomic action. FASEB J 14:2751–2753

    Google Scholar 

  29. Simko F, Simko J (2000) The potential role of nitric oxide in the hypertrophic growth of the left ventricle. Physiol Res 49(1):37–46

    PubMed  CAS  Google Scholar 

  30. Simmons WW, Ungureanu-Longrois D, Smith GK, Smith TW, Kelly RA (1996) Glucocorticoids regulate inducible nitric oxide synthase by inhibiting tetrahydrobiopterin synthesis and l-arginine transport. J Biol Chem 271:23928–23937

    PubMed  CAS  Google Scholar 

  31. Simpson R, Weishaar R (1988) Involvement of 1,25-dihydroxyvitamin D3 in regulating myocardial calcium metabolism: physiological and pathological actions. Cell Calcium 9:285–292

    PubMed  CAS  Google Scholar 

  32. Stohr T, Almeida OF, Landgraf R, Shippenberg TS, Holsboer F, Spanagel R (1999) Stress- and corticosteroid-induced modulation of the locomotor response to morphine in rats. Behav Brain Res 103:85–93

    PubMed  CAS  Google Scholar 

  33. Turner SW, Wen CH, Li M, Whitworth JA (1996) l-Arginine prevents corticotropin-induced increases in blood pressure in the rat. Hypertension 27:184–188

    PubMed  CAS  Google Scholar 

  34. Verhave G, Siegert CE (2010) Role of vitamin D in cardiovascular disease. Neth J Med 68(3):113–118

    PubMed  CAS  Google Scholar 

  35. Walker BR (2007) Glucocorticoids and cardiovascular disease. Eur J Endocrinol 157:545–559

    PubMed  CAS  Google Scholar 

  36. Wallerath T, Witte K, Schafer SC, Schwarz PM, Prellwitz W, Wohlfart P, Kleinert H, Lehr HA, Lemmer B, Forstermann U (1999) Down-regulation of the expression of endothelial NO synthase is likely to contribute to glucocorticoid-mediated hypertension. Proc Natl Acad Sci USA 96:13357–13362

    PubMed  CAS  Google Scholar 

  37. Walters MR, Ilenchuk TT, Claycomb WC (1987) 1,25-dihydroxyvitamin D3 stimulates 45Ca21 uptake by cultured adult rat ventricular cardiac muscle cells. J Biol Chem 262:2536–2541

    PubMed  CAS  Google Scholar 

  38. Walters MR, Wicker DC, Riggle PC (1986) 1,25-dihydroxyvitamin D3 receptors identified in the rat heart. J Mol Cell Cardiol 18:67–72

    PubMed  CAS  Google Scholar 

  39. Wang J, Brown MA, Tam SH, Chen MC, Whitworth JA (1997) The effects of diet on measurement of nitric oxide metabolites. Clin Exp Pharmacol Physiol 24:418–420

    PubMed  CAS  Google Scholar 

  40. Weishaar RE, Simpson RU (1987) Vitamin D3 and cardiovascular function in rats. J Clin Invest 79:1706–1712

    PubMed  CAS  Google Scholar 

  41. Yang S, Zhang L (2004) Glucocorticoids and vascular reactivity. Curr Vasc Pharmacol 2:1–12

    PubMed  Google Scholar 

  42. Yue ZJ, Yu ZB (2011) Cardioprotection by the inhibitory effect of nitric oxide. Sheng Li Xue Bao 63(3):191–197

    PubMed  CAS  Google Scholar 

  43. Zhao G, Robert U, Simpson RU (2010) Interaction between vitamin D receptor and caveolin-3 and regulation by 1,25 dihydroxyvitamin D3 in adult rat cardiomyocytes. J Steroid Biochem Mol Biol 121(1–2):159–163

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Physiology Department, Faculty of Medicine, Ain Shams University, 74 Abbassiya Street, Abdou Pasha Square, Cairo, Egypt

    Mona A. Ahmed

Authors
  1. Mona A. Ahmed
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mona A. Ahmed.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ahmed, M.A. Impact of vitamin D3 on cardiovascular responses to glucocorticoid excess. J Physiol Biochem 69, 267–276 (2013). https://doi.org/10.1007/s13105-012-0209-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13105-012-0209-4

Keywords

Search

Navigation