Skip to main content Accessibility help
×
Home

Both high and low plasma levels of 25-hydroxy vitamin D increase blood pressure in a normal rat model

  • Naghmeh Z. Mirhosseini (a1), Steven J. Knaus (a2), Kaylee Bohaychuk (a1), Jaswant Singh (a1), Hassan A. Vatanparast (a3) and Lynn P. Weber (a1) (a2)...

Abstract

The lower threshold plasma 25-hydroxy vitamin D (25(OH)D) level for optimal cardiovascular health is unclear, whereas the toxicity threshold is less clear. The aim of this study was to examine the cardiovascular–vitamin D dose–response curve in a normal rat model. Doses of cholecalciferol ranged from deficiency to toxic levels (equivalent to human doses of 0, 0·015, 0·25 and 3·75mg/d) for 4 weeks, and then cardiovascular health was examined using blood pressure telemetry and high-resolution ultrasound in normal male rats (n 16/group, 64 rats total). After 1 month, only the 0·25mg/d group had plasma 25(OH)D that was within current recommended range (100–125 nmol/l), and all groups failed to change plasma Ca or phosphate. Systolic blood pressure increased significantly (10–15 mmHg) in the rat groups with plasma 25(OH)D levels at both 30 and 561 nmol/l (groups fed 0 and 3·75mg/d) compared with the group fed the equivalent to 0·015mg/d (43 nmol/l 25(OH)D). Although not significant, the group fed the equivalent to 0·25mg/d (108 nmol/l 25(OH)D) also showed a 10 mmHg increase in systolic blood pressure. Carotid artery diameter was significantly smaller and wall thickness was larger, leading to higher peak carotid systolic blood velocity in these two groups. Despite these vascular changes, cardiac function did not differ among treatment groups. The key finding in this study is that arterial stiffness and systolic blood pressure both showed a U-shaped dose–response for vitamin D, with lowest values (best cardiovascular health) observed when plasma 25(OH)D levels were 43 nmol/l in normal male rats.

  • View HTML
    • Send article to Kindle

      To send this article to your Kindle, first ensure no-reply@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Both high and low plasma levels of 25-hydroxy vitamin D increase blood pressure in a normal rat model
      Available formats
      ×

      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

      Both high and low plasma levels of 25-hydroxy vitamin D increase blood pressure in a normal rat model
      Available formats
      ×

      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

      Both high and low plasma levels of 25-hydroxy vitamin D increase blood pressure in a normal rat model
      Available formats
      ×

Copyright

Corresponding author

* Corresponding author: L. P. Weber, fax +1 306 966 7376, email lynn.weber@usask.ca

References

Hide All
1. Hanley, DA & Davison, KS (2005) Vitamin D insufficiency in North America. J Nutr 135, 332337.
2. Holick, MF (2007) Vitamin D deficiency. N Engl J Med 357, 266281.
3. Institute of Medicine (2011) Dietary Reference Intakes for Calcium and Vitamin D [Committee to Review Dietary Reference Intakes for Vitamin D and Calcium, Food and Nutrition Board, AC Ross, CI Taylor, editors]. Washington, DC: The National Academies Press.
4. Garland, CF, Kim, JJ, Burgette, S, et al. (2014) Meta-analysis of all-cause mortality according to serum 25-hydroxyvitamin D. Am J Pub Health 104, e43e50.
5. Christakos, S, Dhawan, P, Verstuyf, A, et al. (2015) Vitamin D: metabolism, molecular mechanism of action, and pleiotropic effects. Physiol Rev 96, 365408.
6. Grant, WB, Karras, SN, Bischoff-Ferrari, HA, et al. (2016) Do studies reporting ‘U’-shaped serum 25-hydroxyvitamin D–health outcome relationships reflect adverse effects? Dermato Endocrinol 8, e1187349.
7. McDonnel, SL, Baggerly, C, French, CB, et al. (2016) Serum 25-hydroxyvitamin D concentrations ≥40ng/ml are associated with >65% lower cancer risk: pooled analysis of randomized trial and prospective cohort study. PLOS ONE 11, e0152441.
8. Pilz, S, Verheyen, N, Grubler, MR, et al. (2016) Vitamin D and cardiovascular disease prevention. Nat Rev Cardiol 13, 404417.
9. Sharma, S, Barr, AB, Macdonald, HM, et al. (2011) Vitamin D deficiency and disease risk among aboriginal Arctic populations. Nutr Rev 69, 468478.
10. Holick, MF & Chen, TC (2008) Vitamin D deficiency: a worldwide problem with health consequences. Am J Clin Nutr 87, 1080S1086S.
11. Garland, CF, Gorham, ED, Mohr, SB, et al. (2009) Vitamin D for cancer prevention: global perspectives. Ann Epidemiol 19, 468483.
12. Bischoff-Ferrari, HA, Willett, WC, Wong, JB, et al. (2009) Prevention of nonvertebral fractures with oral vitamin D and dose dependency: a meta-analysis of randomized controlled trials. Arch Intern Med 169, 551561.
13. Souberbielle, JC, Body, JJ, Lappe, JM, et al. (2010) Vitamin D and musculoskeletal health, cardiovascular disease, autoimmunity and cancer: recommendations for clinical practice. Autoimmun Rev 9, 709715.
14. Giovannucci, E, Liu, Y, Hollis, BW, et al. (2008) 25-Hydroxyvitamin D and risk of myocardial infarction in men: a prospective study. Arch Intern Med 168, 11741180.
15. Pilz, S, Marz, W, Wellnitz, B, et al. (2008) Association of vitamin D deficiency with heart failure and sudden cardiac death in a large cross-sectional study of patients referred for coronary angiography. J Clin Endocrinol Metab 93, 39273935.
16. Dobnig, H, Pilz, S, Scharnagl, H, et al. (2008) Independent association of low serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels with all-cause and cardiovascular mortality. Arch Intern Med 168, 13401349.
17. Ke, L, Mason, RS, Kariuki, M, et al. (2015) Vitamin D status and hypertension: a review. Integr Blood Press Control 8, 1335.
18. Kunutsor, SK, Apekey, TA & Steur, M (2013) Vitamin D and risk of future hypertension: meta-analysis of 283,537 participants. Eur J Epidemiol 28, 205221.
19. Scragg, R, Slow, S, Stewart, AW, et al. (2014) Long-term high-dose vitamin D3 supplementation and blood pressure in health adults: a randomized controlled trial. Hypertension 64, 725730.
20. Van Ballegooijen, AJ, Gansevoort, RT, Lambers-Heerspink, HJ, et al. (2015) Plasma 1,25-dihydroxyvitamin D and the risk of developing hypertension. Hypertension 66, 563570.
21. Blondon, M, Sachs, M, Hoofnagle, AN, et al. (2013) 25-Hydroxyvitamin D and parathyroid hormone are not associated with carotid intima-media thickness or plaque in the multi-ethnic study of atherosclerosis. Arterioscler Thromb Vasc Biol 33, 26392645.
22. Deleskog, A, Piksasova, O, Silveira, A, et al. (2013) Serum 25-hydroxyvitamin D concentration in subclinical carotid atherosclerosis. Arterioscler Thromb Vasc Biol 33, 26332638.
23. Pilz, S & Tomaschitz, A (2010) Role of vitamin D in arterial hypertension. Expert Rev Cardiovasc Ther 8, 15991608.
24. Kruger, IM, Kruger, MC, Doak, CM, et al. (2013) The association of 25(OH) D with blood pressure, pulse pressure and carotid-radial pulse wave velocity in African women. PLOS ONE 8, e54554.
25. Reynolds, JA, Haque, S, Berry, JL, et al. (2012) 25-Hydroxyvitamin D deficiency is associated with increased aortic stiffness in patients with systemic lupus erythematosus. Rheumatology 51, 544551.
26. O’Rourke, MF, Staessen, JA, Vlachopoulos, C, et al. (2002) Clinical applications of arterial stiffness; definitions and reference values. Am J Hypertension 15, 426444.
27. O’Rourke, M (1990) Arterial stiffness, systolic blood pressure, and logical treatment of arterial hypertension. Hypertension 15, 339347.
28. Al Mheid, I, Patel, R, Murrow, J, et al. (2011) Vitamin D status is associated with arterial stiffness and vascular dysfunction in healthy humans. J Am College Cardiol 58, 186192.
29. Weng, S, Sprague, JE, Oh, J, et al. (2013) Vitamin D deficiency induces high blood pressure and accelerates atherosclerosis in mice. PLOS ONE 8, e54625.
30. Sundersingh, F, Plum, LA & DeLuca, HF (2015) Vitamin D deficiency independent of hypocalcemia elevates blood pressure in rats. Biochem Biophys Res Commun 461, 589591.
31. Durup, D, Jorgensen, HL, Christensen, J, et al. (2012) A reverse J-shaped association of all-cause mortality with serum 25-hydroxyvitamin D in general practice: the CopD study. J Clin Endocrinol Metab 97, 26442652.
32. Dror, Y, Giveon, SM, Hoshen, M, et al. (2013) Vitamin D levels for preventing acute coronary syndrome and mortality: evidence of a nonlinear association. J Clin Endocrinol Metab 98, 21602167.
33. Zittermann, A, Iodice, S, Pilz, S, et al. (2012) Vitamin D deficiency and mortality risk in the general population: a meta-analysis of prospective cohort studies. Am J Clin Nutr 95, 91100.
34. Wang, TJ, Pencina, MJ, Booth, SL, et al. (2008) Vitamin D deficiency and risk of cardiovascular disease. Circulation 117, 503511.
35. Hathcock, JN, Shao, A, Vieth, R, et al. (2007) Risk assessment for vitamin D. Am J Clin Nutr 85, 618.
36. Pérez-Barrios, C, Hernández-Álvarez, E, Blanco-Navarro, I, et al. (2016) Prevalence of hypercalcemia related to hypervitaminosis D in clinical practice. Clin Nutr 35, 13541358.
37. Vieth, R (1999) Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr 69, 842856.
38. Sharma, V & McNeill, JH (2009) To scale or not to scale: the principles of dose extrapolation. Br J Pharmacol 157, 907921.
39. Andreollo, NA, Dos Santos, EF, Araújo, MR, et al. (2012) Rat’s age versus human’s age: what is the relationship? Braz Arch Dig Surg 25, 4951.
40. Gentner, NJ & Weber, LP (2011) Intranasal benzo[a]pyrene alters circadian blood pressure patterns and causes lung inflammation in rats. Arch Toxicol 85, 337346.
41. Wildemann, TM, Mirhosseini, NM, Siciliano, SD, et al. (2015) Cardiovascular responses to lead are biphasic, while methylmercury, but not inorganic mercury, monotonically increases blood pressure in rats. Toxicology 328, 111.
42. Turk, M, Pretnar-Oblak, J, Zupan, M, et al. (2015) Ultrasound diagnosis of carotid artery stiffness in patients with ischemic leukoaraiosis. Ultrasound Med Biol 41, 6471.
43. Catena, C, Cosma, C, Camozzi, V, et al. (2013) Non-alcoholic fatty liver disease is not associated with vitamin D deficiency in essential hypertension. High Blood Press Cardiovasc Prev 20, 3337.
44. Lindesay, G, Ragonnet, C, Chimenti, S, et al. (2016) Age and hypertension strongly induce aortic stiffening in rats at basal and matched blood pressure levels. Physiol Rep 4, e12805.
45. World Health Organization (2003) World Health Organization (WHO)/International Society of Hypertension (ISH) statement on management of hypertension. J Hypertens 21, 19831992.
46. Kota, SK, Kota, SK, Jammula, S, et al. (2011) Renin–angiotensin system activity in vitamin D deficient, obese individuals with hypertension: an urban Indian study. Indian J Endocrinol Metab 15, Suppl. 4, S395S401.
47. Tomaschitz, A, Pilz, S, Ritz, E, et al. (2010) Independent association between 1,25 dihydroxyvitamin D and the rennin-angiotensin system. The Ludwigshafen Risk and Cardiovascular Health (LURIC) Study. Clin Chim Acta 411, 1718.
48. Carrara, D, Bernini, M, Bacca, A, et al. (2014) Cholecalciferol administration blunts the systemic renin–angiotensin system in essential hypertensives with hypovitaminosis D. J Renin Angiotensin Aldosterone Syst 15, 8287.
49. Li, YC, Qiao, G, Uskokovic, M, et al. (2004) Vitamin D: a negative endocrine regulator of the renin-angiotensin system and blood pressure. J Steroid Biochem Mol Biol 89–90, 387392.
50. Atchison, DK, Hardin, P & Beierwaltes, WH (2013) Vitamin D increases plasma renin activity independently of plasma Ca2+ via hypovolemia and β-adrenergic activity. Am J Physiol 305, F1109F1117.
51. Xiang, W, Kong, J, Chen, S, et al. (2005) Cardiac hypertrophy in vitamin D receptor knockout mice: role of the systemic and cardiac renin-angiotensin systems. Am J Physiol Endocrinol Metab 288, E125E132.
52. Bouillon, R, Carmeliet, G, Verlinden, L, et al. (2008) Vitamin D and human health: lessons from vitamin D receptor null mice. Endocr Rev 29, 726776.
53. Tare, M, Emmett, SJ, Coleman, HA, et al. (2011) Vitamin D insufficiency is associated with impaired vascular endothelial and smooth muscle function and hypertension in young rats. J Physiol 589, 47774786.
54. Nagata-Sakurai, M, Inaba, M, Goto, H, et al. (2003) Inflammation and bone resorption as independent factors of accelerated arterial wall thickening in patients with rheumatoid arthritis. Arthritis Rheum 48, 30613067.
55. Murr, C, Pilz, S, Grammer, TB, et al. (2012) Vitamin D deficiency parallels inflammation and immune activation, the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. Low vitamin D levels predict stroke in patients referred to coronary angiography. Clin Chem Lab Med 50, 22052212.
56. Li, YC, Kong, J, Wei, M, et al. (2002) 1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system. J Clin Invest 110, 229238.
57. Price, PA, Faus, SA & Williamson, MK (2000) Warfarin-induced artery calcification is accelerated by growth and vitamin D. Arterioscler Thromb Vasc Biol 20, 317327.
58. Lai, JK, Lucas, RM, Clements, MS, et al. (2010) Hip fracture risk in relation to vitamin D supplementation and serum 25-hydroxyvitamin D levels: a systematic review and meta-analysis of randomised controlled trials and observational studies. BMC Public Health 10, 14712458.
59. Holick, MF, Binkley, NC, Bischoff-Ferrari, HA, et al. (2011) Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 96, 19111930.
60. Blacher, J, Guerin, AP, Pannier, B, et al. (2001) Arterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease. Hypertension 38, 938942.
61. Cecelja, M & Chowienczyk, P (2012) Role of arterial stiffness in cardiovascular disease. JRSM Cardiovasc Dis 1, cvd.2012.012016.
62. Bodyak, N, Ayus, JC, Achinger, S, et al. (2007) Activated vitamin D attenuates left ventricular abnormalities induced by dietary sodium in Dahl salt-sensitive animals. Proc Natl Acad Sci 104, 1681016815.
63. Mancuso, P, Rahman, A, Hershey, SD, et al. (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, 559564.
64. Jones, G (2013) Extrarenal vitamin D activation and interactions between vitamin D2, vitamin D3 and vitamin D analogs. Annu Rev Nutr 33, 2344.
65. Jono, S, Nishizawa, Y, Shioi, A, et al. (1998) 1,25-Dihydroxyvitamin D3 increases in vitro vascular calcification by modulating secretion of endogenous parathyroid hormone–related peptide. Circulation 98, 13021306.
66. Watson, KE, Bostrom, K, Ravindranath, R, et al. (1994) TGF-beta 1 and 25-hydroxycholesterol stimulate osteoblast-like vascular cells to calcify. J Clin Invest 93, 21062113.
67. Price, PA, June, HH, Buckley, JR, et al. (2001) Osteoprotegerin inhibits artery calcification induced by warfarin and by vitamin D. Arterioscler Thromb Vasc Biol 21, 16101616.
68. Callegari, A., Coons, ML, Ricks, JL, et al. (2013) Bone marrow- or vessel wall-derived osteoprotegerin is sufficient to reduce atherosclerotic lesion size and vascular calcification. Arterioscler Thromb Vasc Biol 33, 24912500.
69. Garland, CF, French, CB, Baggerly, LL, et al. (2011) Vitamin D supplement doses and serum 25-hydroxyvitamin D in the range associated with cancer prevention. Anticancer Res 31, 607611.
70. Knutson, JC, LeVan, LW, Valliere, CR, et al. (1997) Pharmacokinetics and systemic effect on calcium homeostasis of 1α,24-dihydroxyvitamin D2 in rats. Biochem Pharmacol 53, 829837.
71. Borel, P, Caillaud, D & Cano, NJ (2015) Vitamin D bioavailability: state of the art. Crit Rev Food Sci Nutr 55, 11931205.

Keywords

Metrics

Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed