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Disorders of Blood Pressure Regulation—Role of Catecholamine Biosynthesis, Release, and Metabolism

  • Pathogenesis of Hypertension: Genetic and Environmental Factors (DT O’Connor, Section Editor)
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Abstract

Catecholamines (epinephrine and norepinephrine) are synthesised and produced by the adrenal medulla and postganglionic nerve fibres of the sympathetic nervous system. It is known that essential hypertension has a significant neurogenic component, with the rise in blood pressure mediated at least in part by overactivity of the sympathetic nervous system. Moreover, novel therapeutic strategies aimed at reducing sympathetic activity show promise in the treatment of hypertension. This article reviews recent advances within this rapidly changing field, particularly focusing on the role of genetic polymorphisms within key catecholamine biosynthetic enzymes, cofactors, and storage molecules. In addition, mechanisms linking the sympathetic nervous system and other adverse cardiovascular states (obesity, insulin resistance, dyslipidaemia) are discussed, along with speculation as to how recent scientific advances may lead to the emergence of novel antihypertensive treatments.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Esler M, Ferrier C, Lambert G, et al. Biochemical evidence of sympathetic hyperactivity in human hypertension. Hypertension. 1991;17(4 Suppl):29–35.

    Google Scholar 

  2. Newcombe CP, Shucksmith HS, Suffern WS. Sympathectomy for hypertension; follow-up of 212 patients. Brit Med J. 1959;1:142–4.

    Article  PubMed  CAS  Google Scholar 

  3. • Esler MD, Krum H et al. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet 2010, 376:1903–9. This study illustrates the safety and blood pressure–lowering effects of renal “sympathectomy” and offers an exciting alternative treatment strategy for resistant hypertension.

    Article  PubMed  Google Scholar 

  4. Julius S, Krause L, Schork NJ, et al. Hyperkinetic borderline hypertension in Tecumseh, Michigan. J Hypertens. 1991;9:77–84.

    PubMed  CAS  Google Scholar 

  5. Grassi G, Cattaneo BM, Seravalle G, Lanfranchi A, Mancia G. Baroreflex control of sympathetic nerve activity in essential and secondary hypertension. Hypertension. 1998;31:68–72.

    PubMed  CAS  Google Scholar 

  6. Seravalle G, Quarti-Trevano F, Dell’Oro R, et al. Sympathetic, baroreflex and metabolic abnormalities in the optimal, normal and high blood pressure state. J Hypertens. 2010;28:e437.

    Article  Google Scholar 

  7. Flaa A, Eide IK, Kjeldsen SE, Rostrup M. Sympathoadrenal stress reactivity is a predictor of future blood pressure: an 18-year follow-up study. Hypertension. 2008;52:336–41.

    Article  PubMed  CAS  Google Scholar 

  8. • Hassellund SS, Flaa A, Sandvik L, Kjeldsen SE, Rostrup M. Long-term stability of cardiovascular and catecholamine responses to stress tests: an 18-year follow-up study. Hypertension 2010, 55:131–6. This was the first study to illustrate the long-term stability of stress-mediated cardiovascular reactivity. It adds weight to the hypothesis that altered stress responses are implicated in the development of hypertension.

    Article  PubMed  CAS  Google Scholar 

  9. Beetz N, Harrison MD, Brede M, et al. Phosducin influences sympathetic activity and prevents stress-induced hypertension in humans and mice. J Clin Invest. 2009;119:3597–612.

    PubMed  CAS  Google Scholar 

  10. Flatmark T. Catecholamine biosynthesis and physiological regulation in neuroendocrine cells. Acta Physiol Scand. 2000;168:1–17.

    Article  PubMed  CAS  Google Scholar 

  11. Rao F, Zhang L, Wessel J, et al. Tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis: discovery of common human genetic variants governing transcription, autonomic activity, and blood pressure in vivo. Circulation. 2007;116:993–1006.

    Article  PubMed  CAS  Google Scholar 

  12. Zhang K, Zhang L, Rao F, et al. Human tyrosine hydroxylase natural genetic variation: delineation of functional transcriptional control motifs disrupted in the proximal promoter. Circ Cardiovasc Genet. 2010;3:187–98.

    Article  PubMed  CAS  Google Scholar 

  13. Nielsen SJ, Jeppesen J, Torp-Pedersen C. Tyrosine hydroxylase polymorphism (C-824T) and hypertension: a population-based study. Am J Hypertens. 2010;23:1306–11.

    Article  PubMed  CAS  Google Scholar 

  14. •• Gu Y, Zhang K, Biswas N et al. Urocortin 2 lowers blood pressure and reduces plasma catecholamine levels in mice with hyperadrenergic activity. Endocrinology 2010, 151:4820–9. This important study highlights the future therapeutic potential of manipulating plasma urocortin 2 in hypertension.

    Article  PubMed  CAS  Google Scholar 

  15. Chen Y, Wen G, Rao F, et al. Human dopamine beta-hydroxylase (DBH) regulatory polymorphism that influences enzymatic activity, autonomic function, and blood pressure. J Hypertens. 2010;28:76–86.

    Article  PubMed  CAS  Google Scholar 

  16. Ohlstein EH, Kruse LI, Ezekiel M, et al. Cardiovascular effects of a new potent dopamine beta-hydroxylase inhibitor in spontaneously hypertensive rats. J Pharmacol Exp Ther. 1987;241:554–9.

    PubMed  CAS  Google Scholar 

  17. Chen Y, Zhang K, Wen G, et al. Human dopamine beta-hydroxylase promoter variant alters transcription in chromaffin cells, enzyme secretion, and blood pressure. Am J Hypertens. 2011;24:24–32.

    Article  PubMed  CAS  Google Scholar 

  18. Videen JS, Mezger MS, Chang YM, O’Connor DT. Calcium and catecholamine interactions with adrenal chromogranins. Comparison of driving forces in binding and aggregation. J Biol Chem. 1992;267:3066–73.

    PubMed  CAS  Google Scholar 

  19. Kim T, Tao-Cheng JH, Eiden LE, Loh YP. Chromogranin A, an “on/off” switch controlling dense-core secretory granule biogenesis. Cell. 2001;106:499–509.

    Article  PubMed  CAS  Google Scholar 

  20. Mahapatra NR, O’Connor DT, Vaingankar SM, et al. Hypertension from targeted ablation of chromogranin A can be rescued by the human ortholog. J Clin Invest. 2005;115:1942–52.

    Article  PubMed  CAS  Google Scholar 

  21. O’Connor DT. Plasma chromogranin A. Initial studies in human hypertension. Hypertension. 1985;7:I76–9.

    PubMed  Google Scholar 

  22. Takiyyuddin MA, Parmer RJ, Kailasam MT, et al. Chromogranin A in human hypertension. Influence of heredity. Hypertension. 1995;26:213–20.

    PubMed  CAS  Google Scholar 

  23. Chen Y, Rao F, Rodriguez-Flores JL, et al. Naturally occurring human genetic variation in the 3'-untranslated region of the secretory protein chromogranin A is associated with autonomic blood pressure regulation and hypertension in a sex-dependent fashion. J Am Coll Cardiol. 2008;52:1468–81.

    Article  PubMed  CAS  Google Scholar 

  24. Salem RM, Cadman PE, Chen Y, et al. Chromogranin A polymorphisms are associated with hypertensive renal disease. J Am Soc Nephrol. 2008;19:600–14.

    Article  PubMed  CAS  Google Scholar 

  25. Grobecker G, Roizen MF, Weise V, Saavedra JM, Kopin IJ. Letter: sympathoadrenal medullary activity in young, spontaneously hypertensive rats. Nature. 1975;258:267–8.

    Article  PubMed  CAS  Google Scholar 

  26. Jirout ML, Friese RS, Mahapatra NR, et al. Genetic regulation of catecholamine synthesis, storage and secretion in the spontaneously hypertensive rat. Hum Mol Genet. 2010;19:2567–80.

    Article  PubMed  CAS  Google Scholar 

  27. Vaingankar SM, Li Y, Corti A, et al. Long human CHGA flanking chromosome 14 sequence required for optimal BAC transgenic “rescue” of disease phenotypes in the mouse Chga knockout. Physiol Genomics. 2010;41:91–101.

    Article  PubMed  CAS  Google Scholar 

  28. Vaingankar SM, Li Y, Biswas N, et al. Effects of chromogranin A deficiency and excess in vivo: biphasic blood pressure and catecholamine responses. J Hypertens. 2010;28:817–25.

    Article  PubMed  CAS  Google Scholar 

  29. Helle KB, Corti A, Metz-Boutigue MH, Tota B. The endocrine role for chromogranin A: a prohormone for peptides with regulatory properties. Cell Mol Life Sci. 2007;64:2863–86.

    Article  PubMed  CAS  Google Scholar 

  30. Mahata SK, O’Connor DT, Mahata M, et al. Novel autocrine feedback control of catecholamine release. A discrete chromogranin a fragment is a noncompetitive nicotinic cholinergic antagonist. J Clin Invest. 1997;100:1623–33.

    Article  PubMed  CAS  Google Scholar 

  31. O’Connor DT, Kailasam MT, Kennedy BP, et al. Early decline in the catecholamine release-inhibitory peptide catestatin in humans at genetic risk of hypertension. J Hypertens. 2002;20:1335–45.

    Article  PubMed  Google Scholar 

  32. Dev NB, Gayen JR, O’Connor DT, Mahata SK. Chromogranin A and the autonomic system: decomposition of heart rate variability and rescue by its catestatin fragment. Endocrinology. 2010;151:2760–8.

    Article  PubMed  CAS  Google Scholar 

  33. Rao F, Wen G, Gayen JR, et al. Catecholamine release-inhibitory peptide catestatin (chromogranin A (352-372)): naturally occurring amino acid variant Gly364Ser causes profound changes in human autonomic activity and alters risk for hypertension. Circulation. 2007;115:2271–81.

    Article  PubMed  CAS  Google Scholar 

  34. Fung MM, Salem RM, Mehtani P, et al. Direct vasoactive effects of the chromogranin A (CHGA) peptide catestatin in humans in vivo. Clin Exp Hypertens. 2010;2010(32):278–87.

    Article  Google Scholar 

  35. Gill BM, Barbosa JA, Dinh TQ, Garrod S, O’Connor DT. Chromogranin B: isolation from pheochromocytoma, N-terminal sequence, tissue distribution and secretory vesicle processing. Regul Peptides. 1991;33:223–35.

    Article  CAS  Google Scholar 

  36. Zhang K, Rao F, Rana BK, et al. Autonomic function in hypertension; role of genetic variation at the catecholamine storage vesicle protein chromogranin B. Circ Cardiovasc Genet. 2009;2:46–56.

    Article  PubMed  CAS  Google Scholar 

  37. • Zhang K, Rao F, Wang L et al. Common functional genetic variants in catecholamine storage vesicle protein promoter motifs interact to trigger systemic hypertension. J Am Coll Cardiol 2010, 55:1463–75. This study illustrates that functionally significant SNPs in the CHGB promoter influence blood pressure in both European and African populations.

    Article  PubMed  CAS  Google Scholar 

  38. Flockerzi V. An introduction on TRP channels. Handbook Exp Pharmacol. 2007;179:1–19.

    Article  CAS  Google Scholar 

  39. Nilius B. TRP channels in disease. Biochimica Biophys Acta. 2007;1772:805–12.

    CAS  Google Scholar 

  40. •• Mathar I, Vennekens R, Meissner M et al. Increased catecholamine secretion contributes to hypertension in TRPM4-deficient mice. J Clin Invest 2010, 120:3267–79. This elegant study identified in mice a novel gene that plays a role in hypertension with increased sympathetic tone.

    Article  PubMed  CAS  Google Scholar 

  41. Lambert E, Lambert G. Stress and its role in sympathetic nervous system activation in hypertension and the metabolic syndrome. Curr Hypertens Rep. 2011;2:327–34.

    Google Scholar 

  42. Grassi G. Assessment of sympathetic cardiovascular drive in human hypertension: achievements and perspectives. Hypertension. 2009;54:690–7.

    Article  PubMed  CAS  Google Scholar 

  43. Grassi G. Sympathetic neural activity in hypertension and related diseases. Am J Hypertens. 2010;23:1052–60.

    Article  PubMed  Google Scholar 

  44. Greenfield JR, Miller JW, Keogh JM, et al. Modulation of blood pressure by central melanocortinergic pathways. N Engl J Med. 2009;2009(360):44–52.

    Article  Google Scholar 

  45. Ni XP, Butler AA, Cone RD, Humphreys MH. Central receptors mediating the cardiovascular actions of melanocyte stimulating hormones. J Hypertens. 2006;24:2239–46.

    Article  PubMed  CAS  Google Scholar 

  46. Grassi G, Padmanabhan S, Menni C, et al. Association between ADRA1A gene and the metabolic syndrome: candidate genes and functional counterpart in the PAMELA population. J Hypertens. 2011;29:1121–7.

    Article  PubMed  CAS  Google Scholar 

  47. Wirtz PH, Ehlert U, Bartschi C, Redwine LS, von Kanel R. Changes in plasma lipids with psychosocial stress are related to hypertension status and the norepinephrine stress response. Metabolism. 2009;58:30–7.

    Article  PubMed  CAS  Google Scholar 

  48. Grassi G, Seravalle G, Quarti-Trevano F. The ‘neuroadrenergic hypothesis’ in hypertension: current evidence. Exp Physiol. 2010;95:581–6.

    Article  PubMed  Google Scholar 

  49. Levick SP, Murray DB, Janicki JS, Brower GL. Sympathetic nervous system modulation of inflammation and remodeling in the hypertensive heart. Hypertension. 2010;55:270–6.

    Article  PubMed  CAS  Google Scholar 

  50. Li G, Xu J, Wang P, Velazquez H, et al. Catecholamines regulate the activity, secretion, and synthesis of renalase. Circulation. 2008;117:1277–82.

    Article  PubMed  CAS  Google Scholar 

  51. Krum H, Schlaich M, Whitbourn R, et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet. 2009;373:1275–81.

    Article  PubMed  Google Scholar 

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Disclosure

Conflicts of Interest: G. Currie: none; E.M. Freel: none; C.G. Perry: none; A. Dominiczak: payment for manuscript preparation from Servier International.

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Authors and Affiliations

  1. Department of Endocrinology, Western Infirmary, Glasgow, G11 6NT, UK

    Gemma Currie & Colin G. Perry

  2. Institute of Cardiovascular and Medical Sciences, University of Glasgow, 126 University Place, Glasgow, G12 8TA, UK

    E. Marie Freel

  3. College of Medical, Veterinary and Life Sciences, University of Glasgow, Wolfson Medical School Building, University Avenue, Glasgow, G128QQ, UK

    Anna F. Dominiczak

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  1. Gemma Currie
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  2. E. Marie Freel
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  3. Colin G. Perry
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  4. Anna F. Dominiczak
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Correspondence to Anna F. Dominiczak.

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Currie, G., Freel, E.M., Perry, C.G. et al. Disorders of Blood Pressure Regulation—Role of Catecholamine Biosynthesis, Release, and Metabolism. Curr Hypertens Rep 14, 38–45 (2012). https://doi.org/10.1007/s11906-011-0239-2

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