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  • Review Article
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Review Article

Calcium channel blockers, postural vasoconstriction and dependent oedema in essential hypertension

Abstract

Treatment with calcium channel blocker (CCB)s, dihydropyridines and others, is frequently complicated by dependent oedema in the absence of sodium retention or cardiac failure, a bothersome side effect of unclear aetiology. The present paper reviews our own and other work dealing with the antagonism exerted by such drugs on postural vasoconstriction, a mechanism triggered by limb venous congestion during orthostasis and controlled through a local sympathetic axo-axonic reflex and increased myogenic tone in response to changes in transmural pressure. By stabilising capillary pressure, postural vasoconstriction counteracts fluid hyperfiltration consequent to gravitational stimuli, and consistent evidence shows attenuation of this response by L-type calcium channel blockers. Interference with the postural reflex control of skin blood flow may therefore contribute to dependent oedema, although cannot entirely explain its development. Attenuation of postural vasoconstriction may amplify the fluid hyperfiltration induced by CCBs through other mechanisms, such as imbalanced intracapillary pressure or enhanced vascular permeability, which are the main factors determining net fluid filtration into the interstitial compartment.

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References

  1. Opie LH Calcium channel antagonists. Part IV: Side effects and contraindications, interactions and combinations Cardiovasc Drugs Ther 1988 2 177–189

    Article  CAS  PubMed  Google Scholar 

  2. Subramanian VB Calcium antagonists in chronic stable angina pectoris Excerpta Medica: Amsterdam 1983 pp 97–116 152–156 217–229

    Google Scholar 

  3. Nilsson P, Lindholm LH, Hedner T The Diltiazem Different Doses Study – a dose-response study of once-daily diltiazem therapy for hypertension J Cardiovasc Pharmacol 1996 27 469–475

    Article  CAS  PubMed  Google Scholar 

  4. van Hamersvelt HW et alOedema formation with the vasodilators nifedipine and diazoxide: direct local effect or sodium retention? J Hypertens 1996 14 1041–1045

    Article  CAS  PubMed  Google Scholar 

  5. Guyton AC Capillary dynamics, and exchange of fluid between the blood and interstitial fluid In: Textbook of Medical Physiology Sixth Edition. WB Saunders Co: Philadelphia, London, Toronto 1981, Chapter 30 pp 358–369

    Google Scholar 

  6. Mahy IR, Tooke JE, Shore AC Capillary pressure during and after incremental venous pressure elevation in man J Physiol 1995 485 213–219

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Henriksen O Local sympathetic reflex mechanism in regulation of blood flow in human subcutaneous adipose tissue Acta Physiol Scand 1977 Suppl 450 1–48

    Google Scholar 

  8. Henriksen O, Paaske WP Local regulation of blood flow in peripheral tissue Acta Chir Scand 1980 502 63–74

    CAS  Google Scholar 

  9. Henriksen O, Sejrsen P, Paaske WP, Eickhoff JH Effect of chronic sympathetic denervation upon the transcapillary filtration rate induced by venous stasis Acta Physiol Scand 1983 117 171–176

    Article  CAS  PubMed  Google Scholar 

  10. Hassan AA, Tooke JE Mechanism of the postural vasoconstrictor response in the human foot Clin Sci 1988 75 379–387

    Article  CAS  Google Scholar 

  11. Mellander S, Oberg B, Odelram H Vascular adjustments to increased transmural pressure in cat and man with special reference to shifts in capillary fluid transfer Acta Physiol Scand 1964 61 34–48

    Article  CAS  PubMed  Google Scholar 

  12. Davis MJ, Hill MA Signaling mechanisms underlying the vascular myogenic response Physiol Rev 1999 79 387–423

    Article  CAS  PubMed  Google Scholar 

  13. Noddeland H, Aukland K, Nicolaysen G Plasma colloid osmotic pressure in venous blood from the human foot in orthostasis Acta Physiol Scand 1981 113 447–454

    Article  CAS  PubMed  Google Scholar 

  14. Michel CC, Curry FE Microvascular permeability Physiol Rev 1999 79 703–761

    Article  CAS  PubMed  Google Scholar 

  15. Zweifach BW, Lipowsky HH Pressure-flow relations in blood and lymph microcirculation In: Handbook of Physiology. The Cardiovascular System vol 4, Part 1 1987, Chapter 7 pp 251–308

    Google Scholar 

  16. Popoff N The digital vascular system Arch Pathol 1934 18 295–330

    Google Scholar 

  17. Hales JR, Jessen C, Fawcett AA, King RB Skin AVA and capillary dilatation and constriction induced by local skin heating Pflugers Arch 1985 404 203–207

    Article  CAS  PubMed  Google Scholar 

  18. Hassan AAK, Rayman G, Tooke JE Effect of indirect heating on the postural control of skin blood flow in the human foot Clin Sci 1986 70 577–582

    Article  CAS  Google Scholar 

  19. Braverman IM The cutaneous microcirculation: ultrastructure and microanatomical organization Microcirculation 1997 4 329–340

    Article  CAS  PubMed  Google Scholar 

  20. Stern MD In vivo evaluation of microcirculation by coherent light scattering Nature 1975 254 56–58

    Article  CAS  PubMed  Google Scholar 

  21. Nilsson GE, Tenland T, Oberg PA Evaluation of a laser Doppler flowmeter for measurement of tissue blood flow IEEE Trans Biomed Eng 1980 27 597–604

    Article  CAS  PubMed  Google Scholar 

  22. Low C et alEvaluation of skin vasomotor reflexes by using laser Doppler velocimetry Mayo Clinic Proc 1983 58 583–592

    CAS  Google Scholar 

  23. Rayman G, Hassan A, Tooke JE Blood flow in the skin of the foot related to posture in diabetes mellitus Br Med J 1986 292 87–90

    Article  CAS  Google Scholar 

  24. Iabichella ML, Dell’Omo G, Melillo E, Pedrinelli R Calcium channel blockers blunt postural cutaneous vasoconstriction in hypertensivepatients Hypertension 1997 29 931–937

    Article  Google Scholar 

  25. Pedrinelli R, Tarazi RC Interference of calcium entry blockade in vivo with pressor responses to alpha-adrenergic stimulation: effects of two unrelated blockers on responses to both exogenous and endogenously released norepinephrine Circulation 1984 69 1171–1178

    Article  CAS  PubMed  Google Scholar 

  26. Pedrinelli R, Tarazi RC Calcium entry blockade by nitrendipine and alpha-adrenergic responsiveness in vivo. Comparison with non calcium entry blocker vasodilators in absence and presence of Phenoxybenzamine pre-treatment J Pharmacol Exp Therap 1985 233 636–642

    CAS  Google Scholar 

  27. Pedrinelli R, Salvetti A Heterogeneity of calcium entry blockers and adrenergic vascular responsiveness in forearm arterioles of hypertensivepatients Am Heart J 1991 122 342–351

    Article  CAS  PubMed  Google Scholar 

  28. Minneman KP α1-Adrenergic receptor subtypes, inositol phosphates, and sources of cell Ca++ Pharmacol Rev 1988 40 87–119

    CAS  PubMed  Google Scholar 

  29. Fleckenstein A Specific pharmacology of calcium in myocardium, cardiac pacemakers and vascular smooth muscle Ann Rev Pharmacol Toxicol 1977 17 149–166

    Article  CAS  Google Scholar 

  30. Burges RA, Dodd MG, Gardiner DG Pharmacologic profile of amlodipine Am J Cardiol 1989 64 10I–18I

    Article  CAS  PubMed  Google Scholar 

  31. Pedrinelli R, Dell’Omo G, Melillo E, Mariani M Amlodipine, enalapril and dependent leg edema in hypertension Hypertension 2000 35 621–625

    Article  CAS  PubMed  Google Scholar 

  32. Gustafsson D et alMicrovascular effects and oedema formation of felodipine in man J Hypertens 1989 7 S161–S167

    CAS  Google Scholar 

  33. Williams SA, Rayman G, Tooke JE Dependent oedema and attenuation of postural vasoconstriction associated with nifedipine therapy for hypertension in diabeticpatients Eur J Clin Pharmacol 1989 37 333–335

    Article  CAS  PubMed  Google Scholar 

  34. Salmasi A, Belcaro G, Nicolaides AN Impaired venoarteriolar reflex as a positive cause for nifedipine induced ankle oedema Int J Cardiol 1991 30 303–307

    Article  CAS  PubMed  Google Scholar 

  35. Glossmann H et alInteraction between calcium channel ligands and calcium channels Circ Res 1987 61 I30–I36

    CAS  PubMed  Google Scholar 

  36. Alabaster VA, Davey MJ The α1-adrenoceptor antagonist profile of doxazosin: preclinical pharmacology Br J Clin Pharmacol 1986 21 9s–17s

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Gustafsson D, Grande PO, Borgstrom P, Lindberg L Effects of calcium antagonists on myogenic and neurogenic control of resistance and capacitance vessels in cat skeletal muscle J Cardiovasc Pharmacol 1988 12 413–422

    Article  CAS  PubMed  Google Scholar 

  38. Nelson EB et alClinical profile of the first Angiotensin II (AT-1 Specific) receptor antagonists. In: Laragh JH. Brenner BM (eds) Hypertension: Pathophysiology, Diagnosis and Management, Second Edition Raven Press Ltd: New York 1995, Chapter 17 pp 2895–2916

    Google Scholar 

  39. Davies RO, Gomez HJ, Irvin JD, Walker JF An overview of the clinical pharmacology of enalapril Br J Clin Pharmacol 1984 18 (Suppl 2) 215S–229S

    Article  Google Scholar 

  40. Fleming JT, Parekh N, Steinhausen M Calcium antagonists preferentially dilate preglomerular vessels of hydronephrotic kidney Am J Physiol 1987 253 F1157–F1163

    CAS  PubMed  Google Scholar 

  41. Gradman AH et alCombined enalapril and felodipine extended relase (ER) for systemic hypertension. Enalapril-Felodipine ER. Factorial Study Group Am J Cardiol 1997 79 431–435

    Article  CAS  PubMed  Google Scholar 

  42. Guazzi MD et alCalcium-channel blockade with nifedipine and angiotensin converting-enzyme inhibition with captopril in the therapy ofpatients with severe primary hypertension Circulation 1984 70 279–284

    Article  CAS  PubMed  Google Scholar 

  43. Valentin JP, Nafrialdi N, Ribstein J, Mimran A Endogenous angiotensin II but not atrial natriuretic peptide modulates the effect of nicardipine on extracellular fluid partition J Hypertens 1993 11 961–967

    Article  CAS  PubMed  Google Scholar 

  44. Loutzenhiser RD, Epstein M, Fischetti F, Horton C Effects of amlodipine on renal hemodynamics Am J Cardiol 1989 64 122I–127I

    Article  CAS  PubMed  Google Scholar 

  45. Abrams WB, Davies RO, Ferguson RK Overview: the role of angiotensin-converting enzyme inhibitors in cardiovascular therapy Fed Proc 1984 43 1314–1321

    CAS  PubMed  Google Scholar 

  46. Taherzadeh M, Das AK, Warren JB Nifedipine increases microvascular permeability via a direct local effect on postcapillary venules Am J Physiol 1998 275 H1388–H1394

    CAS  PubMed  Google Scholar 

  47. Taherzadeh M, Warren JB Comparison of diltiazem and verapamil on rat microvascular permeability Microvasc Res 1997 54 206–213

    Article  CAS  PubMed  Google Scholar 

  48. Valentin JP, Ribstein J, Mimran A Effect of nicardipine and atriopeptin on transcapillary shift of fluid and proteins Am J Physiol 1989 257 R174–R179

    Article  CAS  PubMed  Google Scholar 

  49. Valentin JP, Ribstein J, Halimi JM, Mimran A Effect of different calcium antagonists on transcapillary fluid shift Am J Hypertens 1990 3 491–495

    Article  CAS  PubMed  Google Scholar 

  50. Hulthen UL et alVascular hypertrophy and albumin permeability in a rat model combining hypertension and diabetes mellitus. Effects of calcium antagonism, angiotensin converting enzyme inhibition, and angiotensin II-ATI-receptor Am J Hypertens 1996 9 895–901

    Article  CAS  PubMed  Google Scholar 

  51. Takayama Y, Ichikawa S, Sakamaki T, Murata K Increase in hematocrit by nifedipine in hypertensivepatients Tohoku J Exp Med 1990 161 251–252

    Article  CAS  PubMed  Google Scholar 

  52. Prigogine T et alAcute nonhemodynamic pulmonary edema with nifedipine in primary pulmonary hypertension Chest 1991 100 563–564

    Article  CAS  PubMed  Google Scholar 

  53. Silverstone PH Periorbital oedema caused by nifedipine (Abstract) Br Med J 1984 288 1654

    Article  Google Scholar 

  54. Friedland S, Kaplan S, Lahav M, Shapiro A Proptosis and periorbital edema due to diltiazem treatment Arch Ophthalmol 1993 111 1027–1028

    Article  CAS  PubMed  Google Scholar 

  55. Rayman G, Williams SA, Gamble J, Tooke JE A study of factors governing fluid filtration in the diabetic foot Eur J Clin Invest 1994 24 830–836

    Article  CAS  PubMed  Google Scholar 

  56. Morgan RH et alPostural changes in femoral artery blood flow in normal subjects,patients with peripheral vascular occlusive disease andpatients undergoing lumbar sympathectomy, measured by duplex ultrasound flowmetry Eur J Vasc Surg 1992 6 408–415

    Article  CAS  PubMed  Google Scholar 

  57. Clozel JP, Ertel EA, Ertel SI Voltage-gated T-type Ca2+ channels and heart failure Proc Assoc Am Physicians 1999 111 429–437

    Article  CAS  PubMed  Google Scholar 

  58. Noll G, Luscher TF Comparative pharmacological properties among calcium channel blockers: T-channel versus L-channel blockade Cardiology 1998 89(Suppl) 10–15

    Article  Google Scholar 

  59. Sabbatini M et alEffect of calcium antagonists on glomerular arterioles in spontaneously hypertensive rats Hypertension 2000 35 775–779

    Article  CAS  PubMed  Google Scholar 

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Pedrinelli, R., Dell’Omo, G. & Mariani, M. Calcium channel blockers, postural vasoconstriction and dependent oedema in essential hypertension. J Hum Hypertens 15, 455–461 (2001). https://doi.org/10.1038/sj.jhh.1001201

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