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Kidney, Sodium, Renin-Angiotensin System Renovascular Hypertension

Kidney, Sodium, Renin-Angiotensin System Renovascular Hypertension. Andreas Pittaras MD. Anatomy and Physiology. The juxtaglomerular apparatus. 5' flanking region of the renin gene. Pathway of active renin in the juxtaglomerular cell. Renin mRNA accumulation in the juxtaglomerular cells.

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Kidney, Sodium, Renin-Angiotensin System Renovascular Hypertension

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  1. Kidney, Sodium, Renin-Angiotensin System Renovascular Hypertension Andreas Pittaras MD

  2. Anatomy and Physiology

  3. The juxtaglomerular apparatus

  4. 5' flanking region of the renin gene

  5. Pathway of active renin in the juxtaglomerular cell

  6. Renin mRNA accumulation in the juxtaglomerular cells

  7. Renin protein in the juxtaglomerular cells of the afferent arteriole

  8. Major mechanisms governing renin release • Individual nephron signals •   Low macula densa sodium chloride (stimulates) •   Decreased afferent arteriolar pressure (stimulates) • Whole kidney modulating signals • Angiotensin II negative feedback (inhibits) •   β-1 receptor stimulation (stimulates) •    Other humoral factors         Vasopressin (inhibits) •          Atrial natriuretic peptide (inhibits) •          Dopamine DA-1 receptor (stimulates) • Local effectors •    Prostaglandins (stimulate) •    Nitric oxide (inhibits) •    Adenosine (inhibits) •    Kinins (stimulate)

  9. Physiologic stimulation of renin release PHYSIOLOGYPHARMACOLOGY Blood pressureAntihypertensive agents Fluid volumeStimulators      Sodium intakeRenin-angiotensin blockade      HydrationDiuretics      DiureticsVasodilators      Menstrual cycleSuppressors      Diurnal changesβ-Adrenergic blockers PostureCentral α2-adrenergic agonists Potassium intakeNeutral Protein intakeCalcium antagonists

  10. In situ hybridization histochemistry of rat kidney

  11. Immunohistochemistry of a section of rat kidney

  12. Plasma renin activity in human subjects

  13. Analysis of human genomic DNA

  14. The renin-angiotensin system

  15. Angiotensinogen in the proximal tubular cells

  16. The human angiotensin-converting enzyme gene

  17. Angiotensin-converting enzyme (ACE)

  18. Actions of ACE

  19. Metabolism of the angiotensin peptides

  20. Half-life of renin and angiotensin Metabolism of the renin-angiotensin system COMPONENTHALF-LIFE IN CIRCULATIONDEGRADING ENZYME(S) Renin15 -20 min - Angiotensinogen4 -16 HRenin Angiotensin I1 -2 minAngiotensin-converting enzyme Angiotensin IISecondsAminopeptidase A, Εndopeptidase, Ρrolylcarboxypeptidase

  21. Angiotensin peptides and receptor subtypes that interact with each peptide RECEPTORANGIOTENSIN NoneAngiotensinogen Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Asn-Glu Renin NoneAngiotensin I NH2-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-COOH Angiotensin-converting enzyme AT1, AT2Angiotensin II Asp-Arg-Val-Tyr-Ile-His-Pro-Phe Angiotensinases AT1, AT2Angiotensin III Arg-Val-Tyr-Ile-His-Pro-Phe Angiotensinases UnknownAngiotensin (1-7) Asp-Arg-Val-Tyr-Ile-His-Pro Angiotensinases AT4Angiotensin (3-7) Val-Tyr-Ile-His-Pro

  22. Heterogeneity in the angiotensin II receptor population Classification criteria of angiotensin receptor subtypes AT1AT2 Potency orderAngiotensin II > angiotensin IIIAngiotensin II =angiotensin III Selective antagonistsILosartanPD 123177 (Parke-Davis, NJ) PD 123319 (Parke-Davis) ValsartanCGP 42112A (Novartis) Eprosartan Zorsartan Irbesartan Candesartan Telmisartan Tasosartan Effector pathwaysPhospholipase CGuanylate cyclase Phospholipase D Adenylate cyclase Sensitivity to dithiothreitol (sulfhydryl-reducing agents)BindingBinding AffinityNo change Effect of GppNHpHill coefficient to no Change ~1

  23. The AT1 receptor

  24. mRNA for the angiotensin AT1 receptor

  25. The angiotensin subtype-2 (AT2) receptor

  26. Signal transduction mechanisms for the AT2 receptor

  27. Renal effects of angiotensin subtype-2 receptor • Release of bradykinin, nitric oxide, and cGMP • Cell differentiation • Antiproliferation • Apoptosis • Vasodilation

  28. Blocking the AT1 receptor with valsartan

  29. Combining benazepril and valsartan

  30. Renal tissue localization of angiotensin II receptors

  31. Cellular action of angiotensin II

  32. Effects of angiotensin II

  33. Renal effects of angiotensin II • Decreased renal blood flow • Proportionately increased efferent arteriolar resistanceincreased glomerular capillary hydrostatic pressure  increased filtration • Glomerular mesangial cell contraction  decreased glomerular capillary surface area available for filtration  decreased filtration (offsets above effect) • Decreased medullary blood flow • Increased tubular sodium reabsorption  sodium retention

  34. Paracrine effects of angiotensin II

  35. Pathophysiology

  36. Circulating components of the renin-angiotensin system

  37. Mechanisms involved in renovascular hypertension

  38. Animal models of renovascular hypertension

  39. Administration of an angiotensin II inhibitor

  40. Sodium dependency in the animal model

  41. Renovascular Hypertension

  42. Causes of renal artery stenosis • Clinical clues suggesting renovascular hypertension • Systolic/diastolic epigastric, subcostal, or flank bruit • Accelerated or malignant hypertension (HTN) • Unilateral small kidney discovered by any clinical study • Severe HTN in child or young adult, or after age 50 y • Sudden development or worsening of HTN at any age • HTN and unexplained impairment of renal function • Sudden worsening of renal function in hypertensive patient • Hypertension refractory to appropriate three-drug regimen • Impairment in renal function in response to ACE inhibitor • Extensive occlusive disease in coronary, cerebral, and peripheral circulation

  43. Work-up for renovascular hypertension

  44. Diagnostic indicators for renovascular hypertension Diagnostic studies for renovascular hypertension • SENSITIVITY, %SPECIFICITY, % • Rapid sequence IVP7486 • Isotope renography 9395 • with ACE inhibitiontest • Peripheral vein PRA with 7489 • ACE inhibition test (captopril test) • Renal vein ratio of PRA test • (stenotic/contralateral): • >1.38540 • >1.97860 • Peripheral vein PRA9296 • Intravenous digital 8889 • subtraction angiography • Doppler ultrasonography8693 • MRI9795 • Renal artery angiography100100

  45. The captopril test • Criteria for renovascular hypertension • Stimulated PRA of 12 ng/mL/h • Absolute increase in PRA of  10 ng/mL/h • Increase in plasma renin activity PRA of  150% or  400% if baseline PRA is <3 ng/mL/h

  46. Plasma renin response to captopril

  47. Objectives in the management of renovascular hypertension Outcome after angioplasty or surgery for renal artery stenosis ETIOLOGYATHEROMAFIBROMUSCULAR DYSPLASIA TreatmentAngioplastySurgeryAngioplastySurgery Patients3911310175486 BP response Cured19455064 ( 56- 81) Improved52294223 ( 5 -40) Failed3024911 ( 0 -25)

  48. Selective renal arteriogram of a 43-year-old nonsmoking male

  49. Selective renal arteriogram of a 31-year-old female

  50. Renal arteriogram of a 31-year-old female

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