Blood pressure and the renin-angiotensin - PowerPoint Presentation

1. Blood pressure and the renin-angiotensin systemDr Nish ArulkumaranSpR and Clinical Research fellowImperial College LondonGEP – Renal, Feb2012

2. Systolic and Diastolic pressureHeart cycle = systole and diastoleSystole = ventricular contraction = ejection Diastole = ventricular relaxation = fillingVessel cycle = distension and relaxationnatural variations from one heartbeat to anotherSystolic pressure is peak pressure in the arteries immediately after the beginning of the cardiac systole Diastolic pressure is minimum pressure in the arteries following the end of systole

3. Blood pressure (BP)BP is the force exerted by circulating blood on the walls of blood vesselsBlood flow (Q) = ∆Pressure/ResistanceDistensible vessel wall: Accumulation of potential energy Release of potential energy Pulsatile flow

4. Pressure waveElastic large arteries (aorta, iliacs etc) are stretched as systolic wave passesAs they return to resting diameter, energy is returned to the circulationThis tends to decrease systolic and increase diastolic pressuresPressure

5. Arterial StiffnessDiabetes, hypertension, atherosclerosis and renal failure all result in arteries becoming calcified Less elastic:Systolic pressure increasesDiastolic pressure decreasesPulse pressure = Systolic-diastolic pressuresCoronary arteries fill in diastole

6. Measurement of arterial BP BP measurement - In everyday clinical practice peripheral Non-invasive – brachial cuff Central – aortic Peripheral – subaortic (brachial, radial, femoral)Invasive – arterial line

7. Normal valuesCategorysystolic, mmHgdiastolic, mmHgHypotension< 90or < 60 Normal90 – 119and 60 – 79Pre-hypertension120 – 139or 80 – 89Stage 1 Hypertension140 – 159or 90 – 99Stage 2 Hypertension≥ 160or ≥ 100British Hypertension Society Guidelines, NICE guidelines

8. Hypertension

9. Why is hypertension bad?Risk factor for stroke, renal failure and heart diseaseDamaging to endotheliumIncreased shear stress damages cells (inflammation)Arterioles become more muscular and multilayeredOxygen delivery impairedEnd organs become scarred – sometimes with microhaemorrhagesCauses left ventricular hypertrophyIn the setting of abnormal arterioles/capillaries this increases risk of infarction and heart failure

10. Control of blood pressureCardiac outputFilling (ie central venous) pressureHeart rate and contractilityResponds rapidly to increased metabolic demandAutonomic nervous systemVasomotor tone/ Systemic vascular resistanceRapid changes mediated by autonomic systemLonger term changes mediated by vasoactive hormonesBlood volumeIntravascular salt and water loadSalt/water intakeThirst/dietSalt/water excretionRegulated by the kidneysSympathetic tone and vasoactive hormones

11. Blood pressure regulation

12. Blood pressure and the kidneyAutoregulatory mechanisms maintain constant renal blood flowKey component is the renin-angiotensin system (RAS)RAS is activated when renal perfusion/function is impairedShockRenal artery stenosisIntrinsic renal diseases: diabetes, glomerulonephritis

13. Bradykinin

14. Angiotensinogen452-amino acid proteinΑ2-globulin member of the serpin familyNo enzymatic activityProduced constitutively by the liver and released into the circulationSubstrate for cleavage by RENINProduced by the juxtaglomerular apparatus in response to reduced salt delivery to nephronCleavage releases N-terminal 12-amino acidsThis peptide is known as ANGIOTENSIN I

15. Angiotensin I12-amino acid peptideProduced by cleavage of angiotensinogen by reninNo intrinsic activitySubstrate for ANGIOTENSIN CONVERTING ENZYME (ACE)ACE is made by the pulmonary and renal endotheliumCleavage by ACE produces the 10-amino acid peptide ANGIOTENSIN II – the active hormoneACE also breaks down bradykinin

16. Angiotensin II10-amino acid peptideHost of actionsAll tend to INCREASE blood pressureIncreased salt and water intake and retentionPowerful vasoconstrictorProtects GFRCleaved by angiotensinases located in red blood cells to form less active cleavage productsHalf life is ~30s in the circulation

17. Actions of Angiotensin IISystemic VasoconstrictionIncreases blood pressureRenal vasoconstriction Efferent>afferent arterioleProtects glomerular filtration pressureReduces medullary blood flow – reducing hydrostatic pressure in pericapillary tubulesSalt retentionStimulates proximal tubular Na+/H+ exchangeStimulates aldosterone release from adrenal glandWater retention and thirstStimulates release of ADH from pituitary

18. Angiotensin IIIAngiotensin III has 40% of the pressor activity of angiotensin II but has 100% of the aldosterone- producing activity

19. AldosteroneAldosterone is synthesized in the zona glomerulosa of the adrenal cortex Aldosterone is produced in response to an increase in the plasma concentration of Angiotensin III, angiotensin II, ACTH, and K+ Aldosterone exerts its effects via the mineralocorticoid receptor (MR) and the resultant activation of specific amiloride-sensitive sodium channels (ENaC) and the Na-K ATP-ase pump.This results in reabsorption of sodium (Na+) ions and water (which follows sodium) into the blood, and secreting potassium (K+) ions into the urine (lumen of collecting duct).

20. Renin-angiotensin systemActive hormone is angiotensin IIProduction regulated by renin release from the JGARequires ACE – produced in the lungs etcActs to maximise glomerular filtration pressureVasoconstriction: Systemic and renal (efferent>afferent arterioles)Proximal sodium resorptionDistal sodium resorption (aldosterone)Water resorption and thirst (ADH)

21. Drugs and the RASb-blockers (usually end in -olol)Renin release is increased by sympathetic stimulationRenin inhibitor (Aliskiren)Blocks cleavage of angiotensinogen by reninAngiotensin Converting Enzyme Inhibitors (ACEIs)End in “-pril”Block production of angiotensin IIAlso inhibit breakdown of bradykinin (dry cough)Angiotensin II receptor blockers End in “-sartan”Block vasoconstriction and release of aldosterone/ADHSpironolactoneAntagonises aldosterone – ie downstream of RAS

22. When to block RASHypertension from any causeHeart failureIntrinsic renal disease (PROTEINURIA)Commonly associated with intraglomerular hypertensionAll proteinuric patients should be on ACEI/ARB unless contraindicatedRenovascular disease (renal artery stenosis)

23. Drugs and autoregulationAngiotensin IIGlomerular filtration pressurePGE2PGE2ACEIsNSAIDs

24. When NOT to block RASAcute illness/haemodynamic stressGFR critically dependent on RAS when haemodynamics are compromisedRAS blockade will reduce GFR by up to 15%If renal function very poor RAS blockade can precipitate need for dialysisHyperkalaemiaReduced aldosterone will impair K+ excretionPersistent cough with ACEI -> ARB

25. Renovascular diseaseConstricted renal artery: poor perfusion Aorta desc.V. CavaRenal arteryRenal veinUreterAdrenalKidneyUnilateralBilateralTissue ischaemia RAS activationSalt/water retention and vasoconstrictionHypertension

26. Renovascular disease and the RASRAS activation is a major consequence of renovascular diseasePrimary mechanism for hypertensionHypertension leads to StrokeHeart failureKidney failureMost effectively treated with RAS blockadeWILL RESULT IN SHORT TERM REDUCTION OF GFRIf renal function very poor may -> ESRFBetter long term renal outcomes if tolerated

27. RAS blockade in clinical practiceGood trial evidence in:Diabetic renal disease (microalbuminuria)HypertensionLeft ventricular failureCoronary artery diseaseProteinuric renal diseaseChronic renal impairmentPatients with heart failure, hypertension or renal disease (especially diabetes) should be on ACEIs/ARBs unless contraindicated

28. Hypertension is endemicCommonest causes of morbidity and mortality in the Western world results from or is exacerbated by hypertension‘Essential’ hypertension: salt-rich lifestyleAtherosclerosisCerebrovascular diseaseHeart failureKidney failurePeripheral vascular diseaseIn diabetes, tight blood pressure control has at least the clinical benefit of tight sugar control (UK PDS, 1998)

29. Mechanisms of hypertensionMany mechanisms contribute to essential hypertensionGeneticDiet (Salt)BMIExerciseETOHAgeSmokingEtc., etc……90- 95% of patients with hypertension have essential hypertension

30. 5- 10% of patients have ‘secondary’ hypertensionRenal disease is the commonest cause of secondary hypertensionEndocrine disorders:CushingsPheochromocytomaHyperaldosteronismThyrotoxicosisVascular disorders:Aortic coarctationSecondary hypertension