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angiotensin II mediated effects on vasculature and kidney
- 1. Angiotensin II Mediated Effects William Kaye, MD Palm Beach Diabetes and Endocrine Florida Lipid Associates
- 2. RENIN-ANGIOTENSIN SYSTEM: CLASSICAL VIEW Angiotensinogen Angiotensin I Angiotensin II Angiotensin II Receptors •Bradykinin •Substance P •Enkephalins Renin ACE •Inactive Fragments Florida Lipid Associates
- 3. PATHOPHYSIOLOGIC ROLE OF ANGIOTENSIN II Angiotensin II AT1 Receptor Cell Growth LVH Vascular Remodeling Vasoconstrictio n Aldosterone prod. Sodium / Water Retention TVR BP BP Hypertension. Feb. 1994;23(2):258 Florida Lipid Associates
- 4. Introduction of ACE Inhibitors Florida Lipid Associates
- 5. Angiotensin Converting Enzyme (ACE) Inhibitors: Mechanism of Action Nitric Oxide Prostaglandin s Angiotensinoge n Renin ACE A-I A-II () ACE Inhibitor Bradykinin () Kininase II Inactive Peptide Florida Lipid Associates
- 6. Over Time Angiotensin II Levels Rise (in tissue and blood) Despite ACE Inhibition and BP Control Time Levels AII BP ACE ACE Inhibitor Florida Lipid Associates
- 7. Are We Really Blocking Angiotensin II With ACE Inhibitors? Florida Lipid Associates
- 9. BP Levels Remain Down With ACE Inhibitors Despite Normal Angiotensin II Levels • Increased Bradykinin Levels • Increased PGE 2 Levels • Increased Nitric Oxide Levels • Vasodilation Florida Lipid Associates
- 10. How Can Angiotensin II Levels Increase Despite Blockade? Florida Lipid Associates
- 11. TISSUE ANGIOTENSIN II FORMATION Alternate Pathway Heart Ventricles Adventitial Layers ACE Angiotensin I Angiotensin II Chymase Angiotensin II Receptors Angiotensinogen Renin Florida Lipid Associates
- 12. Stimulants of Local Angiotensin II Production • Trauma • Stretch • Hypoxia • Hypertension Florida Lipid Associates
- 13. What is the Importance of the Alternate Pathway? • Systemic conversion of Angiotensin I to Angiotensin II • Local conversion of Angiotensin I to Angiotensin II Florida Lipid Associates
- 14. Bottom Line (Regardless of Importance) ACE Inhibitors Reduce BP But Not Angiotensin II Levels (Neither Systemic nor Local) Florida Lipid Associates
- 15. Are High or Normal Levels of Angiotensin II OK in Treated Hypertensive Individuals? Florida Lipid Associates
- 16. PATHOPHYSIOLOGIC ROLE OF ANGIOTENSIN II AT1 Hypertension. Feb. 1994;23(2):258 Angiotensin II Receptor Cell Growth LVH Vascular Remodeling Vasoconstriction Aldosterone prod. Sodium / Water Retention TVR BP BP Florida Lipid Associates
- 17. The Spectrum of Vascular Remodeling Pressure Flow Injury A B C D E F Vessel A represents hypertensive vascular disease with vascular hypertrophy, in which the medial layer is thickened and the luminal diameter is reduced; vessel B, hypertensive vascular disease without medial hypertrophy, in which the luminal diameter is reduced; vessel C, decreased vessel dimensions in response to a long-term decrease in flow; vessel D, increased vessel dimensions in response to a long-term increase in flow; vessel E, neointimal hyperplasia (migration and proliferation of vascular smooth-muscle cells) in response to vascular injury; and vessel F, atherosclerosis in response to vascular injury of conduit vessels. Florida Lipid Associates
- 18. Agents of Vascular Remodeling (Signals, Sensors, and Mediators) Gap junctions Vasoactive substances Growth regulators Matrix modulators Extracellular-matrix receptors Flow or shear stress Stretch Thrombin Angiotensin II ATP Inflammatory mediators Adhesion molecules LDL oxidized LDL Lipoprotein (a) Nucleus Vascular transducer cell Potassium channel Ion channel Ligand receptors ELAMs Integrins Lipoprotein receptors Signal s Sensors Mediators Florida Lipid Associates
- 19. Angiotensin II - Vascular Hypertrophy FGF fibroblast growth factor TGFB1 transforming growth factor beta-1 PDGF platelt derived growth factor insulin-like growth factor Angiotensin II affects factors that modulate growth in cultured vascular smooth muscle cells Koibuchi, Y. et al, Hypertension, 21: 1993 Itoh. H. et al, J clin Invest, 91: 1993 Florida Lipid Associates
- 20. Proposed Angiotensin-II Influence on the Blood Vessel BP Vascular injury Induction of angiotensin II pathways at the tissue level Local angiotensin II production Vascular remodeling Dzau VJ; J Cardiovasc Pharmacol, Vol 22 (Suppl. 5) 1993 Florida Lipid Associates
- 21. Induction of angiotensin II pathways at the tissue level BP Aortic Stenosis Coarctation of Aorta Wall tension Left ventricular pressure Left ventricular volume overload Local angiotensin II production Cardiac remodeling (hypertrophy / dilatation) MI Myocardial Injury Valvular Insufficiency KNOWN INVESTIGATIONAL Angiotensin II Influence and the Heart Adapted from Dzau v.N. Drugs. Vol. 47, Supp. 4, 1994 Florida Lipid Associates
- 22. Proposed Angiotensin II Influence on the Kidney Renal Injury Nephron Mass Glomerular Hypertrophy Glomerular Capillary Pressure BP Adapted from Wier,M.R. et al.:Primarycare 18:3, 1991. Induction of angiotensin II pathways at the tissue level (mesangial cells / vascular endothelium) Local angiotensin II production Glomerulosclerosis Florida Lipid Associates
- 24. Hypothesized Atherosclerotic Effects of Angiotensin II • Causes SMC growth and migration • Activates macrophages • Increases platelet aggregation • Stimulation of PAI 1 • Made directly by SMCs & macrophages • Angiotensin II stimulation causes endothelial dysfunction Gibbons, GH, et al; NEJM. 330:20; Florida Lipid Associates
- 25. ANGIOTENSIN II RECEPTOR BLOCKERS LOSARTAN AT1 Receptor Aldosterone prod. Sodium / Water Retention Hypertension. Feb. 1994;23(2):258 Vasoconstriction TVR BP Cell Growth LVH Vascular Remodeling BP Atherosclerotic Effects Activates Macrophages Platelet Aggregation Stimulation of PAE 1 Endothelial Dysfunction Florida Lipid Associates
- 26. Does This Mean Angiotensin II AT1 Blockers Have Special Effects Beyond Benefits of BP Lowering? • Prevention of remodeling of blood vessels and heart • Kidney sparing effects • Anti-atherogenic effects Florida Lipid Associates
- 27. AII Foundation Hypertension Stroke Retinopathy Cardiac Remodelin g CHF Glomerular hypertension Diabetic nephropathy Proteinuria Renovascular LVH MI Death Renal Failure Cerebrovascular Cardiovascular Sequelae Of Hypertension Current Investigations Florida Lipid Associates
- 28. Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) Presented at the ASH Meeting May 16-19, 2001
- 29. Definition of Abnormalities in Albumin Excretion in the Urine Category 24-h collection Random collection (mg/24h) (mg/g creatinine) Normal <30 <30 Microalbuminuria 30-299 30-299 Clinical albuminuria >300 >300
- 30. The Natural Progression of Diabetic Nephropathy Time (yrs) 0 5 20 30 Proteinuria Hypertension ESRF Onset Preclinical Nephropathy Structural changes (increasing glomerular basement membrane thickining and messangial expansion) Incipient Nephropathy (Hyperfiltration, microalbumiuria rising blood pressure) Overt Nephropathy (Rising S. Creatinine, Decreasing GFR)
- 31. RENAAL • Trial- Reduction of endpoints in NIDDM with the AII Antagonist Losartan Study (1,513 patients) • Patient Type- Type II DM with proteinuria (urinary albumin:creatinine ratio > 300 mg/g or urinary protein excretion >500 mg/24hr) – Hypertensive or normotensive – Age 31-70 yr. – SCr 1.5-3 mg/dL for males >60 kg; 1.3 mg/dL for females and males <60 kg
- 32. RENAAL • Treatment Groups- Losartan 50 mg QD 100 mg QD (dose titrated at 4 weeks if target SBP/DBP <140/90 mm Hg is not met) vs. placebo. Hypertensive patients continued their exisitng therapy (excluding ACE’s or ARB’s) for the duration of the study • Primary Endpoint- Composite endpoint of the time to first event of doubling of serum creatinine, ESRD (dialysis, transplantation), or death • Secondary Endpoint- Assessment of CV events, progression of renal disease, and changes in proteinuria
- 33. Baseline Characteristics for RENAAL Age at entry (mean) 60 years Race Caucasian 49%, Black 15%, Hispanic 185, Asian 17% Gender Male 63%, Female 37% Hypertensive 94% SBP/DBP (means) 153/82 mm Hg Serum Creatinine (mean) 1.9 mg/dL Urinary albumin: 1,867 mg/ gram creatinine ratio (mean)
- 34. Results 43.5 47.1 40 42 44 46 48 Percent of patients Risk of kidney disease progression (primary endpoint) Cozaar Placebo 16% reduction P=0.024
- 35. Results 19.6 25.5 0 10 20 30 Percent of patients Risk of progression to ESRD Cozaar Placebo 28% reduction P=0.002
- 36. Results 21.6 26 0 10 20 30 Percent of patients Risk of doubling of serum creatinine Cozaar Placebo 25% reduction P=0.006
- 37. Results 21 20.3 0 5 10 15 20 25 Percent of patients Risk of death Cozaar Placebo
- 38. Results 34 39.4 0 10 20 30 40 Percent of patients Risk of progression to ESRD or death Cozaar Placebo 20% reduction P=0.010
- 39. Results 11.9 16.7 0 5 10 15 20 Percent of patients Hospitalization for heart failure Cozaar Placebo 32% reduction P=0.005
- 40. Additional Results • Proteinuria- Cozaar plus conventional blood pressure therapy significantly lowered proteinuria by 35% compared to placebo plus conventional blood pressure therapy, p= 0.0001 • Discontinuations- 17 percent in the Cozaar group and 22 percent in the placebo group
- 41. Baseline Characteristics for IDNT-(Irbesartan Type II Diabetic Nephropathy Trial) Patients 1715 Dose titrated to 300mg/day Age at entry (mean) 30-70 years Hypertensive 100% SBP/DBP (means) 160/87 mm Hg Serum Creatinine (mean) 1.67 mg/dL Urinary protein: 4 gram proteinuria >900mg/day
- 42. Results for IDNT-(Irbesartan Type II Diabetic Nephropathy Trial) • Primary composite endpoint: 2x serum creatinine, time to ESRD (need for dialysis, renal transplant or SC > 6mg/dL), death – RR= 20% p=0.02 • 2x serum creatine – RR=33% p=0.001 • Time to loss of renal function – RR=23% p=0.07 (NS) • Time to all cause mortality – RR= 8% NS
- 43. 0 1 2 3 4 5 6 1 .5 .333 .25 .2 .16 1/Cr NO RX BP RX ACE/ARB X X X X Cr 1 2 3 4 5 6 RATE OF RENAL DECLINE YEARS
- 44. 0 1 2 3 4 5 6 1 .5 .333 .25 .2 .16 1/Cr ACE/ARB Cr 1 2 3 4 5 6 RATE OF RENAL DECLINE YEARS X X X