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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)
Physiologic stimulation of renin release
PHYSIOLOGY PHARMACOLOGY
Blood pressure Antihypertensive agents
Fluid volume Stimulators
Sodium intake Renin-angiotensin blockade
Hydration Diuretics
Diuretics Vasodilators
Menstrual cycle Suppressors
Diurnal changes β-Adrenergic blockers
Posture Central α2-adrenergic agonists
Potassium intake Neutral
Protein intake Calcium antagonists
Half-life of renin and angiotensin
Metabolism of the renin-angiotensin system
COMPONENT HALF-LIFE IN CIRCULATION DEGRADING ENZYME(S)
Renin 15 -20 min -
Angiotensinogen 4 -16 H Renin
Angiotensin I 1 -2 min Angiotensin-converting enzyme
Angiotensin II Seconds Aminopeptidase A,
Εndopeptidase, Ρrolylcarboxypeptidase
Angiotensin peptides and receptor subtypes that interact with each peptide
RECEPTOR ANGIOTENSINNone Angiotensinogen Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Asn-Glu ReninNone Angiotensin I NH2-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-COOH Angiotensin-converting enzymeAT1, AT2 Angiotensin II
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe AngiotensinasesAT1, AT2 Angiotensin III
Arg-Val-Tyr-Ile-His-Pro-Phe AngiotensinasesUnknown Angiotensin (1-7) Asp-Arg-Val-Tyr-Ile-His-Pro AngiotensinasesAT4 Angiotensin (3-7)
Val-Tyr-Ile-His-Pro
Heterogeneity in the angiotensin II receptor population
Classification criteria of angiotensin receptor subtypes AT1 AT2
Potency order Angiotensin II > angiotensin III Angiotensin II =angiotensin IIISelective antagonistsI Losartan PD 123177 (Parke-Davis, NJ) PD 123319 (Parke-Davis) Valsartan CGP 42112A (Novartis) Eprosartan Zorsartan Irbesartan Candesartan Telmisartan TasosartanEffector pathways Phospholipase CGuanylate cyclase Phospholipase D Adenylate cyclaseSensitivity to dithiothreitol (sulfhydryl-reducing agents) Binding Binding Affinity No changeEffect of GppNHp Hill coefficient to no Change ~1
Renal effects of angiotensin subtype-2 receptor
•Release of bradykinin, nitric oxide, and cGMP
•Cell differentiation
•Antiproliferation
•Apoptosis
•Vasodilation
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
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
Causes of renal artery stenosis
SENSITIVITY, % SPECIFICITY, %•Rapid sequence IVP 74 86•Isotope renography 93 95 with ACE inhibition test•Peripheral vein PRA with 74 89 ACE inhibition test (captopril test)•Renal vein ratio of PRA test (stenotic/contralateral): >1.3 85 40 >1.9 78 60•Peripheral vein PRA 92 96•Intravenous digital 88 89 subtraction angiography•Doppler ultrasonography 86 93•MRI 97 95•Renal artery angiography 100 100
Diagnostic indicators for renovascular hypertension
Diagnostic studies for renovascular hypertension
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
Objectives in the management of renovascular hypertension
Outcome after angioplasty or surgery for renal artery stenosis
ETIOLOGY ATHEROMA FIBROMUSCULAR DYSPLASIA
Treatment Angioplasty Surgery Angioplasty Surgery
Patients 391 1310 175 486
BP response
Cured 19 45 50 64 ( 56- 81)
Improved 52 29 42 23 ( 5 -40)
Failed 30 24 9 11 ( 0 -25)
Renal causes of hypertension RENAL PARENCHYMAL RENOVASCULAR
•Acute and chronic
glomerulonephritis;
pyelonephritis;
nephrocalcinosis; neoplasms;
glomerulosclerosis; interstitial,
hereditary, or radiation
nephritis
•Obstructive uropathies and
hydronephrosis
•Renin-secreting renal tumors
•Renal trauma
•Renal arterial lesions;
occlusions; stenosis;
aneurysms; thrombosis;
Vasculitis•Connective tissue or
autoimmune disease with
renal vasculitis or
glomerulitis•Coarctation of the aorta with
renal ischemia•Aortitis with renal ischemia