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142 Cards in this Set
- Front
- Back
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RAS
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-major effects: maintains blood pressure, salt & water balance
-many other actions including vasoconstriction & a role in inflammation -composed of systematic and local system -involved in short and long-term regulation of blood pressure |
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Angiotensinogen
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Only precursor protein of RAS
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rate linmiting factor in RAS
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angiotensinogen
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where is angiotensinogen synthesized?
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primarily from hepatocytes
also synthesized in the CNS, heart, vasculature, kidney and adipocytes |
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Pre-pro-angiotensinogen
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in hepatocyte, constitutively secreted
-not stored |
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angiotensinogen regulation by the endocrine system
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insulin- in adipose tissue, upregulates
estrogen- in hepatocytes, upregulates |
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Angiotensin I formation
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cleavage of angiotensinogen by renin
(Ang I=10 peptides) |
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Control of angiotensinogen release
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exert transcriptional control of the angiotensinogen gene
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stimulation of angiotensinogen synthesis...
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by inflammation and Angiotensinogen II
-Ang II may exert a positive feedback via an AT1 receptor |
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Key points to remember about angitensinogen
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-protein from which angiotensins are formed by proteolytic cleavage reactions
-synthesis is under complex control by hormones -levels in plasma affect blood pressure |
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Renin
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protease enzyme
-catalyzes the rate limiting step that results in the formation of angiotensin I |
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What are the systemic source for renin synthesis, storage and release?
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Juxtaglomular cells
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Synthesis of renin
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-Initial step is the formation of pre-pro-renin by renin mRNA
-pre-sequence is cleaved leaving pro-renin that is packaged in granules -In the golgi the "pro sequence" also cleaved leaving active renin |
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What enzyme activates renin?
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cathepsin B
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How are renin storage granules released?
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exocytosis into the blood
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T/F there is a constitutive release of pro-renin
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True
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The 3 pathways of renin release from the JG cells
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Macula Densa Pathway
Intrarenal barorecptor pathway B-adrenergic receptor pathway |
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Macula densa pathway
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-apart of JG apparatus
-monitors SODIUM levels -Low sodium is the signal that initiates a series of steps to stimulate renin release -chronic adaptive system regulation for renin |
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COX 2, PGE 2
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in feedback signal
stimulate renin release -dietary sodium restriction results in an upregulation of inducible COX 2 |
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What inhibits renin release in macula densa pathway?
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adenosine
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Intrarenal baroreceptor pathway
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An interrenal vascular receptor in the afferent arteriole that stimulates renin secretion in response to reduced renal perfusion pressure and attenuates renin secretion as renal profusion is elevated
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What is the most powerful regulator of renin release?
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BLOOD PRESSURE
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B-adrenergic receptor pathway
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-JG cells innervated by sympathetic nerves
-direct stimulation of these nerves will increase renin release -acute pathway where rapid activation of RAS is provoked |
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Short loop negative feedback
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increase in renin secretion results in an increase in Angiotensin II
-ANG II stimulates AT1 receptors on the JG cells to inhibit renin release |
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Long loop negative feedback
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Ang II increases BP via AT1 receptors which inhibit renin release
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Humoral control factors in renin release
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Stimulatory second messenger
-increase in cAMP Inhibitory second messenger -increase in cGMP causes an increase in intracellular calcium (decreases cAMP) |
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T/F loop diuretics stimulate renin release?
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true
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T/F NSAIDs inhibit PGs and decrease renin release
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true
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T/F ACE inhibitors and angotensin (AT1) receptor antagonists interrupt feedback and increase renin release
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True
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T/F B-adrenergic blockers and centerally acting sympatholytic drugs inhibit adrenergic pathway and decrease renin release
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True
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Macula densa chemoreceptors
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long term regulators
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Juxtaglomerular baroreceptors
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most effective regulator
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Angiotensin converting enzyme
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found in plasma and is mainly membrane bound predominately on endothelial and epithelial cell surface
-major function is convert ANG I to ANG II -inactivates bradykinin |
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Alternate pathway in humans for conversion of ANG I to ANG II
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Chymase enzyme
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DD genotype
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may have increased risk of ischemic heart disease, left ventricular hypertrophy, myocardial infarction or diabetic neuropathy
-have double the circulating ACE levels |
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Key points about ACE
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-ACE hydrolyzes Ang I to Ang II by cleaving 2 AAs
-ACE also inactivates the vasodilator bradykinin -found on endothelial cells esp in lung, brain, and retina -also found on epithelial cells in kidney and gut -there is a polymorphism to ACE that may alter risk factors for CV disease states |
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ACE2
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catalyzes the formation of a vasodilator molecule Ang 1-7 from both ANG I & II
-Ang 1-7 may function as an antagonist of AngII action -insensitive to ACE inhibitors -elevated in hypertension and heart failure |
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What kinds of receptors are AT1 and AT2?
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G protein coupled receptor with 7 transmembrane regions
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AT1 receptors
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mediates most of biological effects of ANGII (constricion,hypertrophy)
-glucocorticoids and insulin generally increase receptor number -mineralcorticoids and estrogens decrease receptor number |
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AT2 receptors
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-in fetal tissue development
-Usually acts in opposition to AngII on AT1 recpetors -vasodilatory -anti-proliferative |
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What happens when you inhibit ACE?
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it initially increases the levels of ANGI and decreases the levels of ANGII and aldosterone
-but plasma levels of ANGII may not stay depressed with chronic ACEI use |
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Why ANGII may not stay depressed with chronic ACEI therapy?
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-may indicate incomplete block of enzyme
-Increase in ANGI may exceed inhibitory capacity of ACEI -chymase is another route for ANGII |
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Chronic ACEI blocks degradation of Ang(1-7) which can
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inhibit AngII action
vasodilate, antiproliferate -ACEI will increase bradyinin |
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What is the role of ACEI/ACEII enzymes?
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to regulate the balance between the contrictors and the dilators
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Local RAS
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considered a paracrine/autocrine systems
-locally formed angiotensins can act as growth factors, neurotransmitters, and smooth muscle constrictors |
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tissues with local RAS
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heart brain adrenal gland adipose tissue testes ovaries kidney blood vessels and SKIN
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pancreas and ACE
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increased levels gives rise to dysfunction as seen in obesity, hypertension and diabetes
-weight loss reduces amount of ACE in pancreas -HOPE study showed that patients on ACE1 had a reduction in incidence of heart attacks in patients with CV disease and diabetes |
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Skin and ANGII
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maybe involved in wound healing since levels of ANGII are elevated after injury
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Brain
endocrine RAS paracrine RAS |
endo- stimulates drinking
para- stimulates release of ADH , alters baroreceptor reflex |
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Heart
endocrine RAS paracrine RAS |
endo- cardiac ischemia, positive ionotropic effect
para- myocardial hypertrophy, cardiac remodeling--both due to excessive growth factor |
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Vasculature
endocrine RAS paracrine RAS |
endo- vasoconstriction
para- hypertrophy |
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Adrenal gland
endocrine RAS paracrine RAS |
endo- release of aldosterone
para- hypertrophy and hyperplasia |
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Kidney
endocrine RAS paracrine RAS |
endo- Na and H2O reabsorption, glomerular hemodynamics (inc BP inc GFR)
para- Glomerular hypertrophy |
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Direct & indirect effects of increased TPR due to RAS
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1. direct vasoconstriction
2.enhancement of sympathetic system 3. increases sympathetic tone 4. results in the release of ADH 5 stimulates release of catecholamines from medulla and aldosterone from the cortex of the adrenal gland |
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Mechanisms by which ANGII alters CV structure
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-stimulates hypertrophy of VSM (hemodymanically and non-hemodynamicallu)
-vasoconstriction -mitogenesis of VSM |
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other effects of RAS
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-role in atherosclerosis
-generates reactive oxygen species -pro-thrombotic effects -pro-inflammation effects -effects on adrenal cortex |
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RAS and pro-thrombotic effects
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ANGII stimulates PAI-I which in inhibits the activation of plasmin which breaks down clots
-ANGII can reduce the amount of blood lost by producing a clotting response |
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RAS and pro-inflammatory effects
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may act as cytokine
increases vascular permeability chemotactic factor to recruit monocytes regulates expression of adhesion molecules may participate in cell growth and matrix synthesis |
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RAS and adrenal cortex
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causes release of Aldosterone
-secretion regulated mainly by ANGII and by potassium levels |
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major function of aldosterone
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regulate Na reabsorption and K and H+ excretion
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what is an ARB?
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and AT1R antagonist
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Why should pregant women not take and ACE inhibitor or an ARB?
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because it can cause malformation of fetus' kidney
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facts about hypertenstion
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-most prevalent cardiovascular disease
-2/3 of ppl over 65 are hypertensive -hypertenstion costs about 50 mill/yr -lifestyle change mandatory |
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how many hypertensive patients have their BP adequately controlled?
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34%
-30% unaware have hypertension -10-15% aware, but not treated -remaining patients are on medication but it is not controlled -goal in US is to control 50% by 2010 |
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what is target BP in pateints with added risk factors(diabetes, renal insufficiency or CAD)
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130/85 as opposed to 140/90
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what is hypertension?
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disease characterized by abnormally high systemic BPs either systolic or diastolic or both
P=CO X TPR |
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Factors that affect Cardiac output?
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HR & SV
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prehypertensive
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SBP of 120-139
DBP of 80-89 |
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How many drugs to patients with hypertension usually require to control it?
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2 or more
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Factors that affect TPR
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imbalance of endothelial products
-NO, ACE, ACE2, AngII, endothelin, etc |
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Degrees of hypertension
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1. Labile
2. Borderline 3. Chronic (benign) 4. malignant |
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Labile Hypertension
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-BP characterized by variablility and contractility
-white coat hypertension |
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Borderline hypertension
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around 140/90
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Chronic (benign) hypertension
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Results in premature death and disability if left untreated
-few to no symptoms -death usually a result of artherosclerotic complications |
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Malignant Hypertension
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-Rapid and severe increase in BP
-in untreated 80-90% dies w/in 1 yr -papilledema -Assoc with elevated levels of RAS & hypokalemia -most deaths associated with damage |
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How does sympathetic nervous system regulate Blood pressure?
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negative feedback system via barorecptors
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7 ways the endocrine system regulates blood pressure
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1. Catecholamines
2. renin/ANG/ALDO system 3. ADH 4. insulin 5. local hormone factors 6. ANF or ANH 7. Digitalis-like factor/natriuretic factor/quabain-like factor |
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Catecholamines on BP
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increase cardiac output, increase stroke volume, decrease resistance
(effect CO & TPR) |
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Renin-angiotensin-aldosterone system on BP
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effects CO & TPR
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ADH on BP
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Effects CO & TPR
-fluid retention properties more affect in BP |
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insulin and BP
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hyperinsulinemia-insulin resistance
-strong correlation -antinaturetic -stimulates SNS -w/insulin resistance have elevated LDL and reduced HDL |
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kinins
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release EDRF, NO and PG
vasodilator diuretic, natriuretic(salt loss) |
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prostaglandins (PG)
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generally vasodilator
inhibit catecholamine release diuretic, natriuretic |
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Endothelium Derived Relaxation Factor (EDRF) and NO
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relaxes VSM via cGMP
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Endothelin
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potent vasoconstrictor
mitogen for VSM to enlarge anti-naturetic |
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ANF and ANH (atrial naturetic)
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-major stimulus is an increase in atrial pressure (increase in volume)
-functions as a volume regulator by increasing sodium and water loss -acts as vasodilator |
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ANF and ANH multiple hypertensive actions
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-decreases aldosterone and ADH
-increase GFR by dilating afferent and consticting efferent adteriole -reduces VSM contactile effects -decreases renin release -antagonize response to ANGII -increase in cGMP stimulates |
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digitalis-like factor/natriuretic factor/quabain-like factor
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-stimulus is an increase in volume
-inhibits sodium potassium ATPase causes natiuresis, and bp to increase b/c an inc in intracellular Na and Ca, reduced NE uptake and enhanced vasoconstriction |
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renal arteriogram
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determines arterial sclerosis, necroplasm, location of artery or vein for treatment
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retrograde pyelogram
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diagnostic radiologic exam used to evaluate the condiotion of the renal pelvis and related structures
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T/F the urine pH of a patient with a moderate fever can typically be expected to be lower than normal
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true
pH increases after meals, decreases with sleep and fever |
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Essential or primary or ideopathic
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90-95% of cases
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Secondary hypertension
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5-10% of cases
-a result of another disease process -if possible treat the primary defect |
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Currently is there a cure for hypertension?
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No- try to control blood pressure
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Possible causes of primary hypertension
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1. family history
2. Environment (NaCl plays factor) 3. Age 4. SNS 5. glucose intolerance/insulin resistance 6. kidney |
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Is there a single cause for primary hypertension?
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No
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two kidney one-clip model
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initially there was decreased renal blood flow to clipped kidney, causes renin to be released
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One kidney, one clip model
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Intially there was dereased blood flow to kidney, so there was no normal kidney. Renin was initially elevated then excess volume and sodium pressure shuts down renin release
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Causes of secondary hypertension
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pheochromocytoma
primary aldosteronism (conns syndrome) secondary aldosteronism cushing syndrome |
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pheochromocytoma
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tumor of chromaffin cells in medulla region
has a symptomatic triad of tachycardia, headaches and sweating in addition to hypertension |
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primary aldosteronism
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autonomous production of aldosterone
spontaneous hypokalemia low plasma renin -oral captopril test |
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Secondary aldosteronism
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problem with stimulation of adrenal gland or block of feedback inhibition
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Cushing Syndrome
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increase in ACTH, increase in glucocorticods, normal mineralcorticods, increased CO and TPR, will have Na and Water retention to increase volume
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pre-eclampsia
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when BP is higher than 140/90 after 20th week of gestation
-develop proteinuria &/or edema -ususally have coagulation problems and liver abnormalities, epigastric pain, and visual disturbances -increases perinatal mortality when diastolic pressure is more than 95 |
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pathophysiology of pre-eclampsia
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Vol may not increase (normally does)
CO similar to normal TPR does increase (normally dec) Responsiveness to AngII, NE & ADH is elevated -have 2 fold risk of diabetes after pregnancy |
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Theory to why pre-eclampsia occurs
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Endocrine theory
increasing things that vasoconstrict & decreasing those that vasodilate |
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Summary of pathophysiology of pre-eclampsia
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systemic
-vasospasms -reversal of circadian BP rhythms -increased TPR -endothelial dysfunction -clotting issues |
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additional causes to secondary hypertension
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aortic coarctation
oral contraception thyrotoxicosis atherosclerosis |
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Complications of hypertension
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myocardial complications
atherosclerotic complications cerebral complications renal complication hypertensive retinopathy |
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myocardial complications of hypertension
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left ventricular hypotrophy
coronary artery disease congestive heart failure |
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atherosclerotic cmplications of hypertension
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most important complication
-when systolic BP is over 150, risk of atherosclerosis is doubled -high BP causes injury to endothelium causing WBC migration and plaque formation |
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what are the 3 manifestations of artherosclerotic complications
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angina
myocardial infarction PVD and aneurysm |
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Cerebral complications of hypertension
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when systolic pressure is more than 160 mmhg risk of sroke increases 4 times
-atherothrombosis main cause of stroke -Transient ischemic attack other complication |
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What is the earliest organ affected by hypertension?
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eyeball
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Heart failure
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inability of pumping function of heart to meet the metabolic demands of tissues and venous return
-results in congestion |
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features of passive heart congestion
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dilation of chamber
excess blood in chamber decrease flow out of chamber |
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Risk factors of heart failure
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hypertension
diabetes |
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mortality of heart failure
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80% men and 70% of women under age 65 who have HF will dies w/in 8 years
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Cardiac reserve
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ability to increase Cardiac output with increased activity
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preload
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reflects the loading condition of the heart at the end of diastole
-mainly determined by EDV -pressure or vol in heart before systole |
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afterload
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represents the force that the contracting heart must generate to eject the blood
-approx equal to TPR -refers to amt of tension ventricle must develop to eject blood |
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factors that effect contracting ability of the heart
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primary myocardial disease
restrictions of ventricular filling (diseases of endocardium and pericardium) |
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factors that effect the workload placed on the heart
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increases in peripheral resistance-pressure oveload (afterload)
conditions that cause and increased preload excessive work demands |
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systolic dysfunction
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impaired ejection of blood from heart during systole
-as ejection fraction decreases: get increase in diastolic vol increase in ventricular dilation increase in wall tension rise in ventricular end-diastolic pressure |
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t/f the renal disease occuring most commonly in children in which the proximal convoluted tubules are laden with lipids is fetal glomerulonephritis
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False- diffused glomerulonephritis
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t/fBroad granular casts seen during microscopic examination of a urine sample are considered benign
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Fasle- casts of dead cells are considered a sign of disease
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T/F Proteinuria indicates disease of the renal tubules
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False- failure of glomerular filtration
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t/f the kidneys are responsible for the conversion of Vit D to its active form
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true
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t/f blood levels of nitrogen-containing waste products resulting from the breakdown of muscle creatine are measured as BUN
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False- measured as levels of Creatinine
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BUN
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blood urine nitrogen
8-26 mg/dl |
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t/f Bowman's capsule has an outer parietal layer made up of flattened epithelial cells and an inner visceral layer made up of fenestrated epithelial cells
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false- inner layer of podocytes
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t/f Renal blood flow equals the difference between aortic pressure and renal venous pressure divided by renal vascular resistance
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true
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t/f the internal sphinctor of the bladder consists of a layer of skeletal muscle and is under voluntary control
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false- smooth muscle
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t/f ADH is stored and released from nerve terminal in the posterior lobe of the pituitary gland (neurohypophysis)
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true
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t/f Autoregulation serves to maintain renal blood flow at a relatively constant level as arterial blood pressure changes from appro 80 or 90 up to 180mmHG
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true
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t/f chronic renal disease may develop insidiously over many years due to the large functional reserve of the kidneys
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true- up to 90% of nephrons will be destroyed before significant impairment
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t/f symptoms due to toxic levels of nitrogenous waste products in the blood is referred to as uremia
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true
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t/f a decrease in plasma oncotic pressure often leads to the formation of generalized edema
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true
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t/f The principle causative organism of acute pyelonephritis is streptococcus
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False- e coli
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cause of diffuse proliferative glomerulonephritis (nephrotic syndrome)
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streptococcus
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t/f bladder cancer has a high incidence in individuals working with chemicals, smokers, and those with recurrent infections
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true
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t/f the condition resulting in renal shutdown on a purely function basis in which the kidneys are suitable for transplantation is hydronephritis
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false hepatorenal syndrome
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