Endo new material after midterm 2

what does the R2A system help regulate

-blood pressure homeostasis

-fluid balance

-electrolytes balance

-vascular tone

what makes up the HPA axis

hypothalamus and adrenal gland

what organ systems are used by the R2A system to maintain homeostasis

kidney

HPA axis

pituitary gland

heart

vascular system

pancreas

brain

retina

what is the main effector of the R2A system

angiotensin II

what prohormone is converted into angiotensin II

angiotensinogen

what are the secondary effectors of the R2A system

aldosterone, vasopressin, and epinephrine

what provides negative feedback on the R2A system

ACE2-angiotensin 1-7-MAS receptor axis

what do SARS-CoV-2 and other respiratory viruses use as an entry point into cells

ACE2

what converts angiotensinogen to angiotensin I

renin

what converts angiotensin I into angiotensin II

ACE

what is R2A system overactivity correlated with

-heart disease

-vascular disease

-renal disease

-brain disease (dementia, alzheimers, parkinsons)

-more severe illness following SARS-CoV2 infection

what conditions cause overactivity of the R2A system

-chronic low blood volume/pressure syndromes

-renal artery stenosis

-hyperthyroidism

-addison's disease (primary adrenal insufficiency)

what can cause chronic low blood volume/pressure

-hemorrhage

-nephrotic syndrome --> disease kidney causing loss of albumin in filtrate

-cardiomyopathy

-left heart valve disease

how does renal artery stenosis cause overactivity of the R2A system

decreased kidney blood flow --> decreases GFR --> too much sodium removed from proximal convoluted tubule stimulates macula densa cells --> juxtaglomerular cells stimulates --> release of renin

how does hyperthyroidism cause overactivity of the R2A system

overproduction of thyroid hormone increases sympathetic outflow from vasomotor center --> direct stimulation of juxtaglomerular cells --> release of renin --> PCT takes up too much sodium

how does addison's disease cause overactivity of the R2A system

autoimmune related destruction of the zona fasciculata and zona reticulitis of adrenal cortex --> decreased aldosterone and cortisol --> decreased blood pressure

what is one of the first signs of adrenal insufficiency

increased serum renin

what makes up the juxtaglomerular apparatus

-macula densa

-juxtaglomerular cells

-mesangial cells

what is the job of the juxtaglomerular apparatus

-detect hypotension and renal filtrate sodium content

-release renin to correct any imbalances

which cells directly secrete renin

juxtaglomerular cells

where are juxtaglomerular cells located

afferent (glomerular) arterioles

what is the hormone that starts off the R2A system cascade

renin

what does presence of renin indicate

patient has hypotension/hypovolemia

juxtaglomerular cells are both _______ and _________

endocrine cells; baroreceptors

what is the rate limiting step of the R2A system

ability of juxtaglomerular cells to produce renin

how do BP changes affect juxtaglomerular cells

high BP = inhibits them

low BP = stimulates them

how does sympathetic inflow trigger juxtaglomerular cells

system hypovolemia/hypotension in common carotid arteries detected by baroreceptors in carotid sinus and aortic arch --> sensory branches of CN10 and CN9 --> stimulate vasomotor center --> increased sympathetic outflow --> vasoconstriction in arterioles and renin release in juxtaglomerular cells

what part of the vasomotor center receives signals from the carotid sinus and aortic arch baroreceptors

nucleus of the solitary tract (nucleus solitarius)

how does sympathetic outflow increase blood pressure

-vasoconstriction in arterioles increases afterload

-stimulates SA node to depolarize faster

-stimulate AV node to decrease decremental conduction

-stimulates cardiomyocytes to e more powerful

-stimulates renal afferent arterioles to constrict

how does renal arteriole constriction cause renin release

decreased GFR --> increased macula densa stimulation ---> increased renin

what are the effects of angiotensin II on the heart

same as sympathetic outflow but slower

what does sympathetic efferent outflow travel through to stimulate juxtaglomerular cells to release renin

renal nerves

where are macula densa cells located

thick ascending limb of henle

what are macula densa cells

osmoreceptors (NOT baroreceptors

what ion concentrations are macula densa cells sensing

sodium and chloride

what are macula densa cells in close contact with

juxtaglomerular cells and afferent arteriole

what sets macula densa cells off

hypotonic and slow flowing filtrate --> decreased GFR

what decreases GFR

-renal artery system hypotension/hypovolemia

-sympathetic inflow to afferent arterioles causing vasoconstriction

-AT-2 binding to afferent arteriole causing vasoconstriction

how does low afferent arteriole pressure cause hypotonic filtrate

low afferent arteriole blood pressure --> decreases speed at which the filtrate moves through the PCT --> decreases GFR --> increases sodium removal

aka for hypotonic

hyposomolar

how does slow GFR cause hypotonic filtrate

proximal convoluted tubule cells have too much time to reabsorb salt from filtrate via SGLT2

hypotonic filtrate's effect on macula densa cells

low sodium detected and sets of macula densa cells --> sends signals to juxtaglomerular cells to release more renin

what is the substrate of renin

angiotensinogen

where is angiotensinogen made

liver

what does renin convert angiotensinogen to

angiotensin 1

angiotensinogen is ______ secreted from the liver

constitutively

angiotensinogen is a ______

prohormone

aside from the liver, angiotensinogen can be secreted from other tissues in response to _____

inflammation

what are the two main enzymes of the R2A system

renin and ACE

where does angiotensin 1 travel

through the bloodstream to the pulmonary capillaries

where is ACE primarily found

lungs

what does ACE convert angiotensin 1 to

angiotensin II

why is ACE considered a pressor enzyme

creates pressor agents and destroy vasodilating agents

what vasodilating enzymes does ACE destroy

angiotensin 1-7

bradykinin

kallikrein

aka for angiotensin II

AT2

AT-II

what is considered the most potent vasoconstrictor

angiotensin II

what are the effects of angiotensin II

increases blood pressure

where does angiotensin II bind

AT1 receptors

what are AT2 target tissues

-arterioles

-heart tissue

-kidneys

-adrenal gland (chromaffin cells)

-hypothalamus (magnocellular neurons)

-thirst and salt centers

what effectors does AT2 recruit

aldosterone

vasopressin

aka for mesangial cells

lacis cells

goormaghtigh cells

what are mesangial cells considered

glue that holds the juxtaglomerular apparatus together

what are mesangial cells similar to

smooth muscle cell --> ability to contract and relax

how do mesangial cells control the GFR

they are physically connected to afferent and efferent arterioles --> vasoconstrict and vasodilate important blood vessels

what can mesangial cells secrete

-prostaglandins and proinflammatory cytokines

-non functional form of renin

what can mesangial cells phagocytose

virus, bugs, cancer cells

what turns on the R2A system

-hypotension in afferent arterioles

-increase in sympathetic input

what turns off the R2A system

high pressure in afferent arteriole

what has a negative feedback on the R2A system

-blood pressure in the afferent arteriole pressure

-high pressure --> off

-low pressure --> on

how does filtrate tonicity regulate the R2A system

-hypertonic filtrate --> inhibits

-hypotonic filtrate --> stimulates

what is the effect of high GFR

not enough sodium reabsorbed from PCT --> inhibits macula densa cells

binding of what causes smooth muscle contraction of arterioles and venules

AT-2, norepinephrine, vasopressin

how does binding of AT-2, norepinephrine, vasopressin cause vasoconstriction

triggers release of calcium from ER --> actin and myosin sliding --> muscle contraction

what is the effect of AT-2 binding to the adrenal gland on sodium and water

binds to receptors on glomerulosa cells to cause release of aldosterone --> binds to MR receptors in cytosol of principal cells --> hypernatremia --> release of vasopressin from magnocellular neruons --> vasopressin binds to V2 receptors --> aquaporin 2 channel implantation --> water into principal cell --> aquaporin 3 and 4 channel implantation --> hypervolemia

where are principal cells located

connecting tubules and proximal collecting ducts

what does aldosterone binding to principal cells trigger

-production of ENaC channels --> salt rushes into principal cell --> salt rushes out to interstitium via Na+/K+ ATPase --> salt goes into bloodstream to cause hypernatremia

-production of pendrin channels into apical surface --> Cl- rushes into cytosol --> Cl- rushes into blood via chloride channel and AE4 channel

what does reabsorption of salt and water via angiotensin II cause

increased blood pressure

what is the effect of aldosterone on potassium and hydrogen via binding to principal cells

-implantation of ROMK channels on apical surface of principal cell --> K+ secreted into filtrate

-alpha intercalated cells secrete hydrogen ion and reabsorb HCO3

what does AT-2 binding to magnocellular neurons cause

release of ADH from hypothalamus --> transported to posterior pituitary --> ADH released to blood --> ADH binds to V2 receptors --> reabsorption of free water WITHOUT salt

where does AT-2 bind in the heart to increase blood pressure

cardiomyocytes

SA node

AV node

what is the effect of AT-2 on hypothalamic thirst centers

become very thirsty --> drink water and increases blood pressure

what is the effect of AT- 2 on mesangial cells

binding causes mesangial cells to contract --> narrows glomerular capillaries --> slow GFR --> hypotonic filtrate --> macula densa cells release prostaglandins --> juxtoglomerular cells release renin

what do proximal convoluted tubules use to remove sodium

SGL2 and Na+/H+ exchanger 3

how do GLP-1 agonists cause natriuresis

over driving NHE3 exchangers

what does binding of AT-2 to chromaffin cells cause

production of catecholamines

what are the effects of epinephrine

-binds to arterioles and causes vasoconstriction

-binds to SA node to increase firing

-binds to AV node to decrease decremental conduction

-stimulates cardiomyocytes to beat more powerfully

what is decremental conduction

when the AV node delays depolarization to allow the atria time to contract

what does overactivation of R2A system in heart failure patients cause

-inflames the myocardium --> heart failure

-inflames arterioles --> worsening hypertension

-inflames glomerulus --> kidney failure

what medication can heart failure patients take to decrease AT-2 activity

ACE inhibitors

AT-2 receptor blockers

-mineralcorticoid receptor antagonists

what is an ACE inhibitor

lisinopril

what is an AT-2 receptor blocker

losartan

what is the main job of natriuretic peptides

combat hypervolemia/hypertension

the actions of natriuretic peptides is opposite of ____

angiotensin II (decrease BP and blood volume)

where are natriuretic peptides released from

heart

what are the natriuretic peptides

Atrial natriuretic peptide (ANP)

brain natriuretic peptide (BNP)

C-type natriuretic peptide (CNP)

ANP is considered a ______

true circulating hormone

where is ANP made

right and left atrial cardiomyocytes

how is ANP made

atrial cardiomyocytes stretch --> transcription/translation of pre-proANP --> passed to rough ER --> cut to form pro-ANP --> moves to golgi --> enzyme corin cuts pro-ANP to real hormone ANP

what stimulates the release of ANP

stretch of cardiac atrial myocytes from increased blood pressure or volume or chronic heart failure

the heart is an _____

endocrine organ