ANSC 424- 5 Cardiovascular and Adrenal Medulla

what is blood osmolality?

Solute concentrations

same as osmolarity BUT just different units Osmolarity = Osmol/L; Osmolality = Osmol/Kg ( osmoloaity is better because kg NOT temp dependent)

what is a normal blood osmolality

Normal blood osmolality: 280 to 295 mOsm/kg

what recognizes changes in osmolality

Osmoreceptors

where can Osmoreceptors be found

Osmoreceptors located in OVLT and SFO(hypothalamus) detect osmotic changes in blood

what are osmoreceptors sensitive to

Osmoreceptors most sensitive to sodium (Na+)

what is blood pressure sensed by

baroreceptors located in aortic arch and carotid sinus

what are baroreceptors structurally

Baroreceptors are not a single protein, but a complex of mechanosensitive ion channels

what genes can encode for baroreceptors

Candidate genes include ASIC2, Peizo 1 and 2, and ENaC (DEG/ENaC family proteins)

what is the major determinant of blood pressure in arteries

diameter of arterioles and control the distrubition of blood supply to tissues

Anatomy of nephron?

what are the main hormones responsible in the Regulation of blood volume, pressure and osmolality

Regulated by multiple hormonal mechanisms

❖Vasopressin

❖Renin-Angiotensin-Aldosterone

❖Natriuretic peptides

where does vasopressin come from

Hypothalamic nuclei with magnicellular neurons from SON

—> FROM PSOTERIOR PITUITARY GLAND

what is the main functions of vasopressin

❖ H2O retention by the kidney

❖ Contraction of blood vessels (arterioles)

❖ Involved in regulation of the cardiovascular system

what are the different receptors for vasopressin?

V1 ( a and B) and V2

where are V1a found and function

Target cell: Smooth muscles, Platelets, Hepatocytes

Function: Vasoconstriction, platelet aggregation, Glycogenolysis

where is V1b found and function

Target: Anterior pituitary

Functions: ACTH release

what is the function of V2 and where is it found

Target cell: Collecting tubule (kidney) Endothelium

Functions: AQP2 synthesis and translocation vWF and Factor 8 release

what can cause vasoconstrictrion?

increase myogenic atcivity, oxygen, sympathetic stimulation, vasopressin, angiotensin II

decrased Co2

what can cause vasodilation

decreased myogenic activity, O2, sympathteic stimulation, histamine, heat

increased Co2

explain the vasopressin receptor signaling

explain how vasopressin can correct low bp

what is relationship of vasopressin and water loss

Vasopressin can bring water loss through urine production to minimum but cannot stop it ❖Insensible water loss – respiration and perspiration

—> small water loss

what triggers thirst

Triggered by changes in osmolality or volume, Strongly triggered by hypovolemia and decrease in blood pressure

—> Mechanisms are similar to vasopressin secretion

explain the process by vasopressin leads to thirst

1. ethanol depresses the hypothalamic osmoreceptor

2. less vasopressin

3. increased urine output

4. dehydration

vasopressin and pregnancy?

—> the brain becomes less sensitive, so it allows for more water retention before it signals the need to adjust

—> increased in blood volume

—> Blood vessels dilate (widen) during pregnancy, so the body adjusts and thinks this new, expanded volume is normal.

—> not as mush vasopressin secretion, rather ajustst to a nre threshold

—> the placenta makes an enzyme that breaks down vasopressin BUT if there is too much expression of this can lead to gestational diabetes insipidus

vasopressin and the elderly?

—> By age 80, total body water declines to as low as 50%

—> The kidneys become less efficient at filtering blood, which affects water and salt balance

—> collecting duct in kidney less responsive to vasopressin, harder to retain water

—> brain cant really detect dehydration real well

—> elderly susceptible to both hypo and hypernatremia

what is diabetes insipidus

excretion of a large volume of urine (diabetes) that is hypotonic, dilute and tasteless (insipid)

what are the causes of diabetes insipidus

❖ lack of vasopressin (trauma, tumour etc)

❖ lack of response to vasopressin in kidney

❖ receptor defect or aquaporin defect

❖ Rapid metabolism of vasopressin

❖ Pregnancy i.e. transient diabetes insipidus

what are charcteristic features of people with diabetes inspidus

polydipsia and polyurea

what is polydispsia

people that drink TOO much water

what is polyurea?

people that urinate too much

what are the main functions of aldosterone

❖ Recovery of Na+ in the kidney and enhanced K+ secretion into the urine to balance charge difference

❖Adjustment of extra-cellular fluid (ECF), including blood volume

—> retain sodium and excrete K

pathway of aldosterone synthesis?

where does aldosterone synthesis occur

zona glomerulosa

where is renin produced

kidneys!

main function of renin

Renin is a hormone/enzyme made by the kidney to help regulate blood pressure and fluid balance. I

explain how renin is produced?

—> produced when the kidney senses low blood pressure or low sodium.

1. Macula densa cells detect Na+ levels in kidney tubule

2. Juxtagolomerular cells of afferent arterioles detect blood pressure

3. Pericytes (not shown) near afferent arterioles produce renin

what does renin do

Renin from pericytes in kidney converts angiotensinogen to angiotensin I in the liver

explain the Renin-angiotensin-aldosterone system

1. renin convert angiotensinogen—> angiotensin I in liver

2. ACE from endothelial cells of lungs converts angiotensin I to angiotensin II

3. angiotensin II stimulates aldosterone secretion (ACTH has a modest effect)

4. Aldosterone and Angiotensin II increase Na+ absorption and K+ excretion, water retention in kidney

how is angiotensin II inactivated?

Angiotensin II is inactivated to angiotensin III by Aminopeptidase A

Where Does Aldosterone Act?

tubular epithelium through nuclear receptors

what receptor does aldosterone act on

mineralcorticoid receptor ( MR)

—> found in cytoplasm and then acts as TF in nucleus

What Does Aldosterone Do in Epithelial Tissues?

❖ Regulation of fluid volume

❖ Water absorption

❖ Sodium/potassium homeostasis

❖Na+ transport in distal tubules of kidney, colon, Salivary and Sweat glands

—> basically sodium balance

what specific channel is important in aldosterone pathway

ENac

sodium comes in and therefore water also comes in —> need water excretion with aquaporin through vasopressin signaling

what are the main effects of aldosterone

Mainly: Distal tubules and collecting ducts of the kidney.

Promotes plasma retention of Na+ and excretion of K+

Sensitizes arterioles to vasoconstrictor agents, AVP and Angiotensin II

Net effect: Rise in plasma volume and blood pressure

what is Hyperaldosteronism known as

Conn’s disease

what is the usually cause of Hyperaldosteronism

Hypersecretion of aldosterone usually caused by adrenal hyperplasia (60 %) or tumor (40%)

what are the effects of Hyperaldosteronism

❖Excess excretion of K+ and H+

❖Serum alkalosis and neuropathy (hypokalemia)

❖Increased Na reabsorption

❖Increased water retention

❖Increased blood pressure

—> excess K and H so increased pH—> alklosis and neuropathy

what is Hypoaldosteronism known as

Addison’s disease

what are the causes of addisons

❖ Shortage (deficiency) aldosterone production

❖ Impaired function of aldosterone

what are the symptoms of addison’s

❖ Symptoms:

❖ Low sodium (hyponatremia)

❖ Too much potassium (hyperkalemia)

❖ Low blood pressure

❖ Metabolic acidosis

explain addison crisis pathway

what happens in zona reticularis

andorgen synthesis

explain the androgen synthesis

where are sex steriods usually synthesized

gonads

F: estrogen and progesterone

M: androgens

what regulates sex steriods syntehsis

gonadotrophins

what is the MAIN regulator of aldosterone

angiotensin II

what does the adrenal cortex ( zona reticularis) mainly produce

DHEAS and androstenedione regulated by ACTH

where is androgen—> testesterone

periopheral tissues

what is Congenital adrenal hyperplasia (CAH)

condition in which adrenal glands are enlarged and hyperfunctioning

what causes CAH

mainly genetic due to involves deficiency of CYP21A2 (ZG and ZF)

what happens in CAH

Reduced aldosterone and cortisol

what alternative pathway can be used in CAH

But ZF, with produces 21-deoxycortisol – similar to cortisol but lower glucocorticoid activity

what happens in CAh due to low aldosterone

Low aldosterone leads to Salt wasting, salt and water craving, vomiting and dehydration, low blood pressure (death)

what is highly expressed in CAH

Excessive androgen production in ZR

❖ Masculinization of genitalia

what do Natriuretic peptides do

NP function: Peptides that increase the excretion of H2O and Na+

where can natruitetic peptides found

Produced in the heart muscle cells and stored in granules

where are NP receptors found

Receptors are present in the glomeruli, medullary collecting ducts of the kidney, the zona glomerulosa of the adrenal cortex and in peripheral arterioles

what is the effect of NP

❖ Increases glomerular filtration

\❖ Reduce renin and inhibit aldosterone production

❖ increase water loss (diuresis) and vasodilation

❖ Reduces blood volume and pressure

pathway of NP

what kind of cells can be found in adrenal medulla

modified post ganglionic neurons—> known as chromaffin cells

PART OF SNS

what do Preganglionic neurons release

acetylcholine to stimulate chromaffin cells to release catecholamines

what is the overall effect of catecholamines

Coordinate fight-flight response to alarm by increasing blood pressure and cardiac output, and dilating pupils

what are catecholamines derivatives of

tyrosine

what are examples of catecholamines

norepineprhine and epunephrine

pathway of catecholime synethesis?

what is the rate limiting step of catecholamine syn?

tyrosine hydroxylase

what is PNMT

Phenylethanolamine Nmethyltransferase (PNMT)

converts norepi—> epi

stimulated by CORTISOL

when are catehcolamines released

in response to STIMULI

—> 80% epi and 20% norepi

explain fight or flight response

release CRF—> ACTH

activate SNS—> release epi

—>

what receptor with EPI and NORepi

GPCR

what does epineprhine do

❖ rapidly mobilizes fatty acids as the primary fuel for muscle action

❖ increases muscle glycogenolysis

❖ mobilizes glucose for the brain by increase hepatic glycogenolysis and gluconeogenesis

❖ preserves glucose for CNS by dcrease insulin release leading to reduced glucose uptake by muscle/ adipose (opposes Insulin)

❖ Increases cardiac output

what does norepinephrine do

increase blood flow and decrease insulin secretion

what receptors for epi and norepi

adregenergic receptors:

1. Alpha 1 and 2

2. Beta 1

3. Beta 2

what does α1/2 and β1 receptors bind to

epi and norepi

what does B2 receptor bind to

mostly epi

how can different responses happen with epi and norepi

tissue specific receptors so you have a different response due to different concentrations of epi and norepi

—> use in drugs

what is Salbutamol

drug that takes adv that epi and norepi receptors are tissue specific

activates β2 receptors and dilates bronchioles (relief of asthma) and does not affect β1 receptors in the heart

what are the different adregenic receptors and target tissues

what are the difference between epi and norpepi

1. cardiac stimulation

—> Epinephrine >> norepinephrine – in terms of cardiac stimulation leading to greater cardiac output (beta1 stimulation)

2. constriction of blood vessels

—> Epinephrine < norepinephrine – in terms of constriction of blood vessels – leading to increased peripheral resistance – increased arterial pressure

3. increasing metabolism

—> Epinephrine >> norepinephrine – in terms of increasing metabolism

how can Adrenomedullary deficiency occur

can occur due to surgery/trauma

—> cause cortisol suppression (epinephrine deficiency)

what are symptoms of Adrenomedullary deficiency

Hypotension, Hypoglycemia (central nervous system and glucocorticoid effects are more hindered)

Are Adrenal catecholamines essential for life?

NAUR for normal function just for stress situations

what is Pheochromocytoma

– tumor overproduces catecholamines

NO overt symptoms really ( headache • hypertension • sweating • palpitations • chest pain • anxiety • glucose intolerance • increased metabolic rate)