Renal Control of BP

Question 0

How can the effective circulating volume be increased without changing plasma osmolarity?

Answer 0

Add isosmotic saline (no change in ionic concentrations)

Question 1

What does the effective circulating volume depend on?

Answer 1

Na+ content of ECF

Question 2

How much sodium & water is filtered in each part of the nephron?

Answer 2

SODIUM WATER
PCT: 67% 65%
Desc. limb: 0% 10-15%
Asc. limb: 25% 0%
DCT: 5% 0%
Collecting duct: 3% 5%-24%+ (dehydration-water loading)

Question 3

How is water reabsorbed in the proximal convoluted tubule?

Answer 3

Isosmotic (Na+ & Cl- reabsorption)

S1 (“wiggly” portion):

• increased osmotic gradient established by solute absorption
• increased hydrostatic force in interstitium
• increased oncotic pressure in peritubular capillary (due to 20% loss of filtrate)
• absorption of sodium, glucose, bicarbonate

S2-S3 (straight portion)

• absorption of Cl- (transcellular & paracellular)
• absorption of water

Question 4

How is the glomerular filtration rate maintained by the proximal convoluted tubule?

Answer 4

Sodium excretion is matched to GFR

Increased GFR —> increased filtered load —> sodium excretion blunted —> [Na+] of filtrate leaving PCT only increases slightly

Decreased GFR —> decreased filtered load —> less sodium reabsorbed —> sodium still available for transporters further down the nephron

Question 5

What occurs at the descending limb of the loop of Henle?

Answer 5

Increased concentration of sodium in lumen stimulates paracellular uptake of water

Osmolarity increases as water leaves the lumen

Question 6

What occurs at the thin ascending limb of the loop of Henle?

Answer 6

Increase in osmolarity (due to water reabsorption in descending limb) creates a gradient for passive sodium reabsorption

Question 7

What occurs at the thick ascending limb of the loop of Henle?

Answer 7

Active reabsorption of sodium and chloride via NKCC2

Lots of energy required (sensitive to hypoxia)

Fluid leaving is hypo-osmotic (more dilute)

Question 8

What occurs at the early distal convoluted tubule?

Answer 8

Hypo-osmotic fluid enters and becomes further diluted as sodium os actively reabsorbed (by NCC)

Calcium reabsorbed via NCX (PTH increases activity)

Question 9

What occurs at the late distal convoluted tubule & collecting duct?

Answer 9

Principal cells:
Negative charge created by sodium uptake (via ENaC) creates driving force for paracellular Cl- upatake
Excess potassium removed via ROMK (stimulated by aldosterone)

Intercalated cells:
Active reabsorption of Cl- and secretion of H+ & HCO3-

Variable water reuptake (dependent on no. of aquaporins present)

Variable absorption/secretion of K+, Na+, H+, & ammonia

Question 10

What is Bartter syndrome?

Answer 10

Rare inherited disorder causing down-regulation of NaKCC symports in the thick ascending limb of the loop of Henle, causing hypokalaemia & alkalosis

Question 11

How is blood pressure regulated in the short term?

Answer 11

e.g. lying down to standing up

Baroreceptor reflex in response to stretch

Carotid sinus (bifurcation of carotid artery) -> glossopharyngeal nerve

Aortic arch -> left vagus nerve

Question 12

What part of the kidney is responsible for long term regulation of blood pressure?

Answer 12

Juxtaglomerular apparatus:

• granular cells release renin in response to: beta-adrenergic stimulation, decreased renal perfusion pressure, signalling from macula densa
• macula densa sense [Na+] & volume (both indicate GFR); when GFR is low: signals to granular cells to release renin & releases vasopressive hormone in order to dilate the afferent arteriole of glomerulus
• extraglomerular mesangial cells contract (reduce capillary diameter) in response to sympathetic stimulation (intraglomerular mesangial cells secrete hormones such as erythropoietin and provide structural support to capillaries)
  note: collagen in basement membrane provides strength against high pressure

Question 13

Outline the renin-angiotensin-aldosterone system and explain how it is involved in the long term regulation of blood pressure.

Answer 13

renin ACE
Angiotensinogen ———–> Angiotensin I —————> Angiotensin II

Angiotensin II:

• vasoconstriction of afferent & efferent arteriole of the kidney
• aldosterone secretion by zona glomerulosa of adrenal cortex —-> stimulates ENaC & Na+/K+-ATPase (collecting duct) —> increases sodium reabsorption
• stimulates NHE in the proximal convoluted tubule —> increased sodium reabsorption
• release of noradrenaline (sympathetic stimulation increases renin release and independently reduces renal blood flow and activates NHE & Na+/K+-ATPase)
• sensation of thirst (increases ADH release & increases water intake)

Question 14

What drugs are used to treat hypertension by acting on the renin-angiotensin-aldosterone system?

Answer 14

ACE inhibitors (inhibit action of angiotensin converting enzyme, reducing conversion of angiotensin I to angiotensin II)

Angiotensin I & II receptor antagonists

Spironolactone (aldosterone antagonist)

Question 15

Why do ACE inhibitors frequently cause an irritating cough?

Answer 15

ACE is used to break down bradykinin (a vasodilator)

Bradykinin build up in the lungs can cause a cough

Question 16

What is the function of anti-diuretic hormone? Where is it synthesised and stored? When is it released?

Answer 16

Retains water and controls plasma osmolarity (minor role in the control of BP)

Release stimulated by severe hypovolaemia & increase in plasma osmolarity (stored in posterior pituitary)

Inserts aquaporins into collecting duct apical membrane (water can be reabsorbed)

Stimulates NaKCC2 in thick ascending limb of loop of Henle (increases sodium reabsorption -> increased amount of water reabsorbed)

Question 17

What is the function of atrial natriuretic peptide? Where is it synthesised and stored? When is it released?

Answer 17

Reduces blood pressure:

• reduces sodium reabsorption along nephron
• increases sodium excretion —> large volume of dilute urine produced
• vasodilatation of afferent arteriole (increases GFR)

Synthesised and stored in atrial myocytes

Released in response to stretch in low pressure side of system
Inhibited by reduction in effective circulating volume

Question 18

What is the function of prostaglandins in control of blood pressure? What drugs interfere with prostaglandin synthesis, and what is the significance of this?

Answer 18

Vasodilator which buffers excessive vasoconstriction by the renin-angiotensin-aldosterone system and the sympathetic nervous system
(therefore does not directly cause vasoconstriction)

Local reduction in glomerular filtration and local reduction in sodium reabsorption

NSAIDs inhibit cyclo-oxygenase (COX) which is used in prostaglandin synthesis

Therefore giving NSAIDs when renal perfusion is already reduced can cause a severe reduction in GFR, causing acute renal failure

Question 19

What is the difference between primary and secondary hypertension?

Answer 19

Essential/primary hypertension = sustained increase in BP with unknown cause (?genetic, ?environmental)

Secondary hypertension = sustained increase in BP with defined cause

Question 20

Give some examples of renal causes of secondary hypertension.

Answer 20

Renovascular: renal artery stenosis —> reduction in perfusion pressure of kidney —> release of renin —> vasoconstriction & Na+ retention at the OTHER kidney —> increase in BP

Renal parenchymal: reduction in vasodilators & inadequate glomerular filtration —> sodium & water retention —> volume-dependent hypertension

Conn’s syndrome: aldosterone secreting adenoma causes hypertension & hypokalaemia

Cushing’s syndrome: high amount of cortisol can act on aldosterone receptors

Phaeochromocytoma: tumour secreting adrenaline & noradrenaline —> increased cardiac output and increased total peripheral resistance

Question 21

How does hypertension cause damage?

Answer 21

Increase in afterload causes left-ventricular hypertrophy (—> heart failure) and increases myocardial oxygen demand (—> myocardial ischaemia —> MI)

Arterial damage causes atherosclerosis (myocardial ischaemia) which together with weakened vessels causes: cerebro-vascular disease (—> stroke), aneurysms, retinopathy, nephrosclerosis (—> renal failure)

Question 22

How can hypertension be treated by drugs which act on the renal system?

Answer 22

ACE inhibitors & angiotensin II antagonists act directly on renin-angiotensin-aldosterone system, causing diuresis & vasodilatation

note: ACE inhibitors given in heart failure to prevent sodium & water retention and peripheral arterial & venous vasoconstriction, as well as prevent excessive increases in sympathetic activity (reduces afterload ^ preload, and increase [K+])

Thiazide diuretics (reduces NaCl cotransport in DCT) & spironolactone (aldosterone antagonist) cause diuresis

(other drugs: L-type calcium channel blockers —> reduced calcium entry to vascular smooth muscle, alpha-1 receptor blockers —> reduce sympathetic tone, beta-blockers reduce sympathetic activity, reduce heart rate, and reduce contractility)

Question 23

Why does increased venous pressure cause peripheral oedema, but increased arterial pressure does not?

Answer 23

Local autoregulation by precapillary smooth muscle sphincters prevents a systemic increase in arterial pressure in the capillary bed

Hence why hypertensive patients do not always have oedema

Question 24

How can the hydrostatic pressure within the glomerulus be autoregulated?

Answer 24

Afferent arteriole:
Relaxes -> increases hydrostatic pressure -> increases GFR
Contracts -> decreases hydrostatic pressure -> decreases GFR

Efferent arteriole:
Relaxes -> decreases hydrostatic pressure -> decreases GFR
Contracts -> increases hydrostatic pressure -> increases GFR

note: if both relaxed then the GFR would decrease (pressure gradient more affected efferent arteriole as it is narrower)