Cardiovascular integration

Question 1

abnormal sympathetic nerve activity results in disruption of heart and kidney nerve activity

Answer 1

see diagram
Recording renal nerve activity can contribute to diagnostics

Currently we are unable to decipher whether missignalling is coming from the heart initially and impacting brain signalling or if it originates in the brain

Question 2

The integrated system for arterial pressure control:
short and long-term

Answer 2

Baroreceptors respond to blood pressure changes minute by minute all the time
We need to identify mean BP which stays relatively stable over a healthy human life ~95-96mmHg
Kidneys regulate blood plasma vol to maintain mean pressure

Short-term control AP
Necessary for brief adjustments in response to change in bodily action/ position e.g. standing or sudden exercise
–seconds/minutes
–sympathetic nervous system (TPR/CO)
–baroreceptors

Long-Term control AP
–week/months
–linked with homeostasis body fluid volume
–kidneys controlling salt/water balance using nervous & hormonal mechanisms

–body contains too much extracellular fluid, the blood volume and AP rise.
–Increase AP direct effect to cause kidneys to excrete the excess extracellular fluid, thus returning pressure back toward normal
–phylogenetic history primitive mechanism

Question 3

Renal-Body Fluid system for AP Control:
hagfish and humans

Answer 3

Hagfish:
one of the simplest vertebrates
Hagfish drink sea water and excrete it
–AP ~8-14 mmHg, pressure increases in proportion to blood volume
–continually drinking sea water increases blood volume/pressure
–kidney excretes volume

Human:
–kidney output water/salt just as sensitive to pressure changes
–same mechanism (with refinements so more exact control possible)
(^Fundamental basis for long-term AP control)

Question 4

Quantitation of Pressure Diuresis as a Basis for arterial Pressure Control

Answer 4

If BP increases more urine is produced, if Na vol increases Na excretion increases

Pressure diuretics:­ increased AP -> increased ­ urinary volume output

Pressure natriuresis:­ increased AP -> increased ­ sodium excretion

Question 5

Infinite gain feedback system

Answer 5

Whatever happens to bp you will always produce water excretion to balance this (as a healthy individual) - new insights from 2019-2020 now available in journals

Return arterial pressure always exactly back to equilibrium point is infinite feedback gain principle for control AP by renal-body fluid mechanism –Guyeton & Coleman, 1972

Intake balances output to maintain fluid balance.

*Over long period time water/salt output = intake
*Equilibrium point
*Increase AP ~150 mmHg
Salt/water output ~3X intake
body loses fluid until pressure falls back to equilibrium level.

Eg 1 mmHg above equilibrium, lose more water/salt than intake
1 mmHg below more salt/water conserved than lost

Question 6

Two determinants of the long-term arterial pressure level

Answer 6

MBP is maintained by the kidneys, issues occur when : water/salt intake too high or kidney dysfunction

There are only 2 ways in which the pressure equilibrium point can be changed:
1.Pressure shift of the renal output curve for water and salt
2.Water and salt intake/output

*Impossible change long-term AP level to new value without changing one or both of the two basic determinants of long-term AP

*If they do change, then AP thereafter is regulated at a pressure level where the two curves intersect.

Change in pressure results in change in volume and viceversa - change in one affects the other

Question 7

Salt (NaCl) in the Renal-Body Fluid regulation of Arterial Pressure

Answer 7

*Increased Salt intake far more likely elevate AP than increased water intake

Why:
*Salt main determinant of extracellular fluid volume
*Salt accumulation and extracellular fluid volume
–increase osmolality extracellular fluid -stimulation thirst centre this return osmolality normal but increased extracellular fluid volume.
–increased osmolality -stimulation hypothalamic-posterior pituitary increase anti diuretic hormone (ADH, [arginine vasopressin, AVP])) increase reabsorb water from renal tubular fluid increase extracellular fluid volume.

*HYPERTENSION - Heightened MAP over a prolonged period resulting from cardiovasc issues or excess water/salt consumption, the baroreceptors become accustomed to higher stretch levels as ‘normal’

Eating salt increases fluid content in extracellular fluid volume, to return to normal bp is increased
It is difficult to medicate to return to normal MAP as baroreceptors must be inhibited
New research suggests the potential for baroreceptors to reset to normal levels

Question 8

Hypertension and impaired renal fluid excretion (statistics)

Answer 8

*Chronic Hypertension: MAP >110 mmHg (~100 mmHg)

*Equates diastolic > 90 mmHg: systolic > 135 mmHg

*Severe Hypertension MAP in excess of 150-170 mmHg

(diastolic ~ 130 mmHg: systolic ~250 mmHg)

*Shortened life expectancy even with moderate increase AP

*MAP 50% above normal -live no more than few years unless appropriately treated

1.Excess workload on heart leads to early heart failure and coronary heart disease and heart attack

2.Damage to major blood vessels in the brain, death of brain tissue-cerebral infarct (stroke)

3.Damage to kidneys increase kidney failure, uremia and death

*“volume-loading hypertension” crucial to understanding role of the renal-body fluid volume mechanism for AP regulation

Question 9

Experimental Volume-Loading Hypertension Caused by reduced Renal Mass Along with Simultaneous Increase in Salt Intake.

Answer 9

see diagram of graphs:
An animal subject was used (probably conducted on a dog but today would be done to rats.) During the experiment proportion of left kidney is removed with very little impact. Then the right kidney is fully removed leaving ~55% of the left kidney only. Then the animal is given only sodium chloride infused water resulting in raised MAP, returning to regular water returns the dog to regular MAP. Then providing salt treatment again results in a larger increase in MAP due to induced hypertensive condition.

*55- 65-% left renal mass
*0.9% NaCl: increase MAP ~40 mmHg
(Salt fails to quench thirst so drink 2-4X normal amounts of volume)

*Tap water: decrease MAP
*0.9% NaCl: increase MAP much more rapidly and to higher level. (tolerance of NaCl so drink more)

*reduce kidney mass reduce ability excrete salt/water

*Accumulation salt /water increase AP to enable excretion excess salt/water

Question 10

Sequential Changes in Circulatory Function During the Development of Volume-Loading Hypertension

Answer 10

increase in extracellular fluid -> blood vol increase, cardiac output increase + a decrease in total peripheral resistace MAP increases and after salt treatment it remains high due to the resetting of the baroreceptors despite all other aspects returning to normal

Hypertension initially from salt/water ratio adjustment, then it is maintained due to the resetting of the baroreceptors even in the absence of ratio abnormalities known as ‘volume loading hypertension’

*Prior “0” days kidney mass reduced
*Day “0” increase salt/water
*~Day 2 acute effect
­ - increase in: Extracellular fluid volume, CO and AP (not maximum)
- Initial decrease TPR baroreceptor mechanism opposing rise in AP but after 2-4 days reset so no-longer able to prevent rise in pressure. AP almost maximum because of increased CO even though TPR still almost normal value

*Secondary changes over weeks

*Extracellular fluid volume & blood volume return almost to normal with decrease in CO

Increase in arteriolar resistance decreased capillary pressure, which allowed fluid in the tissue spaces to be absorbed back into blood.

Elevated AP now causes kidneys excrete excess volume that had accumulated.

Question 11

Stages 1-3 of Change in Circulatory Function

Answer 11

During the Development of Volume-Loading Hypertension

1.Hypertension
2.­TPR
3.Almost complete return extracellular fluid volume, blood volume & CO back to normal

Stage 1: results from increased fluid volume accumulation causing increased CO and it is this what causes hypertension.

Stage 2: high BP, high TPR but return CO so near normal that normal measuring techniques cannot detect an abnormally elevated CO
Thus increased TPR occurs after the hypertension has developed and therefore, is secondary to the hypertension rather than being the cause.

Stage 3: Almost complete return extracellular fluid volume, blood volume & CO back to normal

Question 12

Importance of volume loading hypertension in patients maintained on an artificial kidney

Answer 12

–Volume closely regulated to prevent development of hypertension
^ So someone on renal dialysis is told to limit their water intake to 1litre per day as they will only have dialysis every 3-4 days. If they drink too much this will cause/exacerbate hypertension.

Question 13

Hormonal control –The Renin-Angiotensin system: Its Role in Pressure control and in Hypertension

Answer 13

see flow diagram
1.ANG II (angiotensin 2) acts directly on the kidneys to cause salt and water retention.

2.ANG II causes adrenal glands to secrete aldosterone and the aldosterone in turn increases salt and water reabsorption by the kidney tubules.

*Excess ANG II circulation in the blood, entire long-term renal-body fluid mechanism for AP control automatically becomes set to a higher AP than normal).

Question 14

Vasoconstrictor repressor response to RAAS

Answer 14

haemorrhage results in reduction in bp, kidney function changes and vasoconstriction act to correct blood vol. this but this takes time Ang ll allows for a quick increase in bp to counteract immediately

*Haemorrhage
1)-RAAS ~50 mmHg
2)+RAAS ~ 80 mmHg

*RAAS returns BP nearly normal ~few mins
*Full effect ~20 mins
*Slower to act for pressure control than sympathetic-adrenalin-noradrenaline system
*Life-saving mechanism

Question 15

Quantitative Analysis of Arterial Pressure Changes Caused by ANG II

Answer 15

*Shift renal output curve to right under influence of ANG II

*Equilibrium 75 to 115 mmHg

–Direct/indirect effects on kidney function

*ANG II causing renal retention salt/water powerful effect in promoting chronic elevation AP

*Normally functioning RAAS allows consumption small or large amounts of salt

Question 16

primary and secondary hypertension

Answer 16

Primary: Hypertension of unknown origin
- 90-95% cases hypertension
- hereditary link
- Link to poor diet and smoking
- Middle aged men and women with hypertension have a barrel shaped chest

Common features
–excess weight gain
–sedentary lifestyle

Correlation between weight loss & physical activity to reduce AP in hypertensive patients

Secondary hypertension
-related to kidney disease or damage
–Polycystic kidneys

Question 17

Arterial pressure control in essential hypertension

Answer 17

2 categories of hypertensives (see diagram):
1-red – non-salt sensitive, higher MAP whilst still excreting necessary salt
2 – blue – salt sensitive, do not regulate ang ll as well resulting in higher Ang ll, even higher MAP to excrete salt

Causation of these two types is still uncertain

Further categorisation subdivisions: dippers (lower salt at night) / non-dippers
*Sodium loading renal function curves
*Increasing sodium intake to a new level every few days, then waiting for the renal output of sodium to come into balance with the intake, and at the same time recording changes in AP.
*Patients -curve shift to right
–Non salt sensitive
–Salt sensitive

*Non salt vs salt sensitive
structural changes or functional differences in the kidneys of the two types of of hypertensive patients abnormal RAAS can cause blood pressure to become salt-sensitive

Question 18

Hypertension treatments

Answer 18

Inhibitors/ blockers acting at kidney level:
- Na+ inhibitor reabs start DCT
-Loop diuretic inhibit reabs in ascending limb loH
-Carbonic anhydrase inhibitor(altitude sickness-bicarb balance)
- K+ sparing loop diuretic allows loss of NA+ but prevents K+ loss

Inhibitors/ blockers in the rest of body:
- Centrally acting Imadazoline receptors α2-adrenoreceptors – brain acting
-β blocker – In blood
-Renin inhibitor
-Aldosterone receptor blocker(diuretic)
-AT1 receptor blocker
-ACE inhibitor – block enzyme conversion

Surgery
- Renalablation - prevents control of blood flow through the vessel – last resort treatment
^ Murray Esler (Melbourne)
- Chemoreceptor removal – pioneering, remove one receptor only - Paton group, Bristol University

Question 19

Summary of the Integrated Mulifaceted System for Arterial Pressure Regulation

Answer 19

see summary graph

*Arterial pressure regulated by several interrelated systems, each of which performs a specific function

*Haemorrhage - return AP to level to survive acute episode and restore blood volume eventually so circulatory system can re-establish full normality