Lecture Notes: Renal-Body Fluid System and Long-Term Blood Pressure Regulation

Renal-Body Fluid System for Arterial Pressure Control

Long-term control of arterial pressure is intertwined with body fluid volume homeostasis.
Fluid intake and output must be precisely balanced through nervous, hormonal, and local kidney control systems.
This system acts slowly but powerfully.
Increased blood volume (if vascular capacitance is constant) leads to increased arterial pressure.
Elevated pressure causes kidneys to excrete excess volume, returning pressure to normal.
It's a primitive system, fully operative in hagfish (vertebrate with low arterial pressure of $8$ to $14$ mm Hg).
- Hagfish drink seawater, increasing blood volume and pressure.
- Kidneys excrete excess volume when pressure is too high.
- Low pressure leads to less excretion, causing a buildup of volume and pressure.
This mechanism has evolved with nervous, hormonal, and local controls.
In humans, kidney output is highly sensitive to pressure changes.
- A few mmHg increase can double renal water output (pressure diuresis) and salt output (pressure natriuresis).
The renal-body fluid system is a fundamental mechanism for long-term arterial pressure control.
Evolution has refined this system, including the addition of the renin-angiotensin mechanism.

Quantitation of Pressure Diuresis as a Basis for Arterial Pressure Control

Figure 19-1 illustrates the effect of arterial pressure on renal salt and water output.
Increased pressure leads to increased urine output (pressure diuresis).
The curve is called a renal urinary output curve or a renal function curve.
At $50$ mm Hg, urine output is near zero.
At $100$ mm Hg, it is normal.
At $200$ mm Hg, it is $4$ to $6$ times normal.
Increased pressure also increases sodium output (pressure natriuresis).

Experiment Demonstrating the Renal-Body Fluid System for Arterial Pressure Control

Figure 19-2 shows an experiment on dogs with blocked nervous reflex mechanisms.
Infusion of $400$ ml of blood elevated arterial pressure to $205$ mm Hg.
Cardiac output doubled, and urine output increased $12$ -fold.
Fluid loss returned cardiac output and arterial pressure to normal within an hour.
This demonstrates the kidney's ability to eliminate excess fluid volume in response to high arterial pressure.

Renal-Body Fluid Mechanism Provides Nearly Infinite Feedback Gain for Long-Term Arterial Pressure Control

Renal output curve and net water/salt intake line intersect at the equilibrium point (Figure 19-1, point A).
Output must equal intake over the long term.
If arterial pressure rises above the equilibrium point (e.g., $150$ mm Hg, point B), output exceeds intake.
Fluid loss reduces blood volume and arterial pressure until it returns to the equilibrium level.
Even small pressure increases cause more loss than intake, ultimately restoring equilibrium.
If arterial pressure falls below the equilibrium point, intake exceeds output.
Increased body fluid and blood volume raise arterial pressure until it returns to equilibrium.
The return to the equilibrium point illustrates the near-infinite feedback gain principle.

Two Key Determinants of Long-Term Arterial Pressure

Long-term arterial pressure is determined by:
1. The pressure shift of the renal output curve for water and salt.
2. The level of water and salt intake.
If the renal output curve and intake line remain constant (Figure 19-1), mean arterial pressure will stabilize at $100$ mm Hg.
The equilibrium point shifts if either the renal output curve or the intake line changes.
Figure 19-3A: A kidney abnormality shifts the renal output curve $50$ mm Hg higher, also shifting the equilibrium point.
Figure 19-3B: A fourfold increase in salt and water intake shifts the equilibrium point to $160$ mm Hg ( $60$ mm Hg above normal).
Long-term mean arterial pressure cannot change without altering salt/water intake or shifting the renal function curve.

Chronic Renal Output Curve Much Steeper Than the Acute Curve

Chronic changes in arterial pressure have a greater effect on renal salt/water output than acute changes (Figure 19-4).
Normal kidneys have a steeper chronic renal output curve.
Increased pressure has direct and indirect (nervous/hormonal) effects on the kidney.
Increased pressure reduces sympathetic nervous system activity (via baroreceptors) and antinatriuretic hormone formation (angiotensin II, aldosterone).
Reduced activity of these system enhances pressure natriuresis and diuresis.
Reduced blood pressure activates the sympathetic nervous system, increasing antinatriuretic hormones, decreasing renal output.
Neural and hormonal influences are evident during chronic sodium intake changes.
Normal kidneys and nervous/hormonal systems can tolerate up to sixfold increases in salt/water intake with minimal impact on arterial pressure.
Salt-insensitive individuals experience minimal blood pressure changes with large salt intake variations.
Kidney injury or excessive antinatriuretic hormones cause salt sensitivity and a flattened renal output curve (like the acute curve).

Failure of Increased Total Peripheral Resistance to Elevate Long-Term Level of Arterial Pressure if Fluid Intake and Renal Function Do Not Change

The equation for arterial pressure is: $Arterial Pressure = Cardiac Output</p></li><li><p>Total Peripheral Resistance$ .
Acute increases to total peripheral resistance raises arterial pressure, but normal kidneys can restores the arterial pressure to normal in $1$ to $2$ days.
Increased vascular resistance outside the kidneys doesn't alter the blood pressure equilibrium dictated by the kidneys (Figures 19-1, 19-3).
Kidneys initiate pressure diuresis and natriuresis, eliminating salt/water until arterial pressure returns to equilibrium.
Blood pressure normalizes, with extracellular fluid and blood volume decreasing below normal.
Figure 19-5 shows normal arterial pressure in various conditions with varying total peripheral resistance, provided kidneys are normal.
If increased total peripheral resistance also increases intrarenal vascular resistance, kidney function is altered, and hypertension can arise.
Hypertension is due to increased renal resistance, not total peripheral resistance alone.

Increased Fluid Volume Can Elevate Arterial Pressure by Increasing Cardiac Output or Total Peripheral Resistance

Increased extracellular fluid volume can elevate arterial pressure if vascular capacity doesn't increase simultaneously (Figure 19-6).
Sequence: Increased extracellular fluid volume → increased blood volume → increased mean circulatory filling pressure → increased venous return → increased cardiac output → increased arterial pressure.
Increased arterial pressure then increases renal excretion, potentially normalizing extracellular fluid volume if kidney function is normal.
Cardiac output impacts arterial pressure directly and indirectly (by raising total peripheral resistance via blood flow autoregulation).
Excess blood flow triggers tissue vasoconstriction, increasing total peripheral resistance via autoregulation.
Arterial $Pressure = Cardiac Output</p></li><li><p>Total Peripheral Resistance$ , so increased total peripheral resistance elevates arterial pressure.
A small increase in cardiac output ( $5$ % to $10$ %) can elevate arterial pressure from $100$ to $150$ mm Hg with autoregulation-induced total peripheral resistance increase.

Importance of Salt (NaCl) in the Renal-Body Fluid Schema for Arterial Pressure Regulation

Increased salt intake is more likely to elevate arterial pressure than increased water intake, particularly in salt-sensitive people.
Water is rapidly excreted, but salt is not.
Salt accumulation increases extracellular fluid volume via two means:
1. Increased extracellular fluid salt concentration stimulates thirst, leading to increased water intake.
2. Increased salt concentration stimulates antidiuretic hormone secretion, causing kidneys to reabsorb more water.
Relatively small increases in extracellular fluid and blood volume can substantially increase arterial pressure.
If kidneys and antinatriuretic hormone levels are normal, increased salt intake doesn't significantly increase arterial pressure because kidneys rapidly eliminate excess salt.

Chronic Hypertension (High Blood Pressure) Caused by Impaired Renal Function

Chronic hypertension means mean arterial pressure exceeds normal ( $>110$ mm Hg).
- This corresponds to diastolic pressure $>90$ mm Hg and systolic pressure $>135$ mm Hg.
Severe hypertension can reach $150$ to $170$ mm Hg (mean), $130$ mm Hg (diastolic), and $250$ mm Hg (systolic).
Even moderate hypertension shortens life expectancy.
Lethal effects of hypertension:
1. Excess heart workload leads to heart failure/coronary artery disease.
2. High pressure damages brain blood vessels, causing stroke (cerebral infarct).
3. High pressure damages kidneys, leading to kidney failure.

Experimental Volume-Loading Hypertension Caused by Reduced Kidney Mass and Increased Salt Intake

Lessons from volume-loading hypertension (caused by excess extracellular fluid) help understand the renal-body fluid mechanism.
Figure 19-7 demonstrates volume-loading hypertension in dogs with $70$ % kidney mass removed.
Removing $70$ % kidney increased arterial pressure by only $6$ mm Hg.
Providing salt solution increased fluid intake and elevated arterial pressure by ~ $40$ mm Hg.
Switching to tap water normalized pressure, but reintroducing salt solution rapidly increased pressure again.
Reduction of kidney mass impairs salt/water excretion, causing accumulation and elevated pressure.

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

Figure 19-8 shows circulatory changes during volume-loading hypertension.
Acute phase: Reduced kidney mass + increased salt/water intake increases extracellular fluid volume, blood volume, and cardiac output ( $20$ – $40$ % above normal).
Arterial pressure rises, but less initially due to baroreceptor mechanism attenuating rise.
Baroreceptors adapt after $2$ – $4$ days, negating their effect.
Prolonged phase: Total peripheral resistance progressively increases, while cardiac output decreases towards normal (autoregulation mechanism).
Extracellular fluid and blood volume return towards normal as arteriolar resistance decreases capillary pressure, and elevated arterial pressure increases renal excretion.
Several weeks post-volume loading:
1. Hypertension persists.
2. Total peripheral resistance marked increase.
3. Extracellular fluid volume, blood volume, and cardiac output return close to normal.
Volume-loading hypertension has two stages:
1. Increased fluid volume increases cardiac output, mediating hypertension.
2. High blood pressure and total peripheral resistance, with cardiac output returning to normal and the increased total peripheral resistance being secondary.

Volume-Loading Hypertension in Patients Who Have No Kidneys but Are Being Maintained With an Artificial Kidney

Maintaining normal fluid volume via dialysis is crucial.
Failing to do so leads to hypertension: Excess fluid causes increased cardiac output, then autoregulation returns cardiac output to normal while increasing total peripheral resistance.
Hypertension appears as high peripheral resistance type, though initially caused by volume overload.

Hypertension Caused by Excess Aldosterone

Tumors secreting excess aldosterone (primary aldosteronism) increase salt/water reabsorption, increasing blood volume/pressure.
Increased salt intake exacerbates hypertension.
Over time, excess pressure causes pathological kidney changes, further retaining salt/water.
Early stages: Increased cardiac output.
Later stages: Cardiac output normalizes, and total peripheral resistance increases.

Role of the Renin-Angiotensin System in Arterial Pressure Control

Kidneys control arterial pressure via extracellular fluid volume and the renin-angiotensin system.
Renin is released when arterial pressure is low, raising pressure.

Components of the Renin-Angiotensin System

Figure 19-9: Renin is synthesized/stored in juxtaglomerular cells (JG cells) in afferent arteriole walls.
Renin secretion is controlled by the sympathetic nervous system, hormones, and local factors.
1. Pressure-sensitive baroreceptors in JG cells respond to decreased arterial pressure.
2. Decreased NaCl delivery to macula densa cells stimulates renin release.
3. Increased sympathetic activity stimulates renin release via beta-adrenergic receptors.
Renin enters blood, acting on renin substrate (angiotensinogen) to release angiotensin I.
Angiotensin I has mild vasoconstrictor properties.
Renin persist for $30$ to $60$ minutes causing continuous angiotensin I formation.
Within seconds/minutes, angiotensin I is converted to angiotensin II by angiotensin-converting enzyme (ACE) in the lungs and endothelium of blood vessels.
Angiotensin II is a powerful vasoconstrictor, inactivated in $1$ to $2$ minutes by angiotensinases.

Angiotensin II's Principal Effects

Elevates arterial pressure via:
1. Vasoconstriction (arterioles more than veins), increasing total peripheral resistance.
2. Decreased renal excretion of salt/water (via aldosterone stimulation and direct kidney effects), increasing extracellular fluid volume.

Rapidity and Intensity of the Vasoconstrictor Pressure Response to the Renin-Angiotensin System

Figure 19-10: Hemorrhage experiment shows arterial pressure rises more with a functional renin-angiotensin system.
The Renin-angiotensin system is powerful enough to recover at least halfway back to normal pressure within minutes after hemorrhage.

Angiotensin II Causes Renal Retention of Salt and Water—An Important Means for Long-Term Control of Arterial Pressure

Angiotensin II causes kidneys to retain salt/water via:
1. Direct action on kidneys.
2. Stimulation of aldosterone secretion.
Excess angiotensin II shifts the long-term renal–body fluid mechanism to a higher arterial pressure.

Mechanisms of the Direct Renal Effects of Angiotensin II to Cause Renal Retention of Salt and Water

Constricts renal arterioles (especially efferent arterioles), reducing kidney blood flow.
Slowed flow reduces peritubular capillary pressure, increasing tubular fluid reabsorption.
Angiotensin II increases tubular reabsorption of sodium/water.
Combined effects can reduce urine output to less than one-fifth normal.

Angiotensin II Increases Kidney Salt and Water Retention by Stimulating Aldosterone

Angiotensin II strongly stimulates aldosterone secretion, increasing sodium reabsorption and extracellular fluid volume.

Quantitative Analysis of Arterial Pressure Changes Caused by Angiotensin II

Figure 19-11: Angiotensin II shifts the renal output curve to higher pressure levels.
Equilibrium points shift to higher pressures with elevated angiotensin II.
- Zero angiotensin II: $75$ mm Hg.
- Elevated angiotensin II: $115$ mm Hg.
Angiotensin II, promoting renal retention, can strongly elevate chronic arterial pressure.

Role of the Renin-Angiotensin System in Maintaining a Normal Arterial Pressure Despite Large Variations in Salt Intake

Renin-angiotensin system allows for varied salt intake without major impact on fluid volume/arterial pressure (Figure 19-12).
Increased salt intake elevates extracellular fluid volume, increasing arterial pressure.
This reduces renin secretion/angiotensin II formation, promoting salt elimination and minimizes extracellular fluid volume/arterial pressure change increase.
The Renin-angiotensin system is an automatic feedback maintaining arterial pressure near normal despite increased salt intake.
Decreased salt intake causes opposite effects.
Figure 19-13: Pressure usually rises no more than $4$ to $6$ mm Hg with a $100$ -fold increase in salt intake if the system functions normally.
Continuous infusion of small amounts of angiotensin II can cause the pressure to rise $40$ mm Hg or more (see Figure 19-13).
ACE inhibitor blood pressure decreases markedly as salt intake decreases (see Figure 19-13).
This System is perhaps the body's most efficacious means for maintaining constant pressure despite wide variations in salt intake.

HYPERTENSION CAUSED BY RENIN-SECRETING TUMOR OR RENAL ISCHEMIA

Renin-secreting JG cell tumors or continuous infusion of angiotensin II cause severe hypertension.
Angiotensin II increases arterial pressure via:
1. Arteriolar constriction.
2. Renal salt/water retention.

One-Kidney Goldblatt Hypertension

Figure 19-14: Removal of one kidney and constriction of the remaining renal artery reduces pressure in the artery beyond the constriction (dashed curve).
Systemic arterial pressure rises over several days.
Early rise: Renin-angiotensin vasoconstriction.
Later rise: Retention of salt/water.
The Aortic pressure has to rise to cause normal urine output.
Renal artery stenosis post-transplant or increased renal arteriole resistance can cause similar effects.

Two-Kidney Goldblatt Hypertension

Constriction of one renal artery while the other is normal also leads to hypertension.
Constricted kidney secretes renin and retains salt/water.
The Normal kidney retains salt/water due to renin produced by the ischemic kidney.
Both kidneys retain salt/water, causing hypertension.
Clinically, this occurs with atherosclerosis (stenosis) of a single renal artery.

Hypertension Caused by Diseased Kidneys That Secrete Renin Chronically

Patchy kidney disease causes ischemia, triggering renin secretion.
Remaining kidney tissue retains salt/water due to angiotensin II.
Common cause of renal hypertension, especially in older individuals.

Other Types of Hypertension Caused by Combinations of Volume Loading and Vasoconstriction

Hypertension in the Upper Part of the Body Caused by Coarctation of the Aorta

Aortic constriction beyond head/arm arteries but proximal to renal arteries causes higher pressure in the upper body than in the lower body.
Lower body blood flow relies on collateral arteries with high vascular resistance.
Mechanism similar to one-kidney Goldblatt hypertension.
Renin is secreted, forming angiotensin II/aldosterone, causing hypertension.

Role of Autoregulation in Hypertension Caused by Aortic Coarctation

Blood flow in arms (high pressure) and legs (normal pressure) are nearly normal.
Local autoregulation compensates almost fully for pressure differences.

Hypertension in Preeclampsia (Toxemia of Pregnancy)

Preeclampsia (in $5$ – $10$ % of pregnancies) is characterized by hypertension that typically subsides post-delivery.
Placental ischemia releases toxic factors, causing vascular endothelial cell dysfunction.
Decreased nitric oxide leads to vasoconstriction, reduced fluid filtration, and impaired renal pressure natriuresis.
Thickening of glomerular membranes reduces filtration rate.
Arterial pressure required for normal urine formation becomes elevated.
Patients are prone to hypertension with excess salt intake.

Neurogenic Hypertension

Acute neurogenic hypertension: Strong sympathetic nervous system stimulation.
- Excitement or anxiety causes peripheral vasoconstriction.
Cutting baroreceptor nerves or destroying the tractus solitarius:
- Loss of normal inhibition of the vasomotor center increases arterial pressure (resetting of baroreceptor mechanism).
The sympathetic nervous system plays a role in chronic hypertension.
- Excess weight gain and obesity leads to sympathetic activation which impairs renal pressure natriuresis and lead to chronic hypertension.

Genetic Causes of Hypertension

Spontaneous hereditary hypertension found in animal strands causes sympathetic nervous system more active or structural changes in nephrons.
Monogenic hypertension: Caused by single-gene mutations in humans that impair kidney function and lead to excessive salt/water reabsorption.

PRIMARY (ESSENTIAL) HYPERTENSION

Essential hypertension is unknown origin (~ $90$ – $95$ % of hypertension cases).
Excess weight gain and sedentary lifestyle play a role.
Excess adiposity accounts for $65$ – $75$ % of the hypertension risk.

Characteristics of Primary Hypertension

Cardiac output is increased, with an additional blood flow required for extra adipose tissue. As hypertension is sustained total peripheral vascular resistance maybe increased.
Sympathetic nerve activity, especially in the kidneys, is increased in overweight patients because of fat cells influence on the hypothalamus, as well as reduced sensitivity in arterial baroreceptors.
Angiotensin II and aldosterone levels are increased in obese patients who have increased sympathetic nerve stimulation.
The renal-pressure natriuresis mechanism is impaired due to increased sympathetic nerve activity and increased levels of angiotensin II and aldosterone.

Graphic Analysis of Arterial Pressure Control in Essential Hypertension

Figure 19-15: Two types of hypertension can be recorded
1. Salt-insensitive: Arterial pressure does not increase significantly when increasing salt intake.
2. Salt-sensitive: High salt intake exacerbates the hypertension.
Salt-sensitivity is a quantitative measure not a fixed characteristic.
Blood-pressure becomes more sensitive as a person ages.

Summary of Integrated Multifaceted Systems for Arterial Pressure Regulation

Arterial pressure is maintained not by one pressure system, but multiple, each playing a role.
For example, in event of blood loss, rapid pressure is required for survival, followed by long-term restoration of the blood volume and pressure.

Arterial Pressure Control Mechanisms That Act Within Seconds or Minutes

Rapidly acting control occur in the nervous system (acute nervous reflexes):
1. The baroreceptor feedback mechanism
2. The central nervous system ischemic mechanism.
3. The chemoreceptor mechanism.
These mechanisms constrict the veins (transferring blood to the heart) and provides great pumping by the heart and periphery arterioles.

Arterial Pressure Control Mechanisms That Act After Many Minutes

The renin-angiotensin vasoconstrictor mechanism.
Stress relaxation of the vasculature.
Shift of fluid through the tissue capillary walls in and out of the circulation to readjust the blood volume if needed.

Long-Term Mechanisms for Arterial Pressure Regulation

The renal-blood volume pressure control mechanism takes a few hours but provides with great feedback.
This mechanism has multiple interactions with the renin-angiotensin-aldosterone mechanism.
Salt intake can vary yet the regulated level of pressure levels will change a few mm HG, however without the renin-angiotensin-aldosterone system, blood becomes sensitive to large variations in salt intake.
Thus, regulation begins in a life saving measure carried out by the nervous controls, followed by intermediate pressure controls, and then stabilized at a long-term pressure level by the renal body fluid mechanism.
This has many interactions between the described mechanisms and several other factors.