Renal Physiology

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Renal Hemodynamics III

Chris Baylis, PhD

Learning Objectives: To learn and understand:

• How the tone of the afferent and efferent arterioles (RA and RE) determine RPF and glomerular blood pressure and how Kf is controlled by glomerular mesangial cell tone.

• How the tone of RA and RE is regulated in responses to a reduction in blood volume via activation of renal nerve activity and angiotensin II (ANGII).

• How RA and RE are controlled n response to plasma volume expansion via activation of nitric oxide (NO), atrial natriuretic peptide (ANP) and possibly other factors.

• How volume mediated changes in the tone of RA and RE influence GFR.

GFR = RPF x FF

Control of GFR is by regulation of: 1. RPF 2. The PGC (which controls hydrostatic Pressure

Gradient (P) 3. Glomerular Capillary Ultrafiltration Coefficient,

Kf = water permeability x surface area 4. Oncotic pressure of blood arriving at

Glomerulus (A) due to nonfilterable plasma proteins

RPF is controlled by changes in afferent and/or efferent arteriolar resistances (RA and RE). Relaxation of RA and/or RE increase RPF. In this example, both RA and RE relax. Flow increases.

Afferent glomerulus efferent arteriole arteriole Afferent glomerulus efferent

arteriole arteriole

Impact of resistance changes on plasma flow and Pgc,.

Afferent glomerulus efferent arteriole  PGC arteriole

Afferent glomerulus efferent arteriole  PGC arteriole

Afferent glomerulus efferent arteriole Normal PGC arteriole

Afferent glomerulus efferent arteriole Normal PGC arteriole

Impact of changes in RA and RE on RPF, PGC and GFR

• The impact of a change in resistance on flow is easy to predict. When resistance falls (vessel radius increases) flow will always increase. ie. Relaxation of RA, RE and both RA and RE, all increase flow.

• The impact of a change in resistance on PGC is variable and depends on which resistance is affected. If RA constricts, both flow and PGC fall, so GFR falls. If RE constricts, flow falls and PGC increases. Here the determinants of GFR have offsetting actions. There will be litlle change in GFR. If both RA and RE constrict, flow falls but PGC doesn’t change, so GFR falls (Remember GFR = RPF x FF).

HIDDEN SLIDE: Experiment to illustrate effect of changes in RA and RE on flow and pressure. For this you need access

to a garden hose.

Turn on a garden hose at the faucet. 1). Put your right foot on the hose to partly

obstruct (ie. increase resistance to flow). What happens to flow out of the hose?

2). What happens to pressure at the downstream (open end) of the hose?

3). What happens to pressure at the upstream, faucet side of the hose?

Answers

1). Flow falls 2). Downstream pressure falls. 3). Upstream pressure increases.

HIDDEN SLIDE (cont): Experiment to illustrate effect of changes in RA and RE

on flow and pressure. Now put both feet on the hose. What

happens to pressure between your feet when:

1). You press on the right foot (nearest to faucet?

2). You press on the left foot, nearest to open end of hose.

3). You press equally on both feet.

ANSWERS Pressure between your feet will 1). Fall (by increasing upstream resistance to flow,

more pressure is need to drive fluid forward so a greater pressure drop occurs).

2). Increases (by increasing the downstream resistance a back pressure is created between your feet).

3). No change (the 2 resistance increases counteract each other with respect to pressure).

In every case, 1-3, flow through the hose will fall.

Individual Regulatory Systems which control afferent and efferent arteriolar resistance

KIDNEY IS PRIMARILY A VOLUME SENSING AND REGULATING ORGAN.

Most of the physiologic control of GFR is secondary to volume status.

Volume depletion (low blood volume) activates vasoconstrictors (and suppresses vasodilators).

Volume expansion (high blood volume) activates vasodilators (and suppresses vasoconstrictors).

Glomerular Capillary Ultrafiltration Coefficient, Kf Kf = filtration surface area and water permeability.

Both SA and water permeability are high at the glomerulus vs. other capillaries.

Variations in Kf can influence glomerular filtration rate.

Regulation is by changes in the mesangial cell tone, which control SA. Mesangial cells contain receptors and respond to vasoactive substances.

NOTE: In normals, Kf is usually sufficiently high that changes don’t alter GFR

The important "regulated " determinants of GFR are : plasma flow

glomerular blood pressure (P) Kf

All controlled by tone in contractile cells. Tone in vascular smooth muscle (vsm) in afferent

resistance and efferent arterioles (RA and RE) controls plasma flow and PGC

Tone in the glomerular mesangial cells, determines Kf via regulation of glomerular filtration surface area. Kf is normally high enough that it does not usually control GFR.

In practice, glomerular filtration is primarily

regulated by the tone of vsm cells in RA and RE.

Volume

Arterial BP

RAPID INTERMEDIATE

SLOW

SNS by baroreceptor

activation Renal RENIN

release and ANGII Renal volume

retention

Vasoconstriction

BP

vasodilators

Mechanisms of renal volume retention.

Control of glomerular filtration.

Filter less Na and H2O at the glomerulus, excrete less Na and H2O, conserving volume.

Renal nerves and catecholamines. The renal efferent nerves, mainly sympathetic. Renal nerve

activity normally low. Renal nerve stimulation above threshold leads to constriction

of afferent and efferent vessels. This lowers GFR by reducing RPF.

Renal nerve activity vasoconstricts kidney during : Physical and mental stress upright posture (via baroreceptor reflex). GFR falls about 10%

on standing volume depletion (also involved in stimulation of renin release) Exercise, intensity-dependent renal vasoconstriction

The circulating renin-angiotensin system

Circulating Angiotensinogen (Renin substrate)

Renin (enzyme)

Angiotensin I

Angiotensin converting enzyme

Angiotensin II

PLASMA ANGIOTENSIN II (PANGII) INCREASES AS BLOOD VOLUME FALLS.

Euvolemia: Low PANGII concentrations. These directly and indirectly promote sodium retention. No direct vascular effects.

Mild- moderate volume deletion: Moderate PANGII concentrations. Greater sodium retention. Moderate vasoconstriction.

Severe volume deletion: Maximum PANGII concentrations. Maximum sodium retention. Severe vasoconstriction.

As PANGII increases constriction of both afferent and efferent arterioles occurs. This reduces RPF which lowers GFR. There is a preferential constriction of the efferent arteriole so PGC increases. This blunts the fall in GFR.

Afferent glomerulus efferent arteriole  PGC arteriole

NET EFFECT OF ANGII ON GFR DEPENDS ON CONCENTRATION.

Moderate concentrations of angiotensin II cause a small fall in GFR because of offsetting effects of decreased flow and increased PGC .

High concentrations cause intense renal vasoconstriction and marked falls in GFR.

In normal (volume) individuals, angiotensin II is low and does not control BP or renal hemodynamics but does regulate sodium excretion (see later).

In volume depletion angiotensin II constricts renal and extrarenal vessels = physiologic.

VOLUME EXPANSION ACTIVATES VASODILATORS AND SUPPRESSES

VASOCONSTRICTORS. NITRIC OXIDE (NO). Extremely important, physiologic regulator of renal

hemodynamics (and total peripheral resistance). Vascular endothelial NO release is increased by an

increase in blood flow. Blood flow increases when volume expands.

NO actions: vasodilation, increases Na excretion Made in many locations. Vascular endothelium, diffuses to adjacent vascular smooth

muscle to cause relaxation. Renal epithelium, inhibits Na+reabsorption and increases

Na+ excretion. Continual, basal production.

Within the renal circulation, nitric oxide generated by endothelium vasodilates afferent resistance and efferent resistance and relaxes the mesangial cells.

Raises GFR by increasing RPF and maintaining a high Kf.

Afferent glomerulus efferent arteriole arteriole

Prostaglandins

Made in the vascular endothelium. Mainly vasodilator and inhibit platelet aggregation. Natriuretic.

Minimal role in control of renal hemodynamics in normals. Cyclooxygenase inhibition (aspirin, naproxen etc) has no effect on GFR in normals.

When kidney is vasoconstricted eg. volume depletion, aging, renal disease ,the vasodilatory PGs become more involved in maintaining renal perfusion and GFR.

In vulnerable individuals COX inhibitors decrease renal perfusion and GFR; can lead to acute renal failure.

Atrial Natriuretic Peptide (ANP or ANF).

ANP released in response to volume overload (atrial stretch). Vasodilator and natriuretic (increases sodium excretion).

ANP vasodilates afferent arterioles which increases plasma flow and PGC . Particularly effective at increasing GFR.

ANP also directly inhibits sodium reabsorption in the tubule, increases sodium excretion.

Afferent glomerulus efferent arteriole  PGC arteriole

GFR is regulated by changes in blood volume. Volume depletion: • Activates SNS which vasoconstricts RA and RE which lowers

RPF and GFR. • Increases plasma ANGII which constricts RA and RE (more)

and lowers RPF. PGC increases. Increasing ANGII has a graded effect on GFR, with a fall when levels are high and produce marked falls in RPF.

Volume expansion: • Increases NO, relaxes RA and RE, increases RPF and GFR. • Releases ANP, relaxes RA, increases RPF, PGC and GFR.

You will understand the significance of these changes in GFR with volume when we discuss volume homeostasis and sodium balance.

Summary of key concepts.

• The series resistance arterioles (RA and RE) that surround the glomerulus play a critical role in control of RPF and PGC.

• Vasoconstriction of RA, RE or both, reduces RPF. Vasoconstriction of RA lowers PGC while constriction of RE increases PGC. So the net effect on GFR depends on the balance between RA and RE.

• Volume status is the major physiologic regulator of GFR with volume depletion activating vasoconstrictor renal nerve activity and ANGII which lowers GFR.

• Volume expansion activates vasodilatory systems (NO and ANP) which increase GFR.