Introduction to the Cardiovascular System - part 6 pps

This increases arterial blood pressure pressor response owing to both an increase in cardiac output and an increase in systemic vascular resistance.. If norepinephrine is injected intra-

epinephrine are different because

epineph-rine binds to -adrenoceptors as well as to

-adrenoceptors Increasing concentrations of

epinephrine result in further cardiac

stimula-tion along with -adrenoceptor mediated

acti-vation of vascular smooth muscle leading to

vasoconstriction This increases arterial blood

pressure (pressor response) owing to both an

increase in cardiac output and an increase in

systemic vascular resistance

Circulating norepinephrine affects the

heart and systemic vasculature by binding to

1, 2, 1, and 2adrenoceptors; however, the

affinity of norepinephrine for 2 and 2

-adrenoceptors is relatively weak Therefore,

the predominant affects of norepinephrine

are mediated through 1 and 1

-adrenocep-tors If norepinephrine is injected

intra-venously, it causes an increase in mean

arter-ial blood pressure (systemic vasoconstriction)

and pulse pressure (owing to increased stroke

volume) and a paradoxical decrease in heart

rate after an initial transient increase in heart

rate (Fig 6-9; Table 6-3) The transient

in-crease in heart rate is due to norepinephrine binding to 1-adrenoceptors in the sinoatrial node, whereas the secondary bradycardia is due to a baroreceptor reflex (vagal-mediated), which is in response to the increase in arterial pressure

High levels of circulating catecholamines, caused by a catecholamine-secreting adrenal

tumor (pheochromocytoma), causes

tachy-cardia, arrhythmias, and severe hypertension (systolic arterial pressures can exceed 200 mm Hg)

Other actions of circulating catecholamines include (1) stimulation of renin release with subsequent elevation of angiotensin II (AII) and aldosterone, and (2) cardiac and vascular smooth muscle hypertrophy and remodeling These actions of catecholamines, in addition to the hemodynamic and cardiac actions already described, make them a frequent therapeutic target for the treatment of hypertension, heart failure, coronary artery disease, and arrhyth-mias This has led to the development and use

of many different types of  and

-adrenocep-How would the changes in arterial pressure and heart rate shown in Figure 6-8 be dif-ferent if1 -adrenoceptors were blocked before the administration of low-dose epi-nephrine?

1-adrenoceptor activation is responsible for the tachycardia and increased cardiac output produced by epinephrine Blocking 1-adrenoceptors would abolish this re-sponse Epinephrine also binds to vascular 2-adrenoceptors to cause vasodilation;

therefore arterial pressure would fall during epinephrine infusion in the presence of

1-adrenoceptor blockade because the decrease in systemic vascular resistance would not be offset by an increase in cardiac output

P R O B L E M 6 - 2

How would the norepinephrine-induced changes in arterial pressure and heart rate shown in Figure 6-9 be different in the presence of bilateral cervical vagotomy?

Bilateral cervical vagotomy would prevent vagal slowing of the heart and denervate the aortic arch baroreceptors Heart rate (and inotropy) would increase owing to nor-epinephrine binding to 1-adrenoceptors on the heart that is now unopposed by the vagus This, along with aortic arch denervation, would enhance the pressor response of norepinephrine

P R O B L E M 6 - 3

tor antagonists to modulate the effects of

cir-culating catecholamines as well as the

norepi-nephrine released by sympathetic nerves

Renin-Angiotensin-Aldosterone

System

The renin-angiotensin-aldosterone system

plays an important role in regulating blood

vol-ume, cardiac and vascular function, and arterial

blood pressure Although the pathways for

renin and angiotensin formation have been

found in a number of tissues, the most

impor-tant site for renin formation and subsequent

formation of circulating angiotensin is the

kid-ney Sympathetic stimulation of the kidneys

(via 1-adrenoceptors), renal artery

hypoten-sion, and decreased sodium delivery to the

dis-tal tubules (usually caused by reduced

glomerular filtration rate secondary to reduced

renal perfusion) stimulate the release of renin

into the circulation The renin is formed within,

and released from, juxtaglomerular cells

as-sociated with afferent and efferent arterioles of

renal glomeruli, which are adjacent to the

mac-ula densa cells of distal tubule segments that

sense sodium chloride concentrations in the

distal tubule Together, these components are

referred to as the juxtaglomerular apparatus

Renin is an enzyme that acts upon

an-giotensinogen, a circulating substrate

syn-thesized and released by the liver, which un-dergoes proteolytic cleavage to form the de-capeptide angiotensin I Vascular endothe-lium, particularly in the lungs, has an enzyme,

angiotensin-converting enzyme (ACE),

that cleaves off two amino acids to form the

octapeptide, angiotensin II.

Angiotensin II has several important func-tions that are mediated by specific angiotensin

II receptors (AT1) (Figure 6-10) It

1 Constricts resistance vessels, thereby in-creasing systemic vascular resistance and arterial pressure

2 Facilitates norepinephrine release from sympathetic nerve endings and inhibits norepinephrine re-uptake by nerve end-ings, thereby enhancing sympathetic adrenergic affects

3 Acts upon the adrenal cortex to release al-dosterone, which in turn acts upon the kid-neys to increase sodium and fluid reten-tion, thereby increasing blood volume

4 Stimulates the release of vasopressin from the posterior pituitary, which acts upon the kidneys to increase fluid retention and blood volume

5 Stimulates thirst centers within the brain, which can lead to an increase in blood vol-ume

6 Stimulates cardiac and vascular hypertrophy

60

80

100 140 180

100 120

60

FIGURE 6-9 Effects of intravenous administration of a moderate dose of norepinephrine on arterial pressure and heart rate Norepinephrine increases mean arterial pressure and arterial pulse pressure; heart rate transiently increases ( 1-adrenoceptor stimulation), then decreases owing to baroreceptor reflex activation of vagal efferents to the heart Mean arterial pressure rises because norepinephrine binds to vascular 1-adrenoceptors, which increases systemic vascular resistance.

Angiotensin II is continuously produced under basal conditions, and this production

can change under different physiologic

condi-tions For example, when a person exercises,

circulating levels of angiotensin II increase

An increase in renin release during exercise

probably results from sympathetic stimulation

of the kidneys Changes in body posture

like-wise alter circulating AII levels, which are

in-creased when a person stands As with

exer-cise, this results from sympathetic activation

Dehydration and loss of blood volume

(hypo-volemia) stimulate renin release and

an-giotensin II formation in response to renal

artery hypotension, decreased glomerular

fil-tration rate, and sympathetic activation

Several cardiovascular disease states are as-sociated with changes in circulating

an-giotensin II For example, secondary

hyper-tension caused by renal artery stenosis is

associated with increased renin release and

circulating angiotensin II Primary

hyperal-dosteronism, caused by an adrenal tumor

that secretes large amounts of aldosterone,

in-creases arterial pressure through its effects on

renal sodium retention This increases blood

volume, cardiac output, and arterial pressure

In this condition, renin release and circulating angiotensin II levels are usually depressed be-cause of the hypertension In heart failure, circulating angiotensin II increases in re-sponse to sympathetic activation and de-creased renal perfusion Therapeutic manipu-lation of the renin-angiotensin-aldosterone system has become important in treating hy-pertension and heart failure ACE inhibitors and AT1receptor blockers effectively decrease arterial pressure, ventricular afterload, blood volume, and hence ventricular preload, and they inhibit and reverse cardiac and vascular remodeling that occurs during chronic hyper-tension and heart failure

Note that local, tissue-produced an-giotensin may play a significant role in cardio-vascular pathophysiology Many tissues and organs, including the heart and blood vessels, can produce renin and angiotensin II, which have actions directly within the tissue This may explain why ACE inhibitors can reduce arterial pressure and cause cardiac and vascu-lar remodeling (e.g., diminish hypertrophy) even in individuals who do not have elevated

Renin

AII

Arterial Pressure

Aldosterone

↑

Renal Sodium & Fluid Retention

Angiotensinogen

Sympathetic Stimulation Hypotension Sodium

Systemic Vasoconstriction

Blood Volume

AI Kidney

Cardiac Output

Cardiac &

Vascular Hypertrophy

Adrenal Cortex

↓

↑

↑

Thirst

FIGURE 6-10 Formation of angiotensin II and its effects on renal, vascular, and cardiac function Renin is released by the kidneys in response to sympathetic stimulation, hypotension, and decreased sodium delivery to distal tubules.

Renin acts upon angiotensinogen to form angiotensin I (AI), which is converted to angiotensin II (AII) by angiotensin-converting enzyme (ACE) AII has several important actions: it stimulates aldosterone release, which increases renal

sodium reabsorption; directly stimulates renal sodium reabsorption; stimulates thirst; produces systemic vasocon-striction; and causes cardiac and vascular smooth muscle hypertrophy The overall systemic effect of increased AII is increased blood volume, venous pressure, and arterial pressure.

circulating levels of angiotensin II In

hyper-tension and heart failure, for example, tissue

ACE activity is often elevated, and this may be

the primary target for the pharmacologic

ac-tions of ACE inhibitors

Atrial Natriuretic Peptide

Atrial natriuretic peptide (ANP) is a 28-amino

acid peptide that is synthesized, stored, and

released by atrial myocytes in response to

atrial distension, angiotensin II stimulation,

endothelin, and sympathetic stimulation

(-adrenoceptor mediated) Therefore, elevated

levels of ANP are found during conditions

such as hypervolemia and congestive heart

failure, both of which cause atrial distension

ANP is involved in the long-term

regula-tion of sodium and water balance, blood

vol-ume, and arterial pressure (Figure 6-11)

Most of its actions are the opposite of

angiotensin II, and therefore ANP is a

counter-regulatory system for the

renin-angiotensin-aldosterone system ANP

de-creases aldosterone release by the adrenal

cortex; increases glomerular filtration rate;

produces natriuresis and diuresis (potassium sparing); and decreases renin release, thereby decreasing angiotensin II These actions re-duce blood volume, which leads to a fall in central venous pressure, cardiac output, and arterial blood pressure Chronic elevations of ANP appear to decrease arterial blood pres-sure primarily by decreasing systemic vascular resistance

The mechanism of systemic vasodilation may involve ANP receptor-mediated eleva-tions in vascular smooth muscle cGMP (ANP activates particulate guanylyl cyclase) ANP also attenuates sympathetic vascular tone This latter mechanism may involve ANP act-ing upon sites within the central nervous sys-tem as well as through inhibition of norepi-nephrine release by sympathetic nerve terminals

A new class of drugs that are neutral en-dopeptidase (NEP) inhibitors may be useful

in treating heart failure By inhibiting NEP, the enzyme responsible for the degradation of ANP, these drugs elevate plasma levels of ANP NEP inhibition is effective in some models of heart failure when combined with

Release

Natriuresis Diuresis

↑GFR

↓

↓ CO

↓

↓ SVR

Degradation

Atrial distension Sympathetic stimulation Angiotensin II Endothelin

NEP

Blood Volume

CVP

↓

ANP

Arterial Pressure

FIGURE 6-11 Formation and cardiovascular/renal actions of atrial natriuretic peptide (ANP) ANP, which is released

from cardiac atrial tissue in response to atrial distension, sympathetic stimulation, increased angiotensin II, and en-dothelin, functions as a counter-regulatory mechanism for the renin-angiotensin-aldosterone system ANP decreases renin release, angiotensin II and aldosterone formation, blood volume, central venous pressure, and arterial pressure.

NEP, neutral endopeptidase; GFR, glomerular filtration rate; CVP, central venous pressure; CO, cardiac output; SVR,

systemic vascular resistance.

an ACE inhibitor The reason for this is that

NEP inhibition, by elevating ANP, reinforces

the effects of ACE inhibition

Brain-type natriuretic peptide (BNP), a 32-amino acid peptide hormone related to ANP,

is synthesized and released by the ventricles in

response to pressure and volume overload,

particularly during heart failure BNP appears

to have actions that are similar to those of

ANP Recently, circulating BNP has been

shown to be a sensitive biomarker for heart

failure

Vasopressin (Antidiuretic Hormone)

Vasopressin (arginine vasopressin, AVP; anti-diuretic hormone, ADH) is a nonapeptide hormone released from the posterior pituitary (Figure 6-12) AVP has two principal sites of action: the kidneys and blood vessels The most important physiologic action of AVP is that it increases water reabsorption by the kidneys by increasing water permeability in the collecting duct, thereby permitting the formation of concentrated urine This is the

A 56-year old male patient is found to have an arterial pressure of 190/115 mm Hg.

Two years earlier he was normotensive Diagnostic tests reveal bilateral renal artery stenosis Describe the mechanisms by which this condition elevates arterial pressure.

Bilateral renal artery stenosis reduces the pressure within the afferent arterioles, which causes release of renin This, in turn, increases circulating angiotensin II, which stimulates aldosterone release Activation of the renin-angiotensin-aldosterone system causes sodium and fluid retention by the kidneys and an increase in blood volume, which increases cardiac output Increased vasopressin (stimulated by angiotensin II) contributes to the increase in blood volume Increased angiotensin II increases systemic vascular resistance by binding to vascular AT1receptors and by enhancement of sympa-thetic activity These changes in cardiac output and systemic vascular resistance lead to

a hypertensive state

C A S E 6 - 1

Angiotensin II Hyperosmolarity Decreased atrial receptor firing Sympathetic stimulation

Vasoconstriction

Pituitary

Renal Fluid Reabsorption

Increased Blood Volume

Increased Arterial Pressure

Vasopressin

FIGURE 6-12 Cardiovascular and renal effects of arginine vasopressin (AVP) AVP release from the posterior pituitary

is stimulated by angiotensin II, hyperosmolarity, decreased atrial receptor firing (usually in response to hypovolemia), and sympathetic activation The primary action of AVP is on the kidney to increase water reabsorption (antidiuretic effect), which increases blood volume and arterial pressure AVP also has direct vasoconstrictor actions at high con-centrations.

antidiuretic property of AVP, and it leads to an

increase in blood volume and arterial blood

pressure This hormone also constricts arterial

blood vessels; however, the normal

physio-logic concentrations of AVP are below its

va-soactive range Studies have shown,

neverthe-less, that in severe hypovolemic shock, when

AVP release is very high, AVP contributes to

the compensatory increase in systemic

vascu-lar resistance

Several mechanisms regulate the release

of AVP Specialized stretch receptors within

the atrial walls and large veins

(cardiopul-monary baroreceptors) entering the atria

de-crease their firing rate when atrial pressure

falls (as occurs with hypovolemia) Afferents

from these receptors synapse within the

hy-pothalamus, which is the site of AVP

synthe-sis AVP is transported from the

hypothala-mus via axons to the posterior pituitary, from

where it is secreted into the circulation Atrial

receptor firing normally inhibits the release

of AVP With hypovolemia and decreased

central venous pressure, the decreased firing

of atrial stretch receptors leads to an increase

in AVP release AVP release is also stimulated

by enhanced sympathetic activity

accompany-ing decreased arterial baroreceptor activity

during hypotension An important

mecha-nism regulating AVP release involves

hypo-thalamic osmoreceptors, which sense

extra-cellular osmolarity When osmolarity rises, as

occurs during dehydration, AVP release is

stimulated Finally, angiotensin II receptors

located within the hypothalamus regulate

AVP release; an increase in angiotensin II

stimulates AVP release

Heart failure causes a paradoxical increase

in AVP The increased blood volume and atrial

pressure associated with heart failure suggest

that AVP secretion should be inhibited, but it

is not It may be that sympathetic and

renin-angiotensin system activation in heart failure

override the volume and low pressure

cardio-vascular receptors (as well as the

osmoregula-tion of AVP) and cause the increase in AVP

se-cretion This increase in AVP during heart

failure may contribute to the increased

sys-temic vascular resistance and to renal

reten-tion of fluid

In summary, the importance of AVP in car-diovascular regulation is primarily through its effects on volume regulation, which in turn af-fects ventricular preload and cardiac output through the Frank-Starling relationship Increased AVP, by increasing blood volume, increases cardiac output and arterial pressure The vasoconstrictor effects of AVP are proba-bly important only when AVP levels are very high, as occurs during severe hypovolemia

INTEGRATION OF NEUROHUMORAL MECHANISMS

Autonomic and humoral influences are neces-sary to maintain a normal arterial blood pres-sure under the different conditions in which the human body functions Neurohumoral mechanisms enable the body to adjust to changes in body posture, physical activity, or environmental conditions The neurohumoral mechanisms act through changes in systemic vascular resistance, venous compliance, blood volume, and cardiac function, and through these actions they can effectively regulate ar-terial blood pressure (Table 6-4) Although each mechanism has independent cardiovas-cular actions, it is important to understand that each mechanism also has complex inter-actions with other control mechanisms that serve to reinforce or inhibit the actions of the other control mechanisms For example, acti-vation of sympathetic nerves either directly or indirectly increases circulating angiotensin II, aldosterone, adrenal catecholamines, and arginine vasopressin, which act together to in-crease blood volume, cardiac output, and ar-terial pressure These humoral changes are accompanied by an increase in ANP, which acts as a counter-regulatory system to limit the effects of the other neurohumoral mecha-nisms

Finally, it is important to note that some neurohumoral effects are rapid (e.g., auto-nomic nerves and catecholamine effects on cardiac output and pressure), whereas others may take several hours or days because changes in blood volume must occur before alterations in cardiac output and arterial pres-sure can be fully expressed

SUMMARY OF IMPORTANT

CONCEPTS

• Autonomic regulation of the heart and

vas-culature is primarily controlled by special regions within the medulla oblongata of the brainstem that contain the cell bodies of sympathetic and parasympathetic (vagal) efferent nerves

• The hypothalamus plays an integrative role

by modulating medullary neuronal activity (e.g., during exercise)

• Sensory information from peripheral

baroreceptors (e.g., carotid sinus barore-ceptors) synapse within the medulla at the nucleus tractus solitarius, which modulates the activity of the sympathetic and vagal neurons within the medulla

• Preganglionic parasympathetic efferent

nerves exit the medulla as the tenth cranial nerve and travel to the heart within the left and right vagus nerves Preganglionic fibers synapse within ganglia located within the heart; short postganglionic fibers innervate the myocardial tissue Preganglionic sym-pathetic efferent nerves exit from the spinal cord and synapse within paraverte-bral or preverteparaverte-bral ganglia before sending out postganglionic fibers to target tissues in the heart and blood vessels

• Sympathetic activation increases heart rate,

inotropy, and dromotropy through the re-lease of norepinephrine, which binds pri-marily to postjunctional cardiac 

-adreno-ceptors Norepinephrine released by sym-pathetic nerves constricts blood vessels by binding to postjunctional 1 and 2 -adrenoceptors The release of norepineph-rine from sympathetic nerve terminals is modulated by prejunctional 2 -adrenocep-tors, 2-adrenoceptors and muscarinic (M2) receptors

• Parasympathetic activation decreases heart rate, inotropy, and dromotropy, and it pro-duces vasodilation in specific organs through the release of acetylcholine, which binds to postjunctional muscarinic (M2) re-ceptors

• Baroreceptors are mechanoreceptors that respond to stretch induced by an increase

in pressure or volume Arterial barorecep-tor activity (e.g., carotid sinus and aortic arch receptors) tonically inhibits sympa-thetic outflow to the heart and blood ves-sels, and it tonically stimulates vagal out-flow to the heart Decreased arterial pressure, therefore, decreases the firing of arterial baroreceptors, which leads to reflex activation of sympathetic influences acting

on the heart and blood vessels and with-drawal of the vagal activity to the heart

• Peripheral chemoreceptors (e.g., carotid bodies) and central chemoreceptors (e.g., medullary chemoreceptors) respond to de-creased pO2and pH or increased pCO2of the blood Their primarily function is to regulate respiratory activity, although

TABLE 6-4 EFFECTS OF NEUROHUMORAL ACTIVATION ON BLOOD VOLUME,

CARDIAC OUTPUT AND ARTERIAL PRESSURE

↑ = increase; ↓ = decrease *dependent upon plasma epinephrine concentration.

chemoreceptor activation generally leads

to activation of the sympathetic nervous

system to the vasculature, which increases

arterial pressure Heart rate responses

de-pend upon changes in respiratory activity

• Reflexes triggered by changes in blood

vol-ume, cerebral and myocardial ischemia,

pain, pulmonary activity, muscle and joint

movement, and temperature alter cardiac

and vascular function

• Sympathetic activation of the adrenal

medulla stimulates the release of

cate-cholamines, principally epinephrine This

hormone produces cardiac stimulation (via

1-adrenoceptors), and it either decreases

(via vascular 2-adrenoceptors) or

in-creases (via vascular 1and 2

-adrenocep-tors) systemic vascular resistance,

depend-ing upon the plasma concentration

• The renin-angiotensin-aldosterone system

plays a major role in regulating renal

excre-tion of sodium and water, and therefore it

strongly influences blood pressure through

changes in blood volume Renin is released

by the kidneys in response to sympathetic

stimulation, hypotension, and decreased

sodium delivery to distal tubules Renin

acts upon angiotensinogen to form

giotensin I, which is converted to

an-giotensin II (AII) by anan-giotensin-convert-

angiotensin-convert-ing enzyme (ACE) AII has the followangiotensin-convert-ing

actions: (1) it stimulates aldosterone

re-lease from the adrenal cortex, which

in-creases renal sodium reabsorption; (2) it

acts on renal tubules to increase sodium

re-absorption; (3) it stimulates thirst; (4) it

produces systemic vasoconstriction; (5) it

enhances sympathetic activity; and (6) it

produces cardiac and vascular hypertrophy

The overall systemic effect of increased AII

is increased blood volume, venous

pres-sure, and arterial pressure

• Atrial natriuretic peptide (ANP), which is

released by the atria primarily in response

to atrial stretch, functions as a

counter-reg-ulatory mechanism for the

renin-an-giotensin-aldosterone system Therefore,

increased ANP reduces blood volume,

ve-nous pressure, and arterial pressure

• Arginine vasopressin (AVP; antidiuretic hormone), which is released by the poste-rior pituitary when the body needs to re-duce renal loss of water, enhances blood volume and increases arterial and venous pressures At high plasma concentrations, AVP constricts resistance vessels

Review Questions

Please refer to the appendix for the answers

to the review questions.

For each question, choose the one best answer:

1 The cell bodies for the preganglionic vagal efferents innervating the heart are found

in which region of the brain?

a Cortex

b Hypothalamus

c Medulla

d Nucleus tractus solitarius

2 Norepinephrine released by sympathetic nerves

a Binds preferentially to 2 -adreno-ceptors on cardiac myocytes

b Constricts blood vessels by binding

to 1-adrenoceptors

c Inhibits its own release by binding

to prejunctional 2-adrenoceptors

d Decreases renin release in the kid-neys

3 Stimulating efferent fibers of the right va-gus nerve

a Decreases systemic vascular resis-tance

b Increases atrial inotropy

c Increases heart rate

d Releases acetylcholine, which binds

to M2receptors

4 A sudden increase in carotid artery pressure

a Decreases carotid sinus barorecep-tor firing rate

b Increases sympathetic efferent nerve activity to systemic circulation

c Increases vagal efferent activity to the heart

d Results in reflex tachycardia

5 Which of the following can cause

tachy-cardia?

a Face submersion in cold water

b Increased blood pCO2

c Increased firing of carotid sinus baroreceptors

d Vasovagal reflex

6 Infusion of a low-to-moderate dose of

epi-nephrine following pharmacologic block-ade of -adrenoceptors will

a Decrease mean arterial pressure

b Have no significant cardiovascular effects

c Increase heart rate

d Increase systemic vascular resis-tance

7 In an experimental protocol, intravenous

infusion of acetylcholine was found to de-crease mean arterial pressure and inde-crease heart rate These results can best be ex-plained by

a Direct action of acetylcholine on muscarinic receptors at the sinoatrial node

b Increased firing of carotid sinus baroreceptors

c Reflex activation of sympathetic nerves

d Reflex systemic vasodilation

8 An increase in circulating angiotensin II concentrations

a Depresses sympathetic activity

b Increases blood volume

c Inhibits aldosterone release

d Inhibits the release of atrial natri-uretic peptide

9 Atrial natriuretic peptide

a Enhances renal sodium retention

b Increases renin release

c Inhibits the release of aldosterone

d Increases blood volume and cardiac output

SUGGESTED READINGS

Berne RM, Levy MN Cardiovascular Physiology 8th

Ed Philadelphia: Mosby, 2001.

Melo LG, Pang SC, Ackermann U Atrial natriuretic peptide: regulator of chronic arterial blood pressure News Physiol Sci 2000;15:143–149.

Mendolowitz D Advances in parasympathetic control of heart rate and cardiac function News Physiol Sci 1999;14:155–161.

Rhoades RA, Tanner GA Medical Physiology 2nd Ed Philadelphia: Lippincott Williams & Wilkins, 2003 Touyz CB, Dominiczak AF, Webb RC, Johns DB Angiotensin receptors: signaling, vascular pathophys-iology, and interactions with ceramide Am J Physiol 2001;281:H2337–H2365.