Aldosterone and thyroid hormone interaction on the sodium

Aldosterone

and

_thyroid

hormone interaction

on

the sodium

and

_potassium

_transport

_pathways

of

rat

colonic

epithelium

C.

J. Edmonds

and

C. L. Willis

Endocrinology

Research

_Group,

Division ofClinical

Sciences,

Clinical Research

Centre,

Watford

Road,

Harrowhai am

REVISED MANUSCRIPT RECEIVED20

_July

1989

ABSTRACT

The effect of

_{hypothyroidism}

on

potassium adaptation

(shown by

increased

_potassium

secretion inresponseto

potassium loading)

andonthe action of aldosteroneon

potassium

secretion and sodium fluxeswasexamined

in theratdistal colon.

Potassium

_{adaptation, particularly}

theresponse to an acute

_potassium

_load,

was

impaired by

hypothy-roidism which also

_considerably

reduced the rise of

transepithelial

electrical

_potential

difference

_(p.d.)

of total and transcellular

_{(active) lumen-to-plasma}

sodium fluxes and of

_potassium

secretion

_normally

produced by

aldosterone. These

_changes

were,in

part,

corrected

_by

ashort

period

(3

days)

of

tri-iodothyronine

replacement.

Moreover in aldosterone-treated

hypo-thyroid

rats, amiloride in the lumenwas

considerably

less effective in

_reducing

the

_p.d.

and sodium fluxes than in aldosterone-treated normalrats.

The intracellular sodium

_transport

_pool

was

_greater

in the

_hypothyroid

than in the normal rats

_{(5\m=.\0\m=+-\}

1\m=.\1

(s.e.m.)

nmol/mg dry weight compared

with 2\m=.\9\m=+-\ 0\m=.\2

_{nmol/mgdry weight; P<0\m=.\02).}

Aldosterone increased the

_pool

in the normal but not in the

hypothyroid

rats while amiloride had little effect on

the

_pool

in the aldosterone-treated

_hypothyroid

rats

but almost abolished it in aldosterone-treated normal

rats.

Aldosterone

_plays

a

major

_part

in the

adaptation

of

colonic sodium and

_potassium

_transport

to sodium

depletion

or

potassium

excess; these

adaptations

were

much

_impaired

in

_hypothyroid

animals. The present

results areconsistent witha

deficiency

inaldosterone

induction of

_potassium-

and amiloride-sensitive sodium

_pathways

in the

_apical

membrane of colonic

epithelial

cells in

_hypothyroid

rats,a

deficiency

which

limits the stimulant effect of aldosterone on sodium

and

_potassium

_transport.

Journal

_{ofEndocrinology (1990)}

124,

47\p=n-\52

INTRODUCTION

When animals are

depleted

of sodium or are fed a

potassium-rich

diet,

_{adaptive changes}

take

_place

in the sodium and

_potassium

transport systems of the colon whichare

analogous

tothose whichoccurinthe

kidney.

Thus,

in theratdistal

_colon,

sodium

_depletion

leadstoincreased active sodium

_{absorption (Edmonds,}

1967)

while

_potassium

excess stimulates

potassium

secretion

_(Fisher,

Binder &

_{Hayslett, 1976).}

The im¬

portanceof aldosteronetothese

_{adaptive changes}

has beendemonstratedina

variety

of

species (Edmonds

&

Marriott,

1967;

Frizzell &

Schultz, 1978; Thomas,

Skadhauge

&

Read, 1979; Foster, Jones,

Hayslett

&

Binder,

1985).

In the rat distal

_colon,

aldosterone induces amiloride-sensitive sodium channels in the

apical

membrane of the

_epithelial

cells and a small

expansion

of the intracellular sodium

_transport

_pool

as

the sodium

_absorption

rateincreases

_(Will,

Lebowitz &

Hopfer,

1980; Sandle,

Hayslett

&

Binder, 1984;

Edmonds &

_Mackenzie,

_1987).

The

_Na,K-ATPase

activity

of the basolateral membranes also rises in

epithelia

stimulated

_by

aldosterone

(Jorgensen,

1972;

Charney, Silva,

Besarab &

_Epstein,

1974;

Botella,

Paris &

Lahlou,

1986; Paccolat,

Geering, Gaeggeler

&

Rossier,

1987).

As

_{regards potassium}

secretion,

the

principal

factors in the action of aldosteroneappear

to be an increase of

potassium-selective

channels in

the

_apical

membrane and of

_Na,K-ATPase

_activity

in the basolateral membrane

_{(Kashgarian, Taylor,}

Binder &

_Hayslett,

_{1980; Sandle,}

Foster,

Lewisetal.

1985;

Edmonds &

Willis,

1988).

Previous work showedthatcolonie

_adaptation

toa

sodium-restricted diet was, like renal

_adaptation,

impaired

when therats were

hypothyroid (Edmonds,

Thompson

&

Marriott,

1970).

Recent studies have

shown,

moreover, that

tri-iodothyronine

(T3)

has a

aldosteroneon thecells of the renal

collecting

tubules

(Barlet-Bas,

Khadouri,

Marsy

&

Doucet,

1988).

In the

_present

work,

we have further

investigated

the

interrelationship

of aldosterone and

_thyroid

hormones

in the rat distal

colon,

particularly

to examine the

potassium-secreting

mechanism and effects on the induction of the amiloride-sensitive sodium channels andon the intracellular sodium_transport

_pool.

MATERIALS AND METHODS

Male albinorats

_{(250-350 g)}

wereused and feda diet

basedon astandardrat

_pellet.

Thestandard

_pellet

diet

contained 0-2 mmol

_potassium/g.

In the two other diets

used,

the

_potassium

contentwasenriched

by

pre¬

liminary

soaking

of

_pellets

in either 01 mol

_KC1/1

or 0-3 mol

_{KC1/1. Subsequently they}

were dried to their

original

form. Pellets

_having

a

potassium

_content

about 0-35

_mmol/g

and 0-7

_mmol/g

were

thereby

obtained. All these diets were consumed in _similar

amounts,

averaging

about 6-7

_g/100

g

body weight

per

_day.

Hypothyroidism

was induced

by

thyroid

ablation

by intraperitoneal injection

of 9

_MBq

I

_(Amersham

International

_pic,

_Amersham,

_Bucks,

_U.K.)

and sub¬

sequently

theratswere

given

propylthiouracil (Sigma

Chemical Co.

Ltd, Poole, Dorset, U.K.;

100mg/l)

in

drinking

waterfor 6 weeks. The

_hypothyroid

animals were maintained in a

constantly

warmed room for

6 weeks until the colonie

_perfusion

studies.

_They

remained in

_good

_general

health but their

_{weight gain}

was

markedly

_{less than that ofthe intactrats.}

The methods usedfor

measuring

transportfunction in the distal colon were as

_previously

_describedin_full

(Edmonds

&

_{Mackenzie, 1987).}

In

_brief,

anaesthesia

wasobtained

_{by i.p. injection}

_{of sodium}

_{pentobarbitone}

(6

mg/100

g

_body

wt)

well awayfrom thedistal colon. A

_segment

of distal

_(descending)

colon about 3cm

long

wasrinsed clean withwarmsaline and cannulated.

The

_{transepithelial}

electrical

_potential

difference

_(p.d.)

wasmeasured

periodically

during

an

experiment

using

a

high input

impedance

millivoltmeter connected

through

calomel

half

cells and saline

_bridges

to the lumen and serosal surface of the colon.

In _{the first series of}

_experiments,

to examine the

potassium

secretion response to an acute

_potassium

load,

theratshadani.v.

polythene

cannula

implanted

into theexternal

_jugular

vein.Thepotassumloadwas

given

as a solution of KC1

(120

_mmol/1),

_KHC03

(30

mmol/1)

using

a 10 ml

syringe

driven

by

a

Sage

constantinfusion_pump

₍₂₇₀

_pl/min

forthe first 10

min,

thereafter 190

_pl/min).

Potassium secretion rate was measured

_{by collecting}

the effluent

_during

_perfusion

of the colonie segment with a solution

containing

NaCl

₍₅₀

_mmol/1)

and mannitol

₍₂₀₀

_mmol/1)

at37°C

and at a rate of 1

_ml/min

_using

a Watson-Marlow

H.R. FlowInducer. The concentration of sodium was

chosen as

being

similar to that of faecal fluid in this

part

of the

_colon;

mannitol was added to render the

solution isotonic. Perfusion was

always

commenced

15 min before collections were

made;

this allowed

the

_potassium

secretion rate to become

_steady.

For

measurement _{of the sodium flux rates, 0-5 ml of} a

solution ofa

composition

similar to that above but

containing

in addition

22Na

₍₂

_Bq/pmol

sodium;

Amersham International

_pic)

wasintroduced into the

lumen of the cannulated segment and allowed to re¬ main there for 10 min. It was then

rapidly

rinsed out

withasolutionof mannitol

(300 mmol/1)

and collected.

The total sodium flux from

_{lumen-to-plasma}

_(Jms)

across intestinal

epithelium comprises

a transcellular

component

which_appearsto

_depend

onactive sodium

transport

anda

passive

diffusive

_component

which is

probably through

the

_paracellular

_pathway.

In the

present

experiments

we used the method described

previously

(Edmonds

&

_Mackenzie,

₁₉₈₇₎

_{to deter¬}

mine

_Jms

from the loss of

22Na

from the lumen and from

the

mean

specific

activity

(22Na/23Na

ratio);

the

transcellular

_(active

_{absorptive) lumen-to-plasma}

flux

wasestimatedfromthe observed values of

Jms,

thenet

sodium flux and the

_{transepithelial p.d.}

To determine the

_epithelial

sodium

_transport

_{pool (Edmonds}

&

Mackenzie,

1987)

a similar

solution,

but

containing

considerably higher radioactivity

(22Na,

200

_Bq/pmol

sodium),

wasleftinthe lumen for 10 min. Thiswasthen

rapidly

washed_out,the

_segment

_removed,

blotted and

scrapings

taken of the

_epithelium,

the whole

_procedure

being completed

within 1 min.

Aldosterone

_(Sigma

Chemical Co.

_Ltd)

was

given

by

osmotic

_minipumps

(Alzet

Corporation,

Palo

_Alto,

CA,

U.S.A.)

inserted into the

_{peritoneal cavity}

_through

a _{small lateral abdominal incision with sterile pre¬}

cautions. Antibioticswere_{notused and}no

problems

_of

infectionwere_encountered

_(Edmonds

_&

Willis,

1988).

A

_supramaximal

_{dose of about 50}

_pg/day

_{per 100g}

body

wtwas

given

forthe 3

days preceeding

the colonie

perfusion.

In the

_experiments

in which

_hypothyroid

ratswere

given

T3,

thiswasaddedtothe solution in the osmotic

_minipump

and1

_pg/day

_per100g

_body

_wtwas

delivered.Insome

experiments,

amiloride

(100

pmol/1)

wasadded to the solution in the lumen. All solutions

were

freshly prepared

beforean

experiment.

Samples

ofvenousbloodweretaken from the inferior

mesenteric vena cava

immediately

before the end of the

_experiment.

Sodium and

_potassium

concentrations were

measured

_by

flame

_photometry

and

22Na

by

gamma

counting.

Fluxresultsare

expressed

_per

cm2

of mucosal area,obtained

by measuring

the

length

ofthe

_segment

used on a

standard

glass

tube after its removal at

means+s.e.m.

Significance

wastested

using

two-tailed

Student's ?-test.

RESULTS

Potassium

_adaptation

and

_{hypothyroidism}

When

_taking

the standard

diet,

the normal and

hypothyroid

rats had a similar rate of

_potassium

secretion into the lumen of the colon

_(Fig.

1).

Inboth

groups,

potassium

secretion rate was about trebled

(P< 0-001)

when the animalswere fed the

potassium-rich diet

(0-7

mmol/g).

When theacutei.v.

potassium

loadwas

given

a cleardifference between the normal

and the

_hypothyroid

_group was

evident,

with the

latter's secretion rate

_averaging

65% of that of the normalrats.The

transepithelial

p.d.

wassimilarin the

normal and

hypothyroid

rats

and,

asfound

previously

(Edmonds

&

Willis,

1988),

unaffected

_by

the

potassium-rich diet or acute

_potassium

infusion. The

_plasma

potassium

concentrationofratsfed the

_{potassium-rich}

dietwassimilar in the normal and

hypothyroid

_groups

averaging

4-3+ 0-2

_mmol/1

(«

=

9). By

the end of

the

intravenous

_potassium

infusion,

the

_{plasma potassium}

concentration had risen to 9-3+ 0-7

mmol/1

(n

=

9).

Again,

therewas no

significant

differencebetween the

normal and

_hypothyroid

animals.

Effect of aldosteroneonsodium fluxes and

potassium

secretion

Preliminary

studies showed that 3

_days

ofadminis¬

trationofaldosteronetorats

_taking

the standard diet

produced

amarked fall in

plasma potassium

to3-2+

0-2

_{mmol/1 (n}

=

4)

compared

with 4-4+ 0-3

mmol/1

(n

=

4)

in untreatedrats

(P

<

002).

Inallthe

subsequent

experiments,

therefore,

adiet basedonthe standard diet

but

_having

a

higher potassium

content

(0-35

mmol/g)

wasused. On this

diet,

both normal and

hypothyroid

ratsmaintained their

_{plasma potassium}

concentration

satisfactorily during

aldosterone administration

(3-8

+0-1

mmol/1 (n

=

8)

after 3

days compared

with

4-1+0-1

_mmol/1

_(n

=

8)

in untreatedrats_onthis

diet).

Neither the sodium fluxes nor the

potassium

se¬

cretion rate were

significantly

different between the untreatednormal and

_hypothyroid

rats

(Fig.

2).

After

3

_days

ofaldosterone administration thesodium

lumen-to-plasma

fluxes had increased in boththenormal and

hypothyroid

rats

(P<0-01

and P<005

respectively);

however,

the rates recorded in the

hypothyroid

rats were

significantly

lower than in thenormalratswith the

total

_{transepithelial}

flux

_being

64% and the estimated transcellular flux

_{being only}

50% of that observed in the normal rats. Potassium secretion rate increased in both groups after aldosterone treatment but

_only

significantly

in the normal rats

_(P<0-05).

The

trans-fì

30-0-1

1

-E -J

-¿

100- 80- 60- 40- 20-O-1

1

1

ABC ABC Normal Hypothyroid

figure1.Secretion of

_potassium

and

_{transepithelial}

electrical

potential

difference

_(p.d.)

in thedistalcolonof normaland

hypothyroid

ratsfed

_(A)

thestandard_{diet, (B)}a

potassium-richdiet(0-7mmol

_potassium/g)

or

(C)

the

potassium-rich

diet and infused withanacute

_potassium

load. Valuesare

means_{±s.e.m.;groups of five and}fourrats.*P<005

compared

with

_{corresponding}

column of the normalrats

(two-tailed

Student's

_i-test).

epithelial p.d.

was

nearly

doubled in the normal animals

(P

<0-01

)

butwasunaffectedinthe

hypothyroid

_group. Therewas no

significant

difference between the

p.d.

of

theuntreatednormal and that of the

_hypothyroid

rats

but

_following

treatmentwithaldosterone the

_p.d.

was

considerably

greater

(P<000\)

in the normal than in

the

_hypothyroid

rats.

Effect of amilorideand I ,

The

_segment

of colon was

perfused initially

for5min

with the standard solution

_containing

amiloride

(100

pmol/1).

This had been

_previously

established as

long enough

for amiloride to bind and block the amiloride-sensitive sodium channels in the

_apical

membrane. The flux rates were then measured

using

solutions whichalso containedamiloride.

In the aldosterone-treated normal rats, amiloride

reduced the total

_{transepithelial}

flux

_(Jms)

_{by nearly}

half while the transcellular sodium flux was almost

completely

abolished

_(Fig.

3).

The

_{transpeithelial}

_p.d.

was reduced to

_nearly

zero. The

potassium

secretion rate was

unaffected.

In the aldosterone-treated

hypothyroid

rats,

by

contrast, amiloride did not

_sig¬

P3

lì

_: H 60—1 30-O-J c 30-0 e

15-|

_"5 O-1 200-1 150-2 E . ci. .E

J

°¿ ö

100-1

1

i

e r • ¬ 50-(I-1 Normal

Hypothyroid

figure2.Sodium

lumen-to-plasma

fluxes,

potassium

secretion and

transepithelial

electrical

_potential

difference

(p.d.)

inthedistal colonofnormaland

_hypothyroid

rats

_(A)

untreatedor(B)treated for 3dayswith aldosterone. The

shaded

_portion

ofthe total

_{lumen-to-plasma}

sodium flux indicates the transcellularcomponent.Valuesare means±

s.e.m.;therewerefourrats_{in each group.}*/><0-05,

**P< 002

_compared

with

_{corresponding}

columnsof the

normalrats

_(two-tailed

Student'si-test).

flux and the reduction in the transcellular flux was

markedly

less than observed in thealdosterone-treated

normalrats.Amiloride also reduced the

transepithelial

p.d.

significantly

(P^005)

but

_again

less

_effectively

than in the normalrats. Potassium secretionwasnot

significantly

affected

_by

amiloride.

Although

the administration of

_T3

with aldosterone

tothe

_hypothyroid

rats

_appeared

toincrease the sodium

fluxes,

the

change

wasnot

significant.

The increase of

potassium

secretion was,

however,

significant

as was the increase of the

_p.d.

_(P<0-02).

_Moreover,

the

p.d.

became

_largely

amiloride-sensitive as shown

by

further

_experiments

onthree

hypothyroid

ratstreated

with

_T3

in which the

_p.d.

fell from 44+7mV to

5 +1mV when amiloride was added to the luminal

solution.

-le

— 60- 30-0-1 -30—1 15- 0-C 200- 150-C — t/5 100- 5

0-i

1

: . : Amil 3

Hypothyroid

Amil Normal

figure3.Sodium

lumen-to-plasma fluxes,

potassium

secretion and

_{transepithelial}

electrical

_potential

difference

(p.d.)

inthe distalcolon of normal and

_hypothyroid

rats

treated with aldosterone for 3

_days

and measuredwith

amiloride(100pmol/l)in thelumen(Amil).A groupof

hypothyroid

ratswasalso treated for 3

days

with

tri-iodothyronine (T3).

The shaded

_portion

of the total

lumen-to-plasma

sodium flux indicates the transcellular_component. Valuesare means+s.e.m.;therewerefourratsineach_group.

*P<005, ***/><0001,

adjacent

columns

_compared;

**p<002,

T3-treated

hypothyroid compared

with untreated

_hypothyroid

rats(two-tailedStudent'si-test).

Changes

in thesodium

_transport

_pool

The sodium

_transport

_pool,

determinedfrom the

22Na

content of the

_{epithelial scrapings following}

10-min

luminalexposuretoa

22Na-containing

solution of

high

specific activity,

wasrecorded in the

variously

treated

groups

_{(Table 1).}

Inthe normalrats,aldosteronetreat¬ ment

_produced

a

significant (. <0 1)

increase in the sodium

_transport

_pool.

Inthe untreated

_hypothyroid

rats,the

_pool

wasalso

expanded

(P

<

0-02)

by comparison

with the untreated normal rats but was not

_{significantly}

affected

_by

aldosterone.

Furthermore,

amiloride did not reduce the sodium

_transport

_pool

inthe aldosterone-treated

table1. Effect ofvarious

_procedures

onthe

_epithelial

sodium_transport

_pool

innormal and

_hypothyroid

rats. Valuesare means+s.e.m.;therewerefourratsineach_group

Sodiumtransportpool(nmol/mgdry wt)

Normal _Hypothyroid Treatment None 2-9+0-2 5-0±l-l Aldosterone 4-2+0-3 3-3+0-3 Aldosterone +amiloride 0-6+01 2-3+0-6 Aldosterone +T, 6-0+0-7

Aldosteronewasgivenfor 3daysat50_{µ§^ per 100 gbody}wt.

Amiloridewasin the lumenataconcentration of 100µ / .

Tjwasgivenfor 3daysat1µg/dayper 100 gbodywt.

effect onaldosterone-treated normalratsin whichthe sodium

_transport

_pool

wasmuch reduced

(P<0001).

Finally,

in the

_hypothyroid

rats treated with

_T3

and

aldosterone,

the sodium

_transport

_pool

was

_greater

than either that observed in the normalrats

_(P<005)

or in the

hypothyroid

rats treated with aldosterone

alone

(P<

0025).

DISCUSSION

In the rat distal

colon,

the

_potassium

secretion rate

increases when theanimaltakesa

potassium-rich

diet

(Fisher

etal.

₁₉₇₆₎

andthereisanenhancedresponse

toanacute

_potassium

load

_(Edmonds

&

Willis,

_1988).

The

_present

resultsshowedthat the colonie

_adaptation

to

_potassium

intake,

like that to restricted sodium

intake

_{(Edmonds, Thompson}

&

Marriott,

1970)

was

impaired

in

_{hypothyroidism.}

Both

_adaptation

to

sodium

restriction and

_potassium

excess

_depend

on

aldosterone

_(Edmonds

&

_{Marriott, 1969;}

Fosteretal.

1985)

and our

_experiments

in _{which aldosterone} was administered

chronically by

osmotic

minipumps

showed that the action of

aldosterone

on colonie

sodium and

_potassium

transport was

considerably

impaired

in

_hypothyroid

animals.

Aldosterone in

_influencing

sodium and

_potassium

movements affects both

_apical

and basolateral mem¬

branes of the

_epithelial

cells.The earliest

_changes,

well

developed

withinafewhoursof stimulation

(Clauss

&

Skadhauge,

1988)

involve alteration in sodium and

potassium

selective

_pathways

in the

_apical

membrane. Sodium diffusion

channels,

which can be blocked

by

amiloride at low concentration

_{(100 pmol/1),}

_appear

and the amiloride-insensitive sodium

_{pathway, by}

which sodium is absorbed in the

unstimulated epi¬

thelium,

is

_{suppressed (Will}

et al.

1980;

Edmonds &

Mackenzie,

1987).

Associated with this

_change

isarise

of the

_{transepithelial}

_p.d.

andof the active transcellular

sodium flux

_together

withasmall increase in the intra¬

cellular sodium transport

_pool.

All theseeffects were

found to be

impaired

in the

_hypothyroid

rats. The

relatively

small effect of

amiloride

inthe aldosterone-treated

_hypothyroid

rats showed that the amiloride-sensitive sodium

_pathway

was

only partly

induced and

the amiloride-insensitive sodium

_pathway

was little

reduced

_despite

the

_high

rate of

aldosterone

adminis¬ tration. Transcellular sodium

_transport

wasmuch less

increased

_by

aldosterone than in the intactrats,while the

_{transepithelial p.d.}

wasnot

increased,

reflecting

the low level of induction of sodium diffusionchannels in the

_apical

membrane.

In addition to

_changes

in the

_apical

membrane,

changes

in the

_plasma

Na,K-ATPase

activity

of the basolateral membrane will also influence sodium

transport. Thus variations in the intracellular sodium

transport

pool

would be

_expected

to

_depend

on the

combined effects of

_changes

in the

_apical

and baso¬ lateral membrane. Previous work

has,

however,

shown that alterations in the sodium

_transport

_pool

arerela¬

tively

smallor evenundetectable

despite

considerable

changes

in

_{transepithelial}

sodium

_{absorption (Eaton,}

1981;

Edmonds &

Mackenzie, 1987;

Krattenmacher &

Clauss, 1988)

indicating

some mechanism ofco¬

ordinating apical

inflow and basolateral outflow of sodium. The

_present

measurements were in accord

with these

_previous

observations

_showing

in

_general

only

small

_changes

in the sodium

_transport

_pool.

In

the

_hypothyroid

rats,

however,

there did appear to

be a small

expansion

of the

pool possibly reflecting

reduction in basolateral membrane

_Na,K-ATPase

previously

demonstrated in both renal and colonie

epithelium (Thompson

&

Edmonds,

1974;

Ismail-Beigi

&

Edelman,

1977).

The most

_{striking finding,}

however,

was in the effect of amiloride which almost

abolished the

_pool

in the aldosterone-treated normal ratsbut had

_relatively

little effect in the

aldosterone-treated

_hypothyroid

rats. This

finding

was_consistent

with the results of the sodium flux and

_p.d.

measure¬

ments in

_indicating

that,

in

_hypothyroid

_rats,

aldosteronewas _{much less effective both in}

inducing

amiloride-sensitive and in

_suppressing

the amiloride-insensitive

_pathways

of the

_apical

membrane.

The administration of

_T3

over3

days

seemed

prin¬

cipally

to influence events in the

_apical

membrane which

_regained

the characteristics found in the

aldosterone-treated normalrats;

_namely,

considerable elevation of the

_{transepithelial p.d.}

and

_sensitivity

of the

_p.d.

amiloride. The sodium

_transport

_pool

remained, however,

relatively

elevated,

suggesting

that,

despite

therecovery of the

apical

membrane,

the

basolateral

Na,K-ATPase

hadnot

_fully

recovered. In

thecaseof

potassium

secretion,

the deficientresponse

to aldosterone in the

_hypothyroid

rats wascorrected

probably depends largely

on

augmentation

of the

potassium

channels in the

_apical

membrane

_(Wills

&

Biagi,

1982;

Sandle et al.

1985; Binder,

McGlone &

Sandle,

1989),

this recovery

presumably

also indicated

a

relatively rapid

restoration ofthe

apical

membrane

responseto

aldosterone.

Precisely

how

_thyroid

hormones influence the action ofaldosterone was not defined in the present

studies.Several

_{possibilities}

exist. Aldosterone

_requires

specific cytosol

receptors for mediation of its inter¬ action with the nucleus and thesemay be affected

_by

hypothyroidism.

Moreover,

aldosterone and

_thyroid

hormones appear to have their

_primary

action on the genome

(Rossier,

Paccolat,

Verrey

et al.

1985;

Oppenheimer,

Schwartz,

Mariash et al.

₁₉₈₇₎

and

recent work has shown that the steroid and

_thyroid

hormonereceptorswhich bindtoDNAhaveacommon

structure

_{(Evans, 1988).}

These observations _suggest that the interaction between

_thyroid

hormones and aldosteronemaywell beatthegenomeitself.

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