Lessons from rat models of hypertension: from Goldblatt to genetic ...


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Cardiovascular Research 39 (1998) 77–88
Lessons from rat models of hypertension:from Goldblatt to genetic
a,b,a,b a,b
Yigal M.Pinto,Martin Paul,Detlev Ganten
Department of Clinical Pharmacology and Toxicology,Benjamin Franklin Medical Center,Free University Berlin,Berlin,Germany
¨Max Delbruck Center for Molecular Medicine,Berlin-Buch,Berlin,Germany
Received 4 November 1997;accepted 23 January 1998
Over the past 50 years various animal models of hypertension have been developed,predominantly in the rat.In this review we discuss
the use of the rat as a model of hypertension,and evaluate what these models have taught us.Interestingly,the spontaneously
hypertensive rat (SHR) is by far the most widely used rat model,although it reflects only a rare subtype of human hypertension,i.e.
primary hypertension that is inherited in a Mendelian fashion.Many other aspects of the etiology of hypertension are found in other rat
models,but these models are less frequently employed.The widespread use of the SHR suggests that this rat model is often chosen
without considering alternative (and possibly better suited) models.To illustrate the importance of the choice for a particular model,we
compared the natural history and response to antihypertensive drugs in different rat models of hypertension (SHR,Dahl,deoxy-
corticosterone acetate (DOCA)–salt,two-kidney one-clip,transgenic TGR(mRen2)27.This revealed that the outcome of hypertension can
be similar in some respects,as all models exhibit cardiac hypertrophy,and all demonstrate impaired endothelium-dependent relaxations.
However,the more severe forms of end-organ damage such as heart failure,stroke and kidney failure,occur only in some models and
then only in a subset of the hypertensive rats.The effects of antihypertensives varies even more in the different models:antihypertensive
treatment only attenuates end-organ damage if it decreases blood pressure.Moreover,if a given antihypertensive is effective,it sometimes
even attenuates end-organ damage in nonhypotensive doses.On the other hand,some agents do decrease blood pressure but do not
prevent end-organ damage (e.g.hydralazine in SHR).Furthermore,not all classes of antihypertensives are equally effective in all rat
models of hypertension:endothelin-receptor antagonists are not effective in SHR,but have beneficial effects in the DOCA–salt model.
The comparison of models,and the comparison of treatment effects suggests that end-organ damage critically depends upon not only on
the stress imposed by high blood pressure and its underlying biochemical disturbance,but also upon the ability of the organism to recruit
adequate ‘coping’ mechanisms.These coping mechanisms deserve greater attention,as failure to recruit such mechanisms may indicate an
increased risk.The current development of transgenic techniques will provide new opportunities,to develop specific models to address
this balance between stress and coping.© 1998 Elsevier Science B.V.All rights reserved.
Keywords:Hypertension;Animal models;End-organ damage;Genetic
1.Use of animal models in hypertension antedating Harvey.Although it has long been realised how
important the circulation is,it is a more recent insight that
In contrast to the idea that the human circulation was high blood pressure may have adverse effects.It probably
first described by Harvey,the essentiality of the heart for dates back to the first half of the 19th century,when Bright
life was already recognised in the Talmud,the collection of observed that high blood pressure was related to increased
Jewish laws that were collected up to 499 AD,and the cardiac mass and renal abnormalities.Subsequently,Jane-
physician Asaph Judaeus realised in the 6th century AD way described that patients with increased blood pressure
that blood circulates through the vessels [1],thereby die prematurely [2].
The first animal model of hypertension was developed
Corresponding author.Tel.:149 (30) 8445 2279;Fax:149 (30)
8445 4482;E-mail:pinto@ukbf.fu-berlin.de Time for primary review 22 days.
0008-6363/98/$19.00 © 1998 Elsevier Science B.V.All rights reserved.
PI I:S0008- 6363( 98) 00077- 7
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Y.M.Pinto et al./Cardiovascular Research 39(1998)77– 88 79
Fig.4.Some rat models of hypertension grouped on one hand according
to their etiology (top panel),and on the other hand grouped according to
the resulting end-organ damage.Rat models are available to investigate
very different hypertensive etiologies.The most common human form,
Fig.3.Variability in the use of a particular rat model.Variability is low
primary hypertension,is often represented by genetic models of hyperten-
with regard to all models (not shown for DOCA and Dahl rats),except for
sion,such as SHR.However,such genetic models are characterised by a
the newly developed transgenic rat which is increasingly used.This
Mendelian type of inheritance,which is rarely encountered in human
stability suggests that the choice for a rat model is not heavily influenced
primary hypertension.The bottom panel displays the end-organ in-
by trends,but may also suggest that researchers stick to their model,even
volvement that is seen in various rat models of hypertension.It is a very
though it may not be the optimal choice in all cases.The variability has
subjective interpretation of the available literature,which is dominated by
been calculated by determining number of publications that use the name
studies in relatively young subjects,with often short lasting hypertension.
of the model (SHR),as a proportion of the number of papers on
This has provided a large body of evidence on milder forms of end-organ
hypertension.the proportion that each model comprised of the total
involvement such as cardiac hypertrophy,whereas severe cardiac failure
number of papers in 1990 is set to 1 (i.e.the number of papers on SHR
is less frequently studied.However,even in studies on heart failure in the
relative to the total number of papers on hypertension in 1990 is set to 1).
SHR,heart failure still is only seen in part (e.g.60%) of all rats studied.
the relative number in a given year is then compared to 1990 so that the
figure displays an ‘indexed proportion’.Papers describing in vitro data
obtained from cells (e.g.cells cultured from SHR) are not excluded.
by evaluating the different etiologies,but also by compar-
ing end-organ damage in different models.
without gross clinical events [5].This suggests that in a As excellent overviews of the different etiologies in
large number of patients some mechanisms protect against different animal models already exist [6],we will focus on
severe hypertension related end-organ damage.hypertensive end-organ damage,as this seems to be less
The etiology of hypertension is widely investigated in clearly paralleled by animal models.Understandably,the
rat models,and more than one model represents a genetic endpoints of studies in animals are quite different from
aetiology (Fig.4),with a classic Mendelian type inheri- those assessed in human subjects:end-organ damage that
tance.However,the most frequently encountered human occurs earlier in human hypertensive disease is often an
type of hypertension is primary hypertension (often called end-point of experimental studies:cardiac hypertrophy (as
essential hypertension),which has genetic aspects,but does opposed to overt heart failure),endothelial dysfunction (as
not usually display a Mendelian type inheritance,and is opposed to gross vascular abnormalities) and proteinuria
therefore not purely represented by animal models.Never- (as opposed to severe kidney failure) (Fig.4).One
theless,many aetiologies of human hypertension can be exception is stroke in the stroke prone SHR (SHR-SP),
mimicked in rat models,so that these models provide which is a main end-point in studies with this model.
ample opportunity to study different types of hypertension.Myocardial infarction,aneurysm formation and athero-
The observation that the SHR is abundantly used,sclerosis are rarely encountered in animal models of
whereas it represents only a particular type of hyperten- hypertension.
sion,suggests that specific properties of a model are not To analyse how different rat models clarify the patho-
always considered when a rat model is chosen.Since the physiology of hypertensive end-organ damage,we will
different rat models have a different etiology,it is conceiv- briefly summarise some often-used rat models of hyperten-
able that the choice of a model significantly influences the sion,and compare them to answer whether every type of
outcome of an experiment.This can be illustrated not only high blood pressure leads to the same end-organ damage
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80 Y.M.Pinto et al./Cardiovascular Research 39(1998)77– 88
and whether every type of blood pressure lowering leads to in various crosses [9–11] which is not always confirmed
the same improvement.[12].Since this is not a strictly inbred strain,individual
variations in genetic background of both SHR and par-
ticularly of their control strain may importantly influence
3.Rat models of hypertension the resulting end-organ changes,so that one can anticipate
considerable variability in end-organ changes,as is also
In this section we will briefly discuss the rat models of clear from the natural history (see next paragraph).
hypertension on which this review focuses,and will
describe the natural occurrence of end-organ damage 3.1.1.End organ damage (see Table 1for references)
(Table 1) and the effect of treatment (Table 2).In the untreated rats,cardiac hypertrophy is found in all
studies (approx.30% increase),and many rats progress to
3.1.Spontaneously hypertensive rats develop heart failure between the age of 18 and 24 months.
However,not all rats exhibit signs of heart failure after 24
By inbreeding Wistar rats with the highest blood pres- months so that despite the uniformity of the model,
sure,Okakamoto and Aoki [7] obtained a strain of rats individual differences are seen.Impaired endothelium
with spontaneous hypertension,the SHR.They described dependent relaxations have been consistently found,al-
how blood pressure rises around 5–6 weeks of age,and though rats until 13–15 weeks of age may sometimes have
steadily increases to reach systolic blood pressures of normal endothelium dependent relaxation (personal ob-
180–200 mm Hg.The SHR develop many features of servation).Renal damage (protenuria and decreased
hypertensive end-organ damage (Table 2):cardiac hy- creatinine clearance) has also been found in older SHRs,
pertrophy,cardiac failure and renal dysfunction.However,but there are no studies describing frank renal failure.
they do not exhibit gross vascular problems:apart from
depressed endothelial dependent relaxations,they have no 3.1.2.Effect of treatment (see Table 2for references)
tendency to develop strokes,and also develop no macro- Blood pressure in SHRs is effectively lowered by
scopic atherosclerosis or vascular thrombosis.The SHR inhibition of the renin–angiotensin system,calcium an-
stroke prone (SHR-SP) is a further developed sub-strain,tagonists and by direct vasodilators (hydralazine).Diuret-
with even higher levels of blood pressure,and a strong ics and endothelin antagonists are less effective.The effect
tendency to die from stroke [8].The SHR have been of beta-blockers is unequivocal (see comment to Table 2).
widely used to evaluate genetic factors in hypertension,The ability to prevent end-organ damage dissociates from
yielding a wide variety of genes that seem to cosegregate the antihypertensive effects:inhibition of the renin–an-
Table 1
Strain Etiology Cardiac hypertrophy Cardiac failure Renal failure Vascular failure Survival
SHR Genetic 30% [23] 60% at age 18– Proteinuria,decreased Impaired endothelium 10–21 months
24 months [23,24] creatinin clearance [25,26] dependent relaxations [27]
DOCA Endocrine 30% [28] None observed Proteinuria,Impaired endothelium
[28],none described glomerulosclerosis [29] dependent relaxations [30]
2K1C/aortic renal/50%/25% [31,32] Minor changes in Impaired endothelium
stenosis mechanic unclipped kidney [33] dependent relaxations [34]
TGR (mRen 2)27 Monogenetic 40% [35] Not yet Moderate proteinuria [36] Impaired endothelium Homozygous 2 mo.
assessed dependent relaxations [35] Heterozygous
unknown (.4 mo.)
Dahl-rat Genetic 16–32% [37] Severe heart failure Severe and early Impaired endothelium 4–6 months after
at 4–5 months [38] proteinuria [39,40] dependent relaxations [41] salt loading
Milan Genetic 10% [42] Only proteinuria and
Hypertensive glomerulosclerosis in
rat normotensive control
strain [43]
The absolute level of blood pressure increase has not been depicted,as this varies depending on the technique and circumstances under which blood
pressure is measured.However,it should be noted that blood pressures are often higher (.225 mm Hg) in Dahl-S rats fed 8% NaCl,when compared to
SHR,who usually display blood pressures up to 220 mm Hg.Also,the Milan Hypertensive rat exhibits lower blood pressures than found in other models
(around 160 mm Hg).Despite the fact that the rats in most models are severely hypertensive (systolic.180 mm Hg),it is of interest that there are large
differences in outcome,which may not be fully explained by blood pressure alone.The Dahl rats seem more prone to develop severe cardiac and renal
failure than the SHR,which may be due on one hand to their even higher blood pressures,but also to the very different etiology involved in this strain.
Also,the TGR(mRen2)27 seem to develop more end-organ damage when directly compared to blood pressure matched SHR.Severe cardiac and renal
failure are hardly described for 2K1C rats,although this probably also depends on the technique and timing of the operation,which influences the blood
pressure increase.
Such a comparison of models is hampered by the fact that direct,prospective comparisons between strains are not often described,so that the represented
data reflects a subjective choice from the vast amount of literature on the subject.
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Y.M.Pinto et al./Cardiovascular Research 39(1998)77– 88 81
Table 2
Strain Hypertension Cardiac hypertrophy Cardiac failure Proteinuria Impaired endothelium
SHR A1 [44,46] A1 [44] A1 [52] A1 [49] A1 [50]
B2[46,48] 6[54] B1 [47,54]2 [55] B1 [54]
C1 [45,46] C1 [51] C1?[53] C1 [50]
D2 [44,46] D2 [44] D2?[56]
E2 [51] E12 [51] E1 [51] E?
F1 [44,46] F2 [44] F2 [58] F2 [57]
DOCA A2 [59] A2 [60] A2 [64] C1 [65] A2 [66]
B2 [67] B?
C1 [45,60] C1 [60]
D1 [62] D1 [62]
E1 [61] E1 [61]
F1 [59,63] F2 [63]
2K 1C/aortic A1 [73] A1 [73]
stenosis B 2 [71] B2 [71]
C1 [45,70] C1 [70]
E2 [68]
F1 [69] F2 [69]
TGR(mRen2)27 A1 [74] A1 [74] A1 [75]
B2 [74] B2 [74,75] B2 [75]
C2 [74] C2 [74]
F2 [32] F2 [75] F2 [75]
Dahl rat A1 [76] A1 [76] A1[78]2[80]
B12 [78] B2 [77]
C2 [79] C2 [79] C2 [81]
D1 [82,84] D2 [82] D2 [82] D1 [84]
E1?[83] E2 [83]
F1 [84] F1 [84]
A5ACE/RAS inhibition,B5beta blockade,C5calcium antagonists,D5diuretics,E5endothelin antagonists,F5direct vasodilators,15protective effect,
25no effect.
Drugs that effectively decrease blood pressure also prevent end-organ damage.However,many studies also suggest discrepancies,so that hydralazine
lowers blood pressure in SHR,but fails to decrease cardiac hypertrophy.On the other hand,a universal finding in all models is that a drug that does not
lower blood pressure will also not affect end-organ damage.In other words,lowering blood pressure does not guarantee that a drug effectively protects
end-organs,but the observation that it decreases blood pressure increases the likelihood that it will be protective.
The effect of b-blockers in SHR is unequivocal,so that some report no effect on blood pressures [85],whereas others describe that metoprolol decreased
both blood pressure and cardiac weight [86].It seems that part of the controversy stems from differences in pharmacokinetics,as rats seem to require 20
times higher dosages than humans [87].The subject of SHR cardiac hypertrophy is excellently described in another review [88].
The table also suggests that ACE inhibitors are not as widely effective in rat models,as is seen in humans:the low renin models (Dahl-S and DOCA) seem
less sensitive to their actions than the high renin models such as the SHR,2K1C and TGR(mRen2)27.Interestingly,the reverse seems true for endothelin
antagonists:they are more effective in low renin models than high renin models.
The effect of calcium antagonists cannot by dichotomized by renin-status,although this evaluation is hampered by the intrinsic differences between the
different type of calcium antagonists used (as is also partly the case for beta-blockers,and less for ACE inhibitors and endothelin blockers).
The important restriction in interpreting this table is the same as for Table 1:few studies directly compare all classes of antihypertensives,so that the table
consists of a subjective selection of papers on the subject,and is meant to illustrate gross differences.
giotensin system also prevents end-organ changes,whereas rats,as well as in humans with unilateral renal artery
hydralazine fails to do so,despite its blood pressure stenosis.In the early 1970s,it was recognised that models
lowering effect.where the nonclipped kidney was left intact (two-kidney
one-clip),differed fundamentally from those where this
3.2.Two-kidney one-clip (Goldblatt hypertension,2K1C) kidney was removed (one-kidney one-clip) [14].In the
two-kidney model,circulating renin and aldosterone levels
In 1939,Wilson and Byrom adapted the method to are increased [15] and play a role most notably in the early
constrict a renal artery in the rat,thereby inducing the now phase of hypertension [16].
classic Goldblatt-hypertension in rats.The differences in
collateral formation make this procedure particularly sus- 3.2.1.End organ damage (see Table 1for references)
ceptible to species variation,so that two-kidney one-clip The natural history of the 2K1C rat depends partly on
hypertension is only of short duration in the dog,who the technique used to narrow the renal artery,and par-
develops efficient collaterals,[13],whereas it is chronic in ticularly on the size of the clip and the age of the rat at the
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82 Y.M.Pinto et al./Cardiovascular Research 39(1998)77– 88
time of clipping.As a result,cardiac hypertrophy ranges develop marked cardiac hypertrophy and impairment of
from 25–50%.The occurrence of cardiac failure in chronic endothelium dependent relaxations.
2K1C has not been systematically described,and renal
failure also seems to be rare:minor changes in the normal 3.3.2.Effect of treatment (see Table 2for references)
kidney have been described.Nevertheless,as in SHR,Obviously,inhibition of the renin–angiotensin system
impaired endothelium dependent relaxations are described.effectively lowers blood pressure,and attenuates the
development of cardiac hypertrophy and improves endo-
thelium dependent relaxation.Direct vasodilatation and
3.2.2.Effect of treatment (see Table 2for references)
beta-blockade significantly decreases blood pressure in this
As can be expected,blood pressure in the 2K1C rat is
model,but does not normalise it.Despite these significant
exquisitely sensitive to inhibition of the renin–angiotensin
reductions,we found no effect of either hydralazine or
system,but also responds to calcium antagonists and direct
carvedilol on cardiac weight or endothelium dependent
vasodilators,but not to diuretics,beta-blockers and endo-
thelin antagonists.This renders a profile comparable to that
of the SHR.Both renin– angiotensin inhibition and
3.4.Dahl salt-sensitive rats
calcium antagonism attenuate cardiac hypertrophy,other
end-organ changes have not been extensively described.
This rat was bred in the 1950s when Meneely et al.
observed ‘a marked degree of individual variation’ in the
3.3.Transgenic rats overexpressing the mouse Ren2
blood pressure response to salt ingestion [18].The salt
gene (TGR (mRen2)27)
sensitive Dahl rats develop severe and fatal hypertension
when fed high salt diets,whereas salt resistance rats do not
The introduction and overexpression of the mouse Ren-2
develop such severe hypertension upon salt loading.Also
gene in the rat led to severe hypertension,lethal in the
when fed normal salt diets,the salt sensitive rats become
homozygous rats if not treated with ACE-inhibitors.This
hypertensive,demonstrating that this is a model of genetic
rat model is characterized by two important features:
hypertension,with the extra feature of salt sensitivity [19].
firstly,it is a genetic,inherited form of hypertension,
Linkage analysis revealed linkage with loci close to the
where the single genetic event is known,and secondly,
ACE and ANF receptor genes [20].
despite the known genetic alteration,the exact mechanism
underlying hypertension remains elusive.It is clear that
3.4.1.End organ damage (see Table 1for references)
hypertension in this rat is related to an increased renin-
The Dahl salt-sensitive rat has a moderately increased
activity,but it has been difficult to pinpoint the crucial
blood pressure,even when fed a normal salt diet.Upon salt
tissue in which renin overactivity is responsible (see for
feeding (8% NaCl),blood pressure rises steeply,to levels
review Langheinrich et al.[21].Therefore,although plas-
slightly higher than those found in SHR.Although cardiac
ma renin is low in this model,we still regard it as a high
hypertrophy is comparable to that found in SHR (up to
(tissue-) renin model.Another very intriguing finding is
32%),cardiac failure has been noted already at 4–5
that the severity of hypertension depends partly upon the
months of age (cf.SHR in which it is seen only after 18
genetic background of the rats used for breeding the TGR
months or more).Also,renal changes seem more severe
(mRen2)27.As Withworth et al.showed [22],an acceler-
than in SHR,with severe early proteinuria.Again in this
ated and malignant type of hypertension occurs when these
model endothelium dependent relaxations were found to be
rats are bred with a different type of Sprague–Dawley rats
(the original background strain) which does not occur
when Lewis rats are used to breed the rats.As they were
3.4.2.Effect of treatment (see Table 2for references)
able to exclude most environmental factors,this suggests
Although seen as a low-renin volume overload model,
that even when a defined genetic alteration,such as the
blood pressure in Dahl rats responds to inhibition of the
introduction of the mouse renin gene,leads to hyperten-
renin–angiotensin system.Furthermore,diuretics,vasodi-
sion,the outcome still depends on other genetic factors,
lators and possibly endothelin-receptor anatgonists are
and not just on the introduced gene.This suggests that
effective,whereas calcium antagonists and beta-blockers
hypertension and its outcome critically depends on the
are less effective.Again,the effect on end-organ changes
interplay between a certain defect,and the genetic (and
dissociates from the effects on blood pressure:renin–
environmental) background.
angiotensin inhibition attenuates cardiac hypertrophy and
proteinuria,whereas diuretics (who decrease blood pres-
3.3.1.End organ damage (see Table 1for references) sure) are not effective.
No descriptions are available for ageing
TGR(mRen2)27,although we know that 70% of the 3.5.DOCA– salt rats
heterozygous rats survive at least until the age of 5 months.
We have recently described that before that age they The administration of deoxycorticosterone acetate
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Y.M.Pinto et al./Cardiovascular Research 39(1998)77– 88 83
(DOCA),in combination with a high salt diet and unilater- time:high blood pressure is a final common pathway for
al nephrectomy induces a low renin form of hypertension different (pathophysiologic) mechanisms.Furthermore,it
[17],which can be opposed to the other artificial model,seems that hypertension related end-organ damage is not
2K1C,where renin is increased.only related to high blood pressure itself (the hemo-
dynamic stress),but also to the underlying adverse bio-
chemical alteration (biochemical stress) and on the other
3.5.1.End organ damage (see Table 1for references)
hand to the ability of the end-organ to withstand this stress
Cardiac weight is increased by 30%,but cardiac failure
(coping).We define coping as the ability of the organism,
is not yet systematically described.Renal changes are
or of one organ,to successfully adapt to an increase in
described with proteinuria and glomerulosclerosis,and
either mechanical or biochemical load:for the heart the
again,as with all other models,this rat also demonstrates
example is cardiac hypertrophy,invariably found as an
impaired endothelium dependent relaxations.
initial mechanism to normalise wall stress.However,
derangements of this coping mechanism,or insufficiency
of this mechanism may result in a maladaptive from of
3.5.2.Effect of treatment (see Table 2for references)
cardiac hypertrophy with loss of function.Another exam-
This is the only model in which renin–angiotensin
ple is the ability of the kidney to normalise intraglomerular
inhibition does not decrease blood pressure,nor end-organ
pressure by constriction of afferent renal arteriole,so that
changes.Diuretics and also endothelin antagonists are
the glomerulus is protected against the adverse effects of
effective both with regard to blood pressure,and with
high intraglomerular pressure:again one can speculate that
regard to end-organ changes.Again the effects on blood
there are individual differences in the effective recruitment
pressure and end-organs dissociates when direct vasodilat-
of such mechanisms.
ors are used:despite an effect on blood pressure,cardiac
In all models,the left ventricle is hypertrophied and
hypertrophy is not attenuated.
endothelium dependent relaxations are impaired.However,
Therefore both Dahl and DOCA rats represent the low
cardiac failure is not always seen,and is mostly en-
renin,volume overload form of hypertension,with a
countered after severely elevated pressures (malignant
different natural history,and a different response to
type).It also occurs in part of the rats with moderate to
antihypertensives,when compared to the high renin
severe high blood pressure (see Table 1).Therefore,not
models [SHR,2K1C,TGR(mRen2)27].This suggests a
every hypertrophy nor every endothelial dysfunction will
parallel between the type of hypertension seen in black
cause severe end-organ failure.This would contradict the
hypertensives and the salt dependent models such as Dahl
belief than any form of cardiac hypertrophy,or any form
and DOCA–salt;both respond less to renin–angiotensin
of endothelial dysfunction is detrimental.
inhibition,but respond well to calcium-antagonism.This is
Renal dysfunction takes various forms in different
exemplified by the fact that calcium antagonism is superior
models,and seems to depend upon the relation between
to ACE inhibition in prolonging survival in the Dahl-S rat
increased pressure,underlying etiology (high renin versus
[95].The differences between these models also underlines
low renin) and genetic background,and on the above
the theory proposed by Laragh and Resnick [5],who
ability to recruit protective mechanisms.
divided hypertension into a low renin form,with salt and
Furthermore,some antihypertensive drugs normalise
water retention (wet hypertension),and a high renin form
blood pressure,but do not prevent hypertrophy or impair-
(dry hypertension),which is amenable to RAS inhibition,
ment of endothelial dependent relaxations.It is clear that if
but responds poorly to salt and water restriction.
a drug of a certain class does not decrease blood pressure,
This underlines again how important it is to make a
it will not prevent end-organ damage.Conversely,if a
rational and deliberate choice for a particular rat model,
certain drug decreases blood pressure in a particular model,
since the many models available represent different aspects
it usually prevents end-organ damage.However,this
of hypertension.
relation is not strictly related to blood pressure:sometimes
a drug decreases blood pressure,but does not prevent
end-organ damage:e.g.hydralazine in SHR,beta-blockade
4.What have we learned?The stress-and-coping in TGR (mRen2)27 (see Table 2 for references).On the
hypothesis other hand,some drugs may even prevent end-organ
changes in nonhypotensive doses.This latter effect is only
The reasoning in this section is based on comparisons of seen with drugs that are particularly effective in decreasing
published effects,and only rarely on direct experimental blood pressure (e.g.:ACE-inhibitors are particularly effec-
comparisons.The first obvious but still important conclu- tive in a two-kidney one-clip model,and were suggested to
sion stems from the observation that many ways lead to prevent cardiac hypertrophy even in a dose that does not
Rome:in spite of very different etiologies,the degree of decrease blood pressure [73]).This demonstrates that to
hypertension is often comparable between very different prevent end-organ damage,a drug has to interfere with
strains.This underlines what has been known for a long biochemical mechanisms in play.The more the drug
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84 Y.M.Pinto et al./Cardiovascular Research 39(1998)77– 88
interferes with this biochemical stress,the more efficient it 5.Choosing a model of hypertension
prevents end-organ damage,so that it sometimes even
works at nonhypotensive dosages.As discussed above,the SHR is by far the most popular
The message for clinical antihypertensive treatment is model,despite the fact that it only represents a small
that for an antihypertensive drug to prevent end-organ proportion of the wide array of etiologies of hypertension.
damage the drug should effectively and easily normalise The widespread use of the SHR encourages new workers
blood pressure.However,even if it does,this does not in the field to use the same model,whereas it may not be
guarantee that the drug will eventually prevent end-organ the optimal choice for many specific experimental ques-
damage.Still the value of monitoring blood pressure is that tions.Ideally,the experimental question should dictate the
it in part predicts whether a drug will prevent end-organ choice of a model.In general,the models with an
damage.When a drug fails to normalise blood pressure,it unknown,mostly genetic aetiology (SHR,SHRSP,and
will not prevent end-organ damage,and when a drug does Dahl rats) provide the opportunity to search for (new)
decrease blood pressure,it is more likely (although not mechanisms and new genes in hypertension.To investigate
certain!) to prevent end-organ damage.the morbidity associated with hypertension,it seems
A simplified model describes the likelihood of end- reasonable to choose a model were the aetiology is known
organ damage in terms of stress and coping,so that both to some extent:DOCA–salt,two-kidney one-clip,or
the amounts of stress,but also the ability to cope,TGR(mRen2)27,so that a more rational approach can be
determines the likelihood of developing end-organ dam- taken towards dissecting the effects of hypertension from
age.This hypothesis predicts that even at relatively normal the underlying dysregulation.Another important aspect is
blood pressures,severe end-organ damage may be seen.that different models can be seen to represent different
This idea is illustrated by the rat with spontaneous types of hypertension,as described above by comparing
noninsulin dependent diabetes mellitus,(Otsuka Long- low renin models (DOCA,Dahl) to high renin models
Evans Tokushima fatty rats;OLETF) described in 1992 (SHR,2K1C,TGR(mRen2)27).As it is well known that in
[89].In this rat model,moderate hypertension develops humans,hypertension in African patients can have a
with blood pressures up to 150–160 mm Hg,without different course in than in Caucasians,one can view these
significant cardiac hypertrophy.However,significant models as representatives of different subsets of hyperten-
changes in cardiac expression of genes coding for extracel- sion.
lular matrix proteins were noted,as well as marked
proteinuria and glomerular changes [90].This underscores
how biochemical stress (such as diabetes mellitus) in-
creases the susceptibility to end-organ damage even at 6.Transgenic models
relatively modest blood pressure increases.
A troublesome conclusion from reviewing animal The ability to specifically introduce genetic construct
models of hypertension is that the rat (and also the mouse),and thereby breed transgenic animals,has also opened new
fails to develop classic thrombotic atherosclerotic lesions possibilities for hypertension research [96].The first of its
and its complications.One could argue that the lifespan of sort was the transgenic rat that was obtained after intro-
rodents is too short to exhibit atherosclerosis,but on the duction of the entire mouse Ren2d gene [97].This
other hand,early signs such as fatty streaks are also hardly rendered a hypertensive model in which the hypertension
encountered in hypertensive rats.Therefore,one could and ensuing end-organ damage is very much dependent
speculate that either hypertension is not sufficient to cause upon increased local angiotensin II formation (for review
atherosclerosis,or that the hypertensive rats have mecha- see [98]) and is exquisitely sensitive to RAS inhibition.
nisms preventing its formation,which humans lack.Even Other transgenic models have been obtained where the
transgenic hypercholesterolemic mice,with severe atheros- introduction of both renin and human angiotensinogen
clerotic-like disease,do not develop classic thrombotic increased blood pressure in mice [99] and in rats [100].
atherosclerotic complications [91].The latter strain is characterised by severe hypertension,
In nonmammalian species veterinarians have described and early mortality.
naturally occurring hypertension and hypertension related Many parts of the cardiovascular system have been
death in turkeys [92],and for research purposes it is evaluated in transgenic rats,but only few led to models of
possible to investigate hypertensive turkeys.The hyperten- hypertension.Noteworthy are the knockout models,were
sive turkey also develops high cholesterol levels and genes for ANF and NO-synthase have been knocked out.
atherosclerotic lesions.However,it is unclear whether The ANF knockout resulted in salt sensitive hypertension
these lesions are strictly correlated with hypertension [101],whereas the knockout of the type A receptor for
[93,94],and it is also unclear whether they exhibit all the ANF resulted in a salt-independent hypertension [102].
classic features of complications of atherosclerosis,such as Such findings make an important point,namely that high
myocardial infarction,stroke etc.blood pressure is not only caused by addition of certain
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Y.M.Pinto et al./Cardiovascular Research 39(1998)77– 88 85
factors,but can also be caused by removal of protective This system is derived from E.coli,where it confers
factors.tetracycline resistance.The quintessence lies in the fact
that an operon is capable of activating certain genes,only
6.1.Rats or mice?when coupled to tetracycline.The system can be en-
gineered such that tetracycline either activates,or represses
A recurrent discussion regarding transgenics is which gene function.This is known as the TET-ON and OFF
species to use,mice or rats.The great advantage of mice is systems.Such systems have been shown to be operational
the availability of knockout technology.This enables the in vivo [106].Obviously,this system has the advantage of
targeted disruption of a given gene,which provides a providing control in timing transgene overexpression by a
powerful animal model to investigate the function of that relatively harmless exogenous substance,and can also be
gene.The disadvantage for hypertension research is that engineered to contain tissue-specific promoters such as the
spontaneous hypertension hardly occurs in mice,so that already used ones.Therefore,this would enable control
the candidate genes for hypertension seem to be relevant over both timing and location of the expression of the
more in rats,of which several models of genetic hyperten- transgene.
sion are known.Another drawback has been that mice are A method that has been employed in mice is the cre-lox
less readily accessible for physiologic studies.However,it system,based on bacteriophage P1.This consists of a
is to be anticipated that physiologic models in mice will be recombinase Cre,that recognises and binds two specific
soon developed.For instance,the classic Goldblatt hy- 38-nucleotide long sequences known as loxP sites,thereby
pertension has been also induced in mice,with conse- cleaving the interposed DNA sequence.By establishing a
quences similar to those found in rats [103].line with a site-targeted loxP insertions,and combining
Therefore,we expect that for the genetic aetiology of this with a line with Cre under a tissue specific promoter,
hypertension,rats will remain the species of first choice.one can obtain hybrid lines with a tissue specific disruption
On the other hand,the power of knockout technology will of a given gene.
lead to adapt physiology so that mice can be investigated
under normal and under artificial pathophysiological con-
ditions.8.Conclusions and outlook
A vast amount of data has appeared over the last
7.Future models employing genetic engineering decades.We have provided a brief overview of the most
widely used animal model strains,and their characteristics.
Most classic models have very complex aetiologies,and The most important lesson from a direct comparison of
have been mainly explored to unravel genetic and these animal models is that despite the well known
pathophysiologic mechanisms in hypertension.Very few heterogeneity of hypertension,the outcome of hyperten-
models are available to explore systematically what the sion can be similar in some respects:rats from all models
end-result of a specific hypertensive mechanism will be.In exhibit cardiac hypertrophy,and all demonstrate impaired
our opinion,the development of the TGR(mRen2)27 has endothelium-dependent relaxations of isolated arteries.
provided the first model in which the underlying mecha- However,the more severe forms of end-organ damage
nism is known (although not fully understood),and the such as heart failure,stroke and kidney failure,occur in
model can be used to specifically address the outcome of only a subset of the hypertensive rats.Therefore,this
angiotensin II driven hypertension.However,despite the comparison demonstrates what was also known for
relatively straightforward concept of the model (intro- humans:at similar levels of high blood pressure,other
duction of the mouse Ren-2 gene into the rat genome),the factors determine outcome and prognosis.This is also
exact mechanism of the hypertension is still unknown.underlined by the effects of antihypertensive drugs in rat
Nevertheless,genetic engineering techniques open up models.These antihypertensives can only attenuate end-
new possibilities to explore quite specifically the contribu- organ damage if they are able to decrease blood pressure,
tion of specific pathophysiologic mechanisms.For in- and if they are effective,they sometimes even attenuate
stance,specific promoters enable the targeting of a trans- end-organ damage in nonhypotensive doses (e.g.ACE
gene to be expressed in specific tissues.inhibition in Goldblatt hypertension).On the other hand,
The MLC2 promoter is particularly suitable for driving some agents do decrease blood pressure but do not prevent
significant overexpression quite exclusively in car- end-organ damage (e.g.hydralazine in SHR).Furthermore,
diomyocytes.For other cell types specific and effective not all classes of antihypertensives are equally effective in
promoter systems still need to be further defined,such as all rat models of hypertension:endothelin-receptor antago-
promoters that drive overexpression specifically in endo- nists are not effective in SHR,but have beneficial effects
thelial cells [104].Another important advantage is pro- in the DOCA–salt model.
vided by the system designed by Gossen and Bujard [105].Thus it seems that rat models of hypertension mainly
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86 Y.M.Pinto et al./Cardiovascular Research 39(1998)77– 88
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