Lessons from rat models of hypertension: from Goldblatt to genetic engineering (original) (raw)

Abstract

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, deoxycorticosterone 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.

Time for primary review 22 days.

1 Use of animal models in hypertension

In contrast to the idea that the human circulation was first described by Harvey, the essentiality of the heart for life was already recognised in the Talmud, the collection of Jewish laws that were collected up to 499 AD, and the physician Asaph Judaeus realised in the 6th century AD that blood circulates through the vessels [1], thereby antedating Harvey. Although it has long been realised how important the circulation is, it is a more recent insight that high blood pressure may have adverse effects. It probably dates back to the first half of the 19th century, when Bright observed that high blood pressure was related to increased cardiac mass and renal abnormalities. Subsequently, Janeway described that patients with increased blood pressure die prematurely [2].

The first animal model of hypertension was developed when Harry Goldblatt clipped the renal artery of a dog, and produced a secondary form of hypertension [3], thereby initiating the development of a wide array of animal models for hypertension. The current review aims to analyse the past experience with animal models, assess what they have taught us, and predict how new animal models will influence hypertension research. No encyclopaedic summary of all models available will be given, as it is explicitly not our intention to provide information that is available through textbooks. Instead, we will aim to point out some new lessons to be learnt from six decades of studies on experimental hypertension.

The number of publications in which animal models are used in hypertension research obviously depends on the total volume of research in the field. To obtain an idea of the use of animal models, though extremely imprecise, a crude estimate can be obtained by searching reference databases (medline CD-ROM) to determine the number of papers that use the word hypertension. Then we calculated this number as a proportion of the total number of papers, by looking for an unspecific term (i). The proportion of papers on hypertension constituted around 15% of the total amount of papers in the mid-sixties, which increased to around 18% in the mid-seventies, at which level it remains until 1997. By using a similar approach we addressed the relative amount of papers that mention different models of hypertension. Again, the crudeness of assessing the number of papers appearing upon request for a key-term must be stressed, since it is simply meant to illustrate, rather than to give any suggestion about the absolute volume of scientific work in this field. Nevertheless, such analyses can be used to exemplify several points:

1. 1. Rats are by far the most popular species in hypertension research (Fig. 1)
      
      Fig. 1
      Absolute number of papers published on hypertension in different species, rat, mouse, dog and cat. It is evident that hypertensive rats are the most often used species in hypertension research.
2. 1. The use of rat models is a stable or slightly increasing proportion of the total volume: each year ca. 18% of all papers containing the word hypertension also mention the use of a rat model
3. 1. Without any doubt the SHR is the most often used model, accounting for the largest proportion of the papers in which rat models are used (Fig. 2). Most rat models comprise a stable proportion of the total volume, with exception of the transgenic TGR(mRen2)27, who are recently described, and are the only model that is increasingly used (Fig. 3).
      
      Fig. 3
      Variability in the use of a particular rat model. Variability is low with regard to all models (not shown for DOCA and Dahl rats), except for the newly developed transgenic rat which is increasingly used. This stability suggests that the choice for a rat model is not heavily influenced by trends, but may also suggest that researchers stick to their model, even though it may not be the optimal choice in all cases. The variability has been calculated by determining number of publications that use the name of the model (SHR), as a proportion of the number of papers on hypertension. the proportion that each model comprised of the total number of papers in 1990 is set to 1 (i.e. the number of papers on SHR relative to the total number of papers on hypertension in 1990 is set to 1). 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.
      
      Fig. 2
      Number of publications on a particular rat model of hypertension, as divided by the total number of papers on hypertension. It is evident that the SHR is by far the most widely used. The importance of this observation lies in the fact that the SHR represent only part of the mechanisms leading to hypertension (see Fig. 4), and that the choice for a particular model importantly influences outcome and response to treatment (Tables 1 and 2). The abundant use of SHR suggests that these factors are not always considered when a rat model of hypertension is chosen.

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, primary hypertension, is often represented by genetic models of hypertension, such as SHR. However, such genetic models are characterised by a Mendelian type of inheritance, which is rarely encountered in human primary hypertension. The bottom panel displays the end-organ involvement that is seen in various rat models of hypertension. It is a very subjective interpretation of the available literature, which is dominated by studies in relatively young subjects, with often short lasting hypertension. This has provided a large body of evidence on milder forms of end-organ involvement such as cardiac hypertrophy, whereas severe cardiac failure is less frequently studied. However, even in studies on heart failure in the SHR, heart failure still is only seen in part (e.g. 60%) of all rats studied.

2 Laboratory experiments versus epidemiology

It is important to stress how difficult it is to define so-called hypertensive disease, particularly since it is futile to try to distinguish between normotension and hypertension. Large epidemiological studies demonstrated that the level of blood pressure is continuously and proportionally related to morbidity and mortality [4]. Thus, epidemiology would suggest that every increase in blood pressure conveys a proportional increase in risk.

An important, but not often stressed, observation is that up to 15% of the patients with established hypertension will demonstrate hypertension related morbidity and mortality, leaving 85% of the clearly hypertensive patients without gross clinical events [5]. This suggests that in a large number of patients some mechanisms protect against severe hypertension related end-organ damage.

The etiology of hypertension is widely investigated in rat models, and more than one model represents a genetic aetiology (Fig. 4), with a classic Mendelian type inheritance. However, the most frequently encountered human type of hypertension is primary hypertension (often called essential hypertension), which has genetic aspects, but does not usually display a Mendelian type inheritance, and is therefore not purely represented by animal models. Nevertheless, many aetiologies of human hypertension can be mimicked in rat models, so that these models provide ample opportunity to study different types of hypertension.

The observation that the SHR is abundantly used, whereas it represents only a particular type of hypertension, suggests that specific properties of a model are not always considered when a rat model is chosen. Since the different rat models have a different etiology, it is conceivable that the choice of a model significantly influences the outcome of an experiment. This can be illustrated not only by evaluating the different etiologies, but also by comparing end-organ damage in different models.

As excellent overviews of the different etiologies in different animal models already exist [6], we will focus on hypertensive end-organ damage, as this seems to be less clearly paralleled by animal models. Understandably, the endpoints of studies in animals are quite different from those assessed in human subjects: end-organ damage that occurs earlier in human hypertensive disease is often an end-point of experimental studies: cardiac hypertrophy (as opposed to overt heart failure), endothelial dysfunction (as opposed to gross vascular abnormalities) and proteinuria (as opposed to severe kidney failure) (Fig. 4). One exception is stroke in the stroke prone SHR (SHR-SP), which is a main end-point in studies with this model. Myocardial infarction, aneurysm formation and atherosclerosis are rarely encountered in animal models of hypertension.

To analyse how different rat models clarify the pathophysiology of hypertensive end-organ damage, we will briefly summarise some often-used rat models of hypertension, and compare them to answer whether every type of high blood pressure leads to the same end-organ damage and whether every type of blood pressure lowering leads to the same improvement.

3 Rat models of hypertension

In this section we will briefly discuss the rat models of hypertension on which this review focuses, and will describe the natural occurrence of end-organ damage (Table 1) and the effect of treatment (Table 2).

A=ACE/RAS inhibition, B=beta blockade, C=calcium antagonists, D=diuretics, E=endothelin antagonists, F=direct vasodilators, +=protective effect, −=no 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 β-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.

A=ACE/RAS inhibition, B=beta blockade, C=calcium antagonists, D=diuretics, E=endothelin antagonists, F=direct vasodilators, +=protective effect, −=no 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 β-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.

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.

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.

3.1 Spontaneously hypertensive rats

By inbreeding Wistar rats with the highest blood pressure, Okakamoto and Aoki [7]obtained a strain of rats with spontaneous hypertension, the SHR. They described how blood pressure rises around 5–6 weeks of age, and steadily increases to reach systolic blood pressures of 180–200 mm Hg. The SHR develop many features of hypertensive end-organ damage (Table 2): cardiac hypertrophy, cardiac failure and renal dysfunction. However, they do not exhibit gross vascular problems: apart from depressed endothelial dependent relaxations, they have no tendency to develop strokes, and also develop no macroscopic atherosclerosis or vascular thrombosis. The SHR stroke prone (SHR-SP) is a further developed sub-strain, with even higher levels of blood pressure, and a strong tendency to die from stroke [8]. The SHR have been widely used to evaluate genetic factors in hypertension, yielding a wide variety of genes that seem to cosegregate in various crosses [9–11]which is not always confirmed [12]. Since this is not a strictly inbred strain, individual variations in genetic background of both SHR and particularly of their control strain may importantly influence the resulting end-organ changes, so that one can anticipate considerable variability in end-organ changes, as is also clear from the natural history (see next paragraph).

3.1.1 End organ damage (see Table 1 for references)

In the untreated rats, cardiac hypertrophy is found in all studies (approx. 30% increase), and many rats progress to develop heart failure between the age of 18 and 24 months. However, not all rats exhibit signs of heart failure after 24 months so that despite the uniformity of the model, individual differences are seen. Impaired endothelium dependent relaxations have been consistently found, although rats until 13–15 weeks of age may sometimes have normal endothelium dependent relaxation (personal observation). Renal damage (protenuria and decreased creatinine clearance) has also been found in older SHRs, but there are no studies describing frank renal failure.

3.1.2 Effect of treatment (see Table 2 for references)

Blood pressure in SHRs is effectively lowered by inhibition of the renin–angiotensin system, calcium antagonists and by direct vasodilators (hydralazine). Diuretics and endothelin antagonists are less effective. The effect of beta-blockers is unequivocal (see comment to Table 2). The ability to prevent end-organ damage dissociates from the antihypertensive effects: inhibition of the renin–angiotensin system also prevents end-organ changes, whereas hydralazine fails to do so, despite its blood pressure lowering effect.

3.2 Two-kidney one-clip (Goldblatt hypertension, 2K1C)

In 1939, Wilson and Byrom adapted the method to constrict a renal artery in the rat, thereby inducing the now classic Goldblatt-hypertension in rats. The differences in collateral formation make this procedure particularly susceptible to species variation, so that two-kidney one-clip hypertension is only of short duration in the dog, who develops efficient collaterals, [13], whereas it is chronic in rats, as well as in humans with unilateral renal artery stenosis. In the early 1970s, it was recognised that models where the nonclipped kidney was left intact (two-kidney one-clip), differed fundamentally from those where this kidney was removed (one-kidney one-clip) [14]. In the two-kidney model, circulating renin and aldosterone levels are increased [15]and play a role most notably in the early phase of hypertension [16].

3.2.1 End organ damage (see Table 1 for references)

The natural history of the 2K1C rat depends partly on the technique used to narrow the renal artery, and particularly on the size of the clip and the age of the rat at the time of clipping. As a result, cardiac hypertrophy ranges from 25–50%. The occurrence of cardiac failure in chronic 2K1C has not been systematically described, and renal failure also seems to be rare: minor changes in the normal kidney have been described. Nevertheless, as in SHR, impaired endothelium dependent relaxations are described.

3.2.2 Effect of treatment (see Table 2 for references)

As can be expected, blood pressure in the 2K1C rat is exquisitely sensitive to inhibition of the renin–angiotensin system, but also responds to calcium antagonists and direct vasodilators, but not to diuretics, beta-blockers and endothelin antagonists. This renders a profile comparable to that of the SHR. Both renin– angiotensin inhibition and calcium antagonism attenuate cardiac hypertrophy, other end-organ changes have not been extensively described.

3.3 Transgenic rats overexpressing the mouse Ren2 gene (TGR (mRen2)27)

The introduction and overexpression of the mouse Ren-2 gene in the rat led to severe hypertension, lethal in the homozygous rats if not treated with ACE-inhibitors. This rat model is characterized by two important features: firstly, it is a genetic, inherited form of hypertension, where the single genetic event is known, and secondly, despite the known genetic alteration, the exact mechanism underlying hypertension remains elusive. It is clear that hypertension in this rat is related to an increased renin-activity, but it has been difficult to pinpoint the crucial tissue in which renin overactivity is responsible (see for review Langheinrich et al. [21]. Therefore, although plasma renin is low in this model, we still regard it as a high (tissue-) renin model. Another very intriguing finding is that the severity of hypertension depends partly upon the genetic background of the rats used for breeding the TGR (mRen2)27. As Withworth et al. showed [22], an accelerated and malignant type of hypertension occurs when these 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 able to exclude most environmental factors, this suggests that even when a defined genetic alteration, such as the introduction of the mouse renin gene, leads to hypertension, the outcome still depends on other genetic factors, and not just on the introduced gene. This suggests that hypertension and its outcome critically depends on the interplay between a certain defect, and the genetic (and environmental) background.

3.3.1 End organ damage (see Table 1 for references)

No descriptions are available for ageing TGR(mRen2)27, although we know that 70% of the heterozygous rats survive at least until the age of 5 months. We have recently described that before that age they develop marked cardiac hypertrophy and impairment of endothelium dependent relaxations.

3.3.2 Effect of treatment (see Table 2 for references)

Obviously, inhibition of the renin–angiotensin system effectively lowers blood pressure, and attenuates the development of cardiac hypertrophy and improves endothelium dependent relaxation. Direct vasodilatation and beta-blockade significantly decreases blood pressure in this model, but does not normalise it. Despite these significant reductions, we found no effect of either hydralazine or carvedilol on cardiac weight or endothelium dependent relaxations.

3.4 Dahl salt-sensitive rats

This rat was bred in the 1950s when Meneely et al. observed ‘a marked degree of individual variation’ in the blood pressure response to salt ingestion [18]. The salt sensitive Dahl rats develop severe and fatal hypertension when fed high salt diets, whereas salt resistance rats do not develop such severe hypertension upon salt loading. Also when fed normal salt diets, the salt sensitive rats become hypertensive, demonstrating that this is a model of genetic hypertension, with the extra feature of salt sensitivity [19]. Linkage analysis revealed linkage with loci close to the ACE and ANF receptor genes [20].

3.4.1 End organ damage (see Table 1 for references)

The Dahl salt-sensitive rat has a moderately increased blood pressure, even when fed a normal salt diet. Upon salt feeding (8% NaCl), blood pressure rises steeply, to levels slightly higher than those found in SHR. Although cardiac hypertrophy is comparable to that found in SHR (up to 32%), cardiac failure has been noted already at 4–5 months of age (cf. SHR in which it is seen only after 18 months or more). Also, renal changes seem more severe than in SHR, with severe early proteinuria. Again in this model endothelium dependent relaxations were found to be impaired.

3.4.2 Effect of treatment (see Table 2 for references)

Although seen as a low-renin volume overload model, blood pressure in Dahl rats responds to inhibition of the renin–angiotensin system. Furthermore, diuretics, vasodilators and possibly endothelin-receptor anatgonists are effective, whereas calcium antagonists and beta-blockers are less effective. Again, the effect on end-organ changes dissociates from the effects on blood pressure: renin–angiotensin inhibition attenuates cardiac hypertrophy and proteinuria, whereas diuretics (who decrease blood pressure) are not effective.

3.5 DOCA–salt rats

The administration of deoxycorticosterone acetate (DOCA), in combination with a high salt diet and unilateral nephrectomy induces a low renin form of hypertension [17], which can be opposed to the other artificial model, 2K1C, where renin is increased.

3.5.1 End organ damage (see Table 1 for references)

Cardiac weight is increased by 30%, but cardiac failure is not yet systematically described. Renal changes are described with proteinuria and glomerulosclerosis, and again, as with all other models, this rat also demonstrates impaired endothelium dependent relaxations.

3.5.2 Effect of treatment (see Table 2 for references)

This is the only model in which renin–angiotensin inhibition does not decrease blood pressure, nor end-organ changes. Diuretics and also endothelin antagonists are effective both with regard to blood pressure, and with regard to end-organ changes. Again the effects on blood pressure and end-organs dissociates when direct vasodilators are used: despite an effect on blood pressure, cardiac hypertrophy is not attenuated.

Therefore both Dahl and DOCA rats represent the low renin, volume overload form of hypertension, with a different natural history, and a different response to antihypertensives, when compared to the high renin models [SHR, 2K1C, TGR(mRen2)27]. This suggests a parallel between the type of hypertension seen in black hypertensives and the salt dependent models such as Dahl and DOCA–salt; both respond less to renin–angiotensin inhibition, but respond well to calcium-antagonism. This is exemplified by the fact that calcium antagonism is superior to ACE inhibition in prolonging survival in the Dahl-S rat [95]. The differences between these models also underlines the theory proposed by Laragh and Resnick [5], who divided hypertension into a low renin form, with salt and water retention (wet hypertension), and a high renin form (dry hypertension), which is amenable to RAS inhibition, but responds poorly to salt and water restriction.

This underlines again how important it is to make a rational and deliberate choice for a particular rat model, since the many models available represent different aspects of hypertension.

4 What have we learned? The stress-and-coping hypothesis

The reasoning in this section is based on comparisons of published effects, and only rarely on direct experimental comparisons. The first obvious but still important conclusion stems from the observation that many ways lead to Rome: in spite of very different etiologies, the degree of hypertension is often comparable between very different strains. This underlines what has been known for a long time: high blood pressure is a final common pathway for different (pathophysiologic) mechanisms. Furthermore, it seems that hypertension related end-organ damage is not only related to high blood pressure itself (the hemodynamic stress), but also to the underlying adverse biochemical alteration (biochemical stress) and on the other hand to the ability of the end-organ to withstand this stress (coping). We define coping as the ability of the organism, or of one organ, to successfully adapt to an increase in either mechanical or biochemical load: for the heart the example is cardiac hypertrophy, invariably found as an initial mechanism to normalise wall stress. However, derangements of this coping mechanism, or insufficiency of this mechanism may result in a maladaptive from of cardiac hypertrophy with loss of function. Another example is the ability of the kidney to normalise intraglomerular pressure by constriction of afferent renal arteriole, so that the glomerulus is protected against the adverse effects of high intraglomerular pressure: again one can speculate that there are individual differences in the effective recruitment of such mechanisms.

In all models, the left ventricle is hypertrophied and endothelium dependent relaxations are impaired. However, cardiac failure is not always seen, and is mostly encountered after severely elevated pressures (malignant type). It also occurs in part of the rats with moderate to severe high blood pressure (see Table 1). Therefore, not every hypertrophy nor every endothelial dysfunction will cause severe end-organ failure. This would contradict the belief than any form of cardiac hypertrophy, or any form of endothelial dysfunction is detrimental.

Renal dysfunction takes various forms in different models, and seems to depend upon the relation between increased pressure, underlying etiology (high renin versus low renin) and genetic background, and on the above ability to recruit protective mechanisms.

Furthermore, some antihypertensive drugs normalise blood pressure, but do not prevent hypertrophy or impairment of endothelial dependent relaxations. It is clear that if a drug of a certain class does not decrease blood pressure, it will not prevent end-organ damage. Conversely, if a certain drug decreases blood pressure in a particular model, it usually prevents end-organ damage. However, this 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 in TGR (mRen2)27 (see Table 2 for references). On the other hand, some drugs may even prevent end-organ changes in nonhypotensive doses. This latter effect is only seen with drugs that are particularly effective in decreasing blood pressure (e.g.: ACE-inhibitors are particularly effective in a two-kidney one-clip model, and were suggested to prevent cardiac hypertrophy even in a dose that does not decrease blood pressure [73]). This demonstrates that to prevent end-organ damage, a drug has to interfere with biochemical mechanisms in play. The more the drug interferes with this biochemical stress, the more efficient it prevents end-organ damage, so that it sometimes even works at nonhypotensive dosages.

The message for clinical antihypertensive treatment is that for an antihypertensive drug to prevent end-organ damage the drug should effectively and easily normalise blood pressure. However, even if it does, this does not guarantee that the drug will eventually prevent end-organ damage. Still the value of monitoring blood pressure is that it in part predicts whether a drug will prevent end-organ damage. When a drug fails to normalise blood pressure, it will not prevent end-organ damage, and when a drug does decrease blood pressure, it is more likely (although not certain!) to prevent end-organ damage.

A simplified model describes the likelihood of end-organ damage in terms of stress and coping, so that both the amounts of stress, but also the ability to cope, determines the likelihood of developing end-organ damage. This hypothesis predicts that even at relatively normal blood pressures, severe end-organ damage may be seen. This idea is illustrated by the rat with spontaneous noninsulin dependent diabetes mellitus, (Otsuka Long-Evans Tokushima fatty rats; OLETF) described in 1992 [89]. In this rat model, moderate hypertension develops with blood pressures up to 150–160 mm Hg, without significant cardiac hypertrophy. However, significant changes in cardiac expression of genes coding for extracellular matrix proteins were noted, as well as marked proteinuria and glomerular changes [90]. This underscores how biochemical stress (such as diabetes mellitus) increases the susceptibility to end-organ damage even at relatively modest blood pressure increases.

A troublesome conclusion from reviewing animal models of hypertension is that the rat (and also the mouse), fails to develop classic thrombotic atherosclerotic lesions and its complications. One could argue that the lifespan of rodents is too short to exhibit atherosclerosis, but on the other hand, early signs such as fatty streaks are also hardly encountered in hypertensive rats. Therefore, one could speculate that either hypertension is not sufficient to cause atherosclerosis, or that the hypertensive rats have mechanisms preventing its formation, which humans lack. Even transgenic hypercholesterolemic mice, with severe atherosclerotic-like disease, do not develop classic thrombotic atherosclerotic complications [91].

In nonmammalian species veterinarians have described naturally occurring hypertension and hypertension related death in turkeys [92], and for research purposes it is possible to investigate hypertensive turkeys. The hypertensive turkey also develops high cholesterol levels and atherosclerotic lesions. However, it is unclear whether these lesions are strictly correlated with hypertension [93, 94], and it is also unclear whether they exhibit all the classic features of complications of atherosclerosis, such as myocardial infarction, stroke etc.

5 Choosing a model of hypertension

As discussed above, the SHR is by far the most popular model, despite the fact that it only represents a small proportion of the wide array of etiologies of hypertension. The widespread use of the SHR encourages new workers in the field to use the same model, whereas it may not be the optimal choice for many specific experimental questions. Ideally, the experimental question should dictate the choice of a model. In general, the models with an unknown, mostly genetic aetiology (SHR, SHRSP, and Dahl rats) provide the opportunity to search for (new) mechanisms and new genes in hypertension. To investigate the morbidity associated with hypertension, it seems reasonable to choose a model were the aetiology is known to some extent: DOCA–salt, two-kidney one-clip, or TGR(mRen2)27, so that a more rational approach can be taken towards dissecting the effects of hypertension from the underlying dysregulation. Another important aspect is that different models can be seen to represent different types of hypertension, as described above by comparing low renin models (DOCA, Dahl) to high renin models (SHR, 2K1C, TGR(mRen2)27). As it is well known that in humans, hypertension in African patients can have a different course in than in Caucasians, one can view these models as representatives of different subsets of hypertension.

6 Transgenic models

The ability to specifically introduce genetic construct and thereby breed transgenic animals, has also opened new possibilities for hypertension research [96]. The first of its sort was the transgenic rat that was obtained after introduction of the entire mouse Ren2d gene [97]. This rendered a hypertensive model in which the hypertension and ensuing end-organ damage is very much dependent upon increased local angiotensin II formation (for review see [98]) and is exquisitely sensitive to RAS inhibition. Other transgenic models have been obtained where the introduction of both renin and human angiotensinogen increased blood pressure in mice [99]and in rats [100]. The latter strain is characterised by severe hypertension, and early mortality.

Many parts of the cardiovascular system have been evaluated in transgenic rats, but only few led to models of hypertension. Noteworthy are the knockout models, were genes for ANF and NO-synthase have been knocked out. The ANF knockout resulted in salt sensitive hypertension [101], whereas the knockout of the type A receptor for ANF resulted in a salt-independent hypertension [102]. Such findings make an important point, namely that high blood pressure is not only caused by addition of certain factors, but can also be caused by removal of protective factors.

6.1 Rats or mice?

A recurrent discussion regarding transgenics is which species to use, mice or rats. The great advantage of mice is the availability of knockout technology. This enables the targeted disruption of a given gene, which provides a powerful animal model to investigate the function of that gene. The disadvantage for hypertension research is that spontaneous hypertension hardly occurs in mice, so that the candidate genes for hypertension seem to be relevant more in rats, of which several models of genetic hypertension are known. Another drawback has been that mice are less readily accessible for physiologic studies. However, it is to be anticipated that physiologic models in mice will be soon developed. For instance, the classic Goldblatt hypertension has been also induced in mice, with consequences similar to those found in rats [103].

Therefore, we expect that for the genetic aetiology of hypertension, rats will remain the species of first choice. On the other hand, the power of knockout technology will lead to adapt physiology so that mice can be investigated under normal and under artificial pathophysiological conditions.

7 Future models employing genetic engineering

Most classic models have very complex aetiologies, and have been mainly explored to unravel genetic and pathophysiologic mechanisms in hypertension. Very few models are available to explore systematically what the end-result of a specific hypertensive mechanism will be. In our opinion, the development of the TGR(mRen2)27 has provided the first model in which the underlying mechanism is known (although not fully understood), and the model can be used to specifically address the outcome of angiotensin II driven hypertension. However, despite the relatively straightforward concept of the model (introduction of the mouse Ren-2 gene into the rat genome), the exact mechanism of the hypertension is still unknown.

Nevertheless, genetic engineering techniques open up new possibilities to explore quite specifically the contribution of specific pathophysiologic mechanisms. For instance, specific promoters enable the targeting of a transgene to be expressed in specific tissues.

The MLC2 promoter is particularly suitable for driving significant overexpression quite exclusively in cardiomyocytes. For other cell types specific and effective promoter systems still need to be further defined, such as promoters that drive overexpression specifically in endothelial cells [104]. Another important advantage is provided by the system designed by Gossen and Bujard [105]. This system is derived from E. coli, where it confers tetracycline resistance. The quintessence lies in the fact that an operon is capable of activating certain genes, only when coupled to tetracycline. The system can be engineered such that tetracycline either activates, or represses gene function. This is known as the TET-ON and OFF systems. Such systems have been shown to be operational in vivo [106]. Obviously, this system has the advantage of providing control in timing transgene overexpression by a relatively harmless exogenous substance, and can also be engineered to contain tissue-specific promoters such as the already used ones. Therefore, this would enable control over both timing and location of the expression of the transgene.

A method that has been employed in mice is the cre-lox system, based on bacteriophage P1. This consists of a recombinase Cre, that recognises and binds two specific 38-nucleotide long sequences known as loxP sites, thereby cleaving the interposed DNA sequence. By establishing a line with a site-targeted loxP insertions, and combining this with a line with Cre under a tissue specific promoter, one can obtain hybrid lines with a tissue specific disruption of a given gene.

8 Conclusions and outlook

A vast amount of data has appeared over the last decades. We have provided a brief overview of the most widely used animal model strains, and their characteristics. The most important lesson from a direct comparison of these animal models is that despite the well known heterogeneity of hypertension, the outcome of hypertension can be similar in some respects: rats from all models exhibit cardiac hypertrophy, and all demonstrate impaired endothelium-dependent relaxations of isolated arteries. However, the more severe forms of end-organ damage such as heart failure, stroke and kidney failure, occur in only a subset of the hypertensive rats. Therefore, this comparison demonstrates what was also known for humans: at similar levels of high blood pressure, other factors determine outcome and prognosis. This is also underlined by the effects of antihypertensive drugs in rat models. These antihypertensives can only attenuate end-organ damage if they are able to decrease blood pressure, and if they are effective, they sometimes even attenuate end-organ damage in nonhypotensive doses (e.g. ACE inhibition in Goldblatt hypertension). 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.

Thus it seems that rat models of hypertension mainly share high blood pressure, but otherwise display a wide variety of biochemical disturbances, with equally varying course and prognosis. The course and prognosis seems to depend on three main factors:

1. 1. the mechanical stress which is the absolute level of blood pressure, and when above a certain threshold will always cause severe end-organ damage (e.g. SHR stroke prone and homozygous TGR(mRen2)27),
2. 1. the biochemical stress which is an important modifier of the course of hypertension, (e.g. diabetic rats (‘OLETF’) with only moderate increases in blood pressure but relatively severe end-organ damage) and,
3. 1. the ability to recruit coping or adaptive mechanisms (e.g. adaptive hypertrophy which normalises wall stress, constriction of the afferent arteriole to normalise intraglomerular pressure).

The rat models of hypertension thus provide ample opportunity not only to investigate the mechanisms involved in the pathogenesis of hypertension, but also to learn about the critical balance between stress and coping, which eventually determines prognosis.

9 Note added in proof

Recently, Brown et al. [107]demonstrated in the fawn-hooded hypertensive rat that two genetic loci are associated with hypertension related renal disease although these loci are not related to hypertension. This suggests the existence of genes that do not cause hypertension, but rather confer susceptibility for hypertension related renal disease.

Acknowledgements

Y.M.P received a 1996 molecular cardiology grant from the Interuniversity Cardiology Institute Netherlands (ICIN).

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