Genetic Models Of Hypertension

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Spontaneously hypertensive rat (SHR)

Males. The SHR is a commonly used model of hypertension (Reckelhoff, 2001). These animals develop increases in blood pressure beginning at six to seven weeks of age and reach a stable level of hypertension by 17 to 19 weeks of age. Inhibitors of the renin-angiotensin system reduce blood pressure in SHR, suggesting a role for the RAS in mediating the hypertension.

Removal of the renal nerves also reduces blood pressure in SHR, suggesting that the sympathetic nervous system is important in mediating the hypertension. Because increased sympathetic activity can stimulate renin release from the kidney, it is possible that the up-regulated RAS in SHR may be due to increased sympathetic activation.

In addition to the RAS and sympathetic nervous system in mediating the hypertension in SHR, treatment with antioxidants also reduces blood pressure, suggesting a role for oxidative stress in the hypertension of SHR. For example, treatment with tempol, a superoxide scavenger, reduces blood pressure as does apocynin, an inhibitor of the assembly of the subunits of NADPH oxidase. However, treatment with allopurinol protects against some of the end organ injury in SHR but fails to reduce blood pressure, suggesting that the oxidative stress in SHR that plays a role in their hypertension is mediated via NADPH oxidase, but not xanthine oxidase.

With aging, renal function decreases with reductions in GFR and renal plasma flow and increases in renal vascular resistance. Modest levels of proteinuria are also present in aging animals. In SHR at nine months of age, studies by Tolbert and colleagues (2000) showed no injury despite mean arterial blood pressure of 160 to 180 mm Hg for at least five months. These investigators attributed the protection against renal injury to increased afferent arteriolar resistance. Glomerular sclerosis is present, although at modest levels at 18 months of age with less than 10% of glomeruli expressing any level of sclerosis (Fortepiani et al., 2003).

A variation of the SHR is the SHR stroke-prone (SHRSP) rat. These animals develop malignant hypertension and die within several weeks due to stroke. They would not be conducive for aging studies.

Female SHR: A model of postmenopausal hypertension. The elucidation of mechanisms responsible for postmenopausal hypertension has been stunted by lack of an animal model (Reckelhoff and Fortepiani, 2004). Most of the studies in postmenopausal women have been correlative. Sheep, rabbits, nonhuman primates, rats, and mice have been used as models of various meno-pausal changes. However, to our knowledge, there have been few studies in which a naturally occurring animal model of postmenopausal hypertension has been described. The female SHR is an exception to this.

Throughout their reproductive lives, female SHR have mean arterial pressures that are 25 to 30 mm Hg lower than male SHR, although they are quite hypertensive compared to normotensive rats (Reckelhoff and Fortepiani, 2004). When female SHR stop estrous cycling at 10 to 12 months of age, the blood pressure begins to increase such that by 16 months of age, the mean arterial pressure is similar or even higher than in males of similar ages. This makes the aging female SHR a good model for the study of postmenopausal hypertension. Most models of postmenopausal changes are performed in young animals that have been ovariectomized, which removes the factor of ''aging'' from the studies. However, if female SHR are ovariectomized at a young age, there is no increase in their blood pressure as they age. If females are ovariectomized at nine months of age or after cessation of estrous cycling, their blood pressure either does not increase or actually falls compared to intact females. These data suggest that there is some factor produced by the ovary that impacts the blood pressure in the aging intact female SHR. However, this makes the aged, ovariectomized female SHR a poor model of postmenopausal hypertension.

The aging female SHRs are protected against target organ damage compared to males. Despite similar or higher blood pressure in aging females compared to males, they exhibit less renal injury (glomerular sclerosis) or protein excretion than age-matched males. Left ventricular hypertrophy is greater in the female SHR, however, but this may be an important compensatory mechanism due to the hypertension that is absent in the males.

The mechanisms responsible for the hypertension in the aging female SHR are related to the endothelin system, which is not the case in aging male SHRs. Blockade of the endothelin ETA receptor reduces blood pressure in aging female SHRs, but not aging males nor in young females (Yanes et al., 2004). In contrast the RAS seems to play a more important role in maintenance of the hypertension in the aging male SHR than females. Treatment of aging male and female SHRs with an angiotensin AT1 receptor antagonist causes a greater reduction in blood pressure in males than females. In addition, angiotensinogen protein expression in kidneys of males is several fold higher than in females. The data suggest that the RAS is up-regulated in aging male SHRs, but not females (Yanes and Reckelhoff, unpublished data).

Advantages and disadvantages of use. The aging SHR is a good model in which to study the effects of chronic hypertension in aging, and in the case of females, to study a model of postmenopausal hypertension. One disadvantage of the model is that they fail to gain a considerable amount of weight, as other rats do. The females are typically 300 and 350 g at 18 months, whereas the males are typically 400 to 450 g at that age. Therefore, for investigators studying aging, metabolic syndrome, and hypertension, these animals would not be appropriate.

Similarly, because the renal vasculature is protected against age-related injury, the SHR is not an appropriate model in which to study chronic renal injury. There are several normotensive rat models that develop considerably more glomerular sclerosis with normal aging than do the SHR.

Dahl salt-sensitive rats

Males. There are a significant number of individuals who are hypertensive who have low plasma renin activity, but whose blood pressure increases further when they ingest salt. Certain populations, such as African-Americans and the elderly, are more susceptible to development of salt-sensitive hypertension. The Dahl salt-sensitive rat is a commonly used model of saltsensitive hypertension. Typical rat chow is 1% salt, and diets of 0.1 to 0.4% are considered low-salt diets. Dahl salt-sensitive rats (DS) exhibit an increase in blood pressure when placed on 1% salt or higher. Many investigators use 2 to 8% salt diets in order to invoke the hypertension. Along with the hypertension, the rats develop significant renal injury, heart failure, and inflammation within three to six weeks of being placed on high-salt diet.

The determination of an appropriate control for the DS is controversial. There is a Dahl salt-resistant rat (DR) that is used by some investigators as a control. These rats do not exhibit an increase in blood pressure when placed on high-salt diet. However, genetic studies have shown that the DR is no more similar to the DS than is another normotensive strain, such as the Brown Norway rat or the Sprague Dawley rat. These normo-tensive rats also fail to develop an increase in blood pressure when placed on a high-salt diet.

The mechanisms responsible for the salt-sensitive hypertension in DS rats include reductions in nitric oxide (NO) and increased oxidative stress. Sanders and colleagues (1996) reported several years ago that treatment of DS rats with L-arginine, the precursor for NO, protects against salt-sensitive hypertension (Sanders, 1996). Manning and colleagues also reported that giving tempol, the superoxide scavenger, attenuates the development of hypertension in DS rats, but has no effect on blood pressure in DR on a high-salt diet, suggesting a role for oxidative stress in the hypertension (Meng et al., 2003). Taken together these data suggest that superoxide may be responsible for the reduction in NO availability in DS rats since superoxide is capable of scavenging NO leading to vasoconstriction and production of another potent oxidant, peroxynitrite, which has been shown to up-regulate vasoconstrictors and down-regulate vasodilators due to its ability to nitrotyrosinate proteins.

Endothelin also plays a role in the development of salt-sensitive hypertension in DS rats, since DS rats given endothelin ETA receptor antagonists are resistant to increases in blood pressure when placed on high-salt diet (Kassab et al., 1998). It is also possible that increased endothelin activity in the DS rat could be responsible for the increase in oxidative stress found in this rat model.

Because a high-salt diet is associated with reductions in renin release and thereby reductions in angiotensin II, the role that the RAS plays in mediating salt-sensitive hypertension is controversial. Navar and colleagues have measured angiotensin II in kidneys of DS and have found that when placed on a high-salt diet, the intrarenal angiotensin II levels do not change as the plasma renin activity does, suggesting an inappropriate level of angio-tensin II for the level of salt and volume. Therefore, it is possible that the intrarenal RAS could play a role in the hypertension in DS rats on a high-salt diet. However, calcium channel blockers have been shown to attenuate the hypertension in DS rats on a high-salt diet better than either angiotensin converting enzyme inhibitors or AT1 receptor antagonists.

There is a paucity of aging studies in the DS rat. Mainly, investigators use these rats to study age-related changes in the brain. However, many so-called aging studies are in rats aged 20 weeks or less. The work of Hinojosa-Laborde and colleagues is an exception, as discussed next.

Female DS rats—Model of postmenopausal hypertension. Hinojosa-Laborde and colleagues were the first to maintain DS rats on a low-salt (0.3%) diet as they aged and followed changes in blood pressure (Maric et al., 2004). Just like many other rat strains that exhibit sex differences in hypertension, the DS females on low-salt diets have slightly higher blood pressure than do males when they are young. Ovariectomy of the females causes a significant increase in blood pressure even when rats are kept on low-salt diets. With aging, however, the blood pressure in all groups of rats increases even on low-salt diets. Eventually males develop higher blood pressure than do females. However, ovariectomized females remain more hypertensive than the other sexes.

Estradiol treatment of the ovariectomized females reduces their blood pressure to the levels found in intact females. Thus, the aging DS rat is a good model in which to study postmenopausal hypertension.

Advantages and disadvantages of use. The use of the DS rat as a model of salt-sensitive hypertension and/or renal injury is attractive since the hypertension develops rapidly and the renal injury is present by three to four weeks. However, the fact that aging DS rats develop increases in blood pressure even when kept on low-salt diets may make them a difficult aging animal model with which to work. The ovariectomized rats do not live past 14 months of age, and the intact females do not live more than 15 to 16 months of age (personal communication, Dr. C. Hinojosa-Laborde). Whether males live longer is not clear from Dr. Hinojosa-Laborde's work, since she mainly focuses on aging females, but this is doubtful. The fact that the rats die at an early age may explain why there is a paucity of data in aging DS rats.

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