Animal Model of Hypertension: Spontaneously Hypertensive Rat: History
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Joanna Niewiadomska

Spontaneously hypertensive rats (SHR) rats were produced by outbreeding Wistar–Kyoto rats, followed by the selective inbreeding of their offspring with the highest blood pressure values. These rats are mainly used in studies on cardiovascular diseases, especially hypertension, metabolic diseases that lead to insulin resistance, hypertriglyceridemia, hyperinsulinemia, hypercholesterolemia, and renal dysfunction.

  • laboratory animal models

1. Introduction

Metabolic syndrome (MetS), a risk factor for cardiovascular diseases (CVD) and type 2 diabetes, affects a significant part of the population worldwide, with a prevalence of 10–30%. It is a clustering of interrelated metabolic disorders, which include insulin [1][2][3][4][5][6] resistance, central obesity, hypertriglyceridemia, lowered HDL cholesterol concentration, and hypertension [1][2]. MetS has had different criteria over the years, mainly associated with distinguishable definitions of abdominal obesity, with the World Health Organization (WHO), the National Cholesterol Education Program Adult Treatment Panel (NCEP/ATP111), the American Association of Clinical Endocrinologists (AACE), and the European Group for Study of Insulin Resistance (EGSIR) all proposing their own diagnostic criteria [3][4]. Finally, in 2005, the International Diabetes Federation (IDF) provided a standardized consensus. The proposed definition includes waist circumference as a precondition for the identification of MetS and embraces the standard features of the previous definition, such as the assessment of triglyceride (TG) level, high-density lipoprotein cholesterol (HDL), blood pressure, and fasting glucose [5][6].
Metabolic pathways comprising the pathomechanism of MetS have not yet been clearly characterized. However, this is a tedious process due to the wide range of different pathophysiological mechanisms needing to be considered. Evidence suggests that various factors may predispose one to the development of MetS, such as genetics, diet, lifestyle, and gut microbiome [7][8]. A syndrome, which is more of a clinical term than a disease entity, suggests an association with other disorders. The current research shows that MetS predisposes one to cardiovascular dysfunctions via, e.g., atherosclerotic changes [9][10][11] and type 2 diabetes [12]. The correlation with other disorders is based on oxidative stress’s role in the pathomechanism. Studies have indicated that there may be an association between MetS and Parkinson’s disease [13], obstructive sleep apnea [14], and the progression and development of different cancers, such as colon cancer or gastric cancer [15][16][17]. Treatment is mainly based on lifestyle changes involving increased physical activity and a balanced diet. Researchers are currently looking for new substances that could significantly mitigate the severity and progression of MetS symptoms by affecting the metabolic pathways involved in the MetS pathophysiology. Numerous studies based on animal models have demonstrated the existence of a relationship between the intake of polyphenol-rich products and the mitigation of individual components of MetS. A beneficial effect was obtained via a reduction in body weight, blood pressure, blood glucose levels, and improved lipid metabolism.

1.1. Cardiovascular Consequences

The changes that occur in the cardiovascular system are extensive and lead to cardiomyopathy, microcirculation damage, and endothelial function impairment [9][10]. Each component of MetS is an independent risk factor for cardiovascular diseases. Studies indicate an association between MetS and the elevated risk of atherosclerosis, myocardial infarction, and heart failure. Obesity-associated cardiomyopathy is characterized by concentric left ventricular hypertrophy and systolic or diastolic dysfunction. In addition, myocardial contractility, systolic velocity, and left ventricular shortening have been proven to be impaired [18][19]. Changes in microvascular tone and density are attributable to the non-equilibrium between oxygen delivery and tissue metabolism in miscellaneous vascular beds. These alternations in MetS are mainly caused by the significant variations existing in the control of arteriolar resistance [20]. Endothelial dysfunction is associated with decreased nitric oxide bioavailability in the setting of MetS. The underlying mechanism contributing to endothelial pathology is the augmented production of vasoconstrictors, including endothelin-1 (ET-1), thromboxane A2 (TXA2), and prostaglandin H2 (PGH2) [20]. The progression of atherosclerosis occurs over the years and is strongly correlated with age. The relation between the metabolic abnormalities occurring in MetS and atherosclerotic disease is undoubted. MetS leads to accelerated and more advanced atherosclerotic disease, which is correlated with a greater incidence of myocardial infractions. The adipose-derived hormones and adipokines released from fat depots, including perivascular adipose tissue, are considered to be the core of the pathological process and thought to mediate vascular calcification [21][22].

1.2. Usability of Animal Models in MetS Research

As the MetS pathophysiology is involved plenty of genetic variations and environmental factors, it is troublesome to discover one by one particular underlying components in such a complex system as a human being. Scientists have established many animal models that mimic the metabolic complications in humans to look for a solution. They are fundamental in discovering the genetic fundamentals of diverse parameters, characteristic of MetS, and their dependence on each other. Given the same environment, it can be explored how certain conditions impact metabolic changes and analyze the effect of environment on phenotype. In vivo models render genetic and environmental factors controlled, adjusted, and monitored in organisms of known origin. Understanding pathophysiology in animal models is crucial for implementing appropriate therapies and prevention strategies. Animal subjects, providing stable conditions, are thought to be small-scale follow-up research embracing relevant human studies [23][24].

2. Animal Model of Hypertension: Spontaneously Hypertensive Rat (SHR)

SHR rats were produced by outbreeding Wistar–Kyoto rats, followed by the selective inbreeding of their offspring with the highest blood pressure values. These rats are mainly used in studies on cardiovascular diseases, especially hypertension, metabolic diseases that lead to insulin resistance, hypertriglyceridemia, hyperinsulinemia, hypercholesterolemia, and renal dysfunction. SHR rats develop hypertension at 6–7 weeks of age, reaching a stable level with accompanying insulin resistance and hyperinsulinemia at 12 weeks of age. The development of hypertension in these rats is probably mediated by the renin–angiotensin axis and the activity of the sympathetic nervous system [23][25]. SHR rats do not develop hypercholesterolemia and hyperlipidemia, except where a specific dietary regimen induces these changes. For many years, these rats have been used in studies on heart failure due to the changes that occur in their cardiac muscle, including the progressive hypertrophy of the left ventricle, which is evident over the first 9 months of life and progresses to systolic dysfunction by 12 months of age. A variation of SHR rats is SHR stroke-prone (SHRSP) rats. SHRSP rats develop malignant hypertension and die from stroke within a few weeks [25].
As this animal model is well suited for assessing the impact of a given substance on the cardiovascular system, one of the most exciting polyphenols studied using SHR rats is resveratrol, a compound with cardioprotective properties. The characterization of metabolic changes in genetic animal models of metabolic syndrome is presented in Table 1.
Table 1. The characterization of metabolic changes in genetic animal models of metabolic syndrome.
Strain Mutation/Genetic Background Metabolic Changes Model References
Zucker Fatty rats (ZF) missense mutation on the leptin receptor gene (fa/fa) 1. obesity
2. hypertension
3. hyperinsulinemia
4. insulin resistance
5. hypercholesterolemia
6. hypertriglyceridemia		 obesity, type II diabetes, MetS [25][26]
Zucker Diabetic Fatty rats (ZDF) non-functional leptin receptor (selective in-bread rat strain) 1. obesity
2. hypertension
3. hyperinsulinemia
4. insulin resistance
5. hyperglycemia
6. hypercholesterolemia
7. hypertriglyceridemia		 type I and II diabetes, MetS [23][25][27][28][29]
Spontaneously Hypertensive rats (SHR) - 1. hypertension
2. hyperinsulinemia
3. insulin resistance		 hypertension, heart failure, renal dysfunction [23][25]

Resveratrol

Resveratrol is an organic chemical compound that is a member of a polyphenol family called viniferins. It is present in numerous plants, such as eucalyptus, mulberry, peanut, bilberry, strawberry, grape, rhubarb, and cranberry [30]. Grapes are considered one of the most abundant sources of resveratrol, as they have the highest levels of this compound, with their concentration in peel and seeds reaching 50–100 µg/g [31]. This stilbene derivative exhibits significant biological potential. In natural conditions, resveratrol is produced by some plants in response to injury. The available studies on this topic have shown that it has estrogenic, anti-inflammatory, cerebroprotective, cardioprotective, anti-angiogenic, antioxidant, and anti-cancer properties [31][32]. The effects of resveratrol are concentration-dependent, as it acts as a chemoprotective agent at a specific dose and promotes apoptotic cell death when used at a higher concentration [33]. In one study, the administration of resveratrol in drinking water to SHR rats for 10 weeks reduced the development of hypertension, as indicated by the lower blood pressure of the treated rats compared with the controls. Resveratrol-treated rats showed reduced hydrogen peroxide (H2O2) content and increased superoxide dismutase activity, thus reducing their oxidative stress. Moreover, the rats displayed the normalization of endothelium-dependent vasorelaxation [34]. Resveratrol may also prevent hypertension-induced cardiac dysfunction. In one experiment, a ten-week treatment with resveratrol significantly reduced concentric hypertrophy and systolic dysfunction in SHR rats. The cardioprotective effects of resveratrol are probably mediated by a lowering of oxidative stress levels in the cardiac muscle tissue [35]. Resveratrol may also play a role in electrophysiological alternations via its influence on chromaffin cells and Ca2+ signaling, exerting antihypertensive effects through these mechanisms. Systolic blood pressure decreased in a group of SHR rats exposed to trans-resveratrol treatment in drinking water (50 mg/L/v.o.) for 28 days. However, no reversal of cardiac hypertrophy was observed. The study exhibited an increase in outward voltage-dependent potassium currents (IK), a reduction in inward voltage-dependent sodium (INa), calcium (ICa), and nicotinic (IAch) currents, and an attenuation of cytosolic Ca2+ concentration overload in chromaffin cells from SHR rats. Based on these findings, the modulation of the sympathoadrenal axis functionality may be a new target that could account for resveratrol’s antihypertensive effect [36].
This entry is adapted from 10.3390/biology11040559

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