Hypertension is one of the most important risk factors for the development of cardiovascular disease and is responsible for >50% of the 17 million deaths per year worldwide (1). It is a heterogeneous condition with a number of etiologies and multiple, interacting genetic and environmental factors (2). Its incidence varies with age, plasma renin activity and sodium sensitivity (3). The use of pre-clinical animal models has significantly increased our understanding of disease processes, as these permit the control of the different contributing factors. However, no single system is ideal, as there are species differences and other limitations of these model systems (4,5). Species, including mice, have been popular for the study of cardiometabolic disorders due to their amenability to genetic and pharmacological modification (6–12). It is not the aim of the present review to provide an exhaustive list of the different models, but to discuss historically important model systems whose use has significantly advanced our understanding of hypertension.

Animal models of hypertension can be categorised according to aetiology (13) (Fig. 1). Renal diseases, including renal arterial stenosis (RAS), are major causes of secondary hypertension. RAS has been modelled by the 2 kidneys-1 clip hypertension model (2K-1C), 1 kidney-1 clip hypertension model (1K-1C) and 2 kidney-2 clip hypertension model (2K-2C). Other systems have been devised to examine the pathophysiology of renal parenchymal hypertension, renal ischemia and perinephric fibrosis. A deoxycorticosterone acetate (DOCA)-induced model imitates the effects of mineralocorticoid- and glucocorticoid-induced hypertension. Pharmacological approaches using a nitric oxide synthase (NOS) inhibitor or by activating the renin-angiotensin-aldosterone-system (RAAS), or introduction of environmental stresses, including stress, cold temperature and diet, have also been performed to induce hypertension. Essential hypertension has been investigated using spontaneously hypertensive rats (SHRs), Dahl salt-sensitive and other rat strains (14). Other molecular models, transgenic strains, consomic and congenic strains, combined with gene knockout techniques have been used to examine the mechanistic basis of essential hypertension.

Initial experiments for the investigation of hypertension were performed in dogs. Such experiments included the renovascular models developed by Goldblatt et al (15) in 1934. Subsequent models using rats, rabbits, sheep and cats were developed (16). Pigs have also been used, in particular, the Yucatan model for the study of DOCA-induced hypertension (17).

Of the different species, rat has been a popular model as a result of the availability of different inbred strains and characteristics, including the SHR, Dahl salt-sensitive rats, New Zealand and Milan strains (18). Numerous justifications for using rats to model hypertension exist. Firstly, its genome has been completely mapped, with a 99% sequence homology to humans (19). Secondly, the pathogenesis of hypertension in rats and humans are largely similar in terms of arterial pressure development from childbirth, response to environmental stressors, haemodynamic factors (including vascular resistance), mechanisms regulating arteriolar and venous constriction, neural modulation (including sympathetic nerve activity) and renal vascular dynamics (including perfusion parameters), as well as humoral influences by RAAS and NOS (20). The advantages are that they are low cost, with wide availability and easy to handle, maintain and breed. However, these models also have their limitations. Firstly, the identical genotype may not induce the same phenotype in all animals (21) due to contributions from numerous genes and the additional environmental influences (22,23). Secondly, the same gene mutations and deletion observed in rats may not induce to the identical phenotypic effects in humans (24).

Larger animals have closer anatomical, physiological and haemodynamic properties to humans when compared with small animals, including rats and mice, making them particularly suitable for the study of flow characteristics (25,26). However, the major disadvantage is the high costs required for their maintenance. Additionally, the domestication of dogs has led to their decreasing use for research (27).

Mineralocorticoids or their synthetic derivatives, including DOCA, are used with sodium chloride in unilateral nephrectomised rats to induce hypertension (41,42). Renin is suppressed and fluid reabsorption is increased, thereby producing a low renin-volume overload model of hypertension (43). Using this model, key sodium-independent mechanisms for mediating hypertension, including upregulation of Ang-II receptors in the central nervous system (44), elevated vasopressin (45), increased oxidative stress (46) and endothelin (47), have been identified. Aside from elucidating the molecular mechanisms underlying renal hypertension, it provides a useful platform for investigating the natural history of disease, including any complications, such as glomerulosclerosis, proteinuria, impaired endothelium-dependent relaxation of the vasculature and cardiac hypertrophy can be investigated (42). In the DOCA-hypertensive Yucatan miniature swine model, excess dietary salt is not required for sustaining hypertension due to enhanced SNS activity at baseline, as evidenced by the increased plasma norepinephrine level (48). Glucocorticoids can also be used to induce hypertension (49). Although hypertension is produced via RAAS activation, this approach is less effective than the DOCA-salt method. An alternative is chronic infusion of RAAS components, including Ang-II (50).

Nitric oxide (NO), a potent vasodilator derived from the intact endothelium, is produced by NOS. This production is triggered by vasoactive messengers, including acetylcholine (51). A NO-deficient model was produced by chronic infusion of N-nitro-L-arginine methyl ester (L-NAME), a NOS inhibitor (52). A low dose produced a volume-dependent increase in blood pressure predominantly due to renal vasoconstriction and decreased glomerular filtration (53). A high dose led to both salt- and volume-independent hypertension since the mechanism is renal and systemic vasoconstriction (54).

Environmental stress, including separate or simultaneous introduction of flashing lights, loud noises and oscillating cages (55–57), or long-term exposure to high salt, fat or sugar in the diet, can be used to induce hypertension (58). Extremes of temperature, particularly coldness, also induces a hypertensive phenotype, as observed in rats exposed to 5°C for 3 weeks (59). In these animals, increases in plasma and urine catecholamines were observed (60). These findings are consistent with findings in humans, where those who work chronically in cold areas develop hypertension (61) and higher values of blood pressure recorded in winter compared with in the summer (62). Increased activity of the sympathetic nervous system and RAAS activation appear to be the common physiological mechanisms responsible for hypertension in the models described above (60,63,64).

Genetic factors are estimated to influence up to 50% of blood pressure variability in essential hypertension (65). The millennium genome project for hypertension was initiated in 2000 to identify genetic variants that predispose individuals to hypertension. This has involved a combination of techniques, including a gene linkage approach using single nucleotide polymorphisms, microsatellite markers and systematic candidate gene analysis (66). In parallel with this has been the development of genetic models using different animal species, which have provided insights into the physiological mechanisms of hypertension. These can be categorised into inbreeding, consomic, congenic and subcongenic strains (18), which will be considered in turn.

The inbreeding method involves sibling mating of hypertensive rats over several generations to produce strains with genetic homogeneity when compared with the reference control group.

Different pharmacological, environmental and genetic models using different animal species have provided useful and valuable information on the aetiology, pathophysiology and complications of human cardiovascular and metabolic disorders, and a platform to examine the efficacy of pharmacotherapy (105–118). However, a major limitation of these experimental models is the anatomical differences between these animal species and humans (119). Although the common mechanism is RAAS activation across different species, species differences must be carefully taken into consideration to ensure the safety of newly developed pharmacological agents.