Genetic Models of Hypertension in Experimental Animals

Abstract

Genetic animal models are central to ongoing efforts to elucidate the pathophysiology and genetic basis of hypertension. The rat is the leading species in experimental hypertension. Several rat models of hypertension are available for research, including inbred strains, congenic lines, transgenic animals and recombinant inbred strains. Each of these models has been designed to express different phenotypes, including spontaneous hypertension, salt sensitivity, stress sensitivity and susceptibility to end-organ damage. All these models have been extremely useful in the search for the physiological mechanisms that underlie hypertension, but some of them have been specifically designed for detecting the hypertension genes. This latter task is extremely complex in spontaneous hypertension, but genetic animal models may simplify the task by enabling to focus on specific phenotypes. Despite intensive efforts over nearly 3 decades, the genetic basis of hypertension has not been unveiled so far in the rat or in other species. Recent dense mapping of the rat genome, the development of new strategies and technologies in molecular genetics including differential gene expression, expressed sequence tags and DNA biochips render hope that the formidable task of identification of new candidate genes in hypertension will move another major step forward. Once these genes are identified, their function and role in hypertension will have to be determined, utilizing functional genomic strategies and bioinformatics. Finally, the findings in genetic animal models of hypertension will have to be extrapolated to humans by homology and syntenic mapping strategies.

Animal models for the study of primary and secondary hypertension in humans

“…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.…”

“…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.…”

Nitric oxide and coronary vascular endothelium adaptations in hypertension

“…The spontaneously hypertensive rat (SHR) model has been particularly useful since several defining characteristics of the SHR are similar to those observed in human essential hypertension including hemodynamic abnormalities, humoral and sympathetic nervous system involvement, renal abnormalities and vascular cellular adaptations. [23][24][25][26][27][28] For example, even though SHR can have similar coronary blood flow compared to their normotensive counterpart Wistar-Kyoto rats (WKY) on a ventricular mass-corrected basis, 13 SHRs have higher coronary vascular resistance (CVR) over a wide pressure range, 14,19 and higher minimal CVR (lower maximal conductance) during maximal coronary vasodilation. 13,16 Changes in coronary hemodynamics accompanying hypertension occur as a result of both structural and functional adaptations in the coronary vasculature.…”

20 Years of Hypertension Research using Genetically Modified Animals: No Clinically Promising Approaches in Sight

“…However, these experiments were not designed carefully enough and are thus without further meaning for future gene therapy (see below). With regard to hywell-known blood pressure regulating systems; however, the meaning of these animal models for the development of a therapy against the human disease was only speculative in terms like "might be a promising model for the future" or "requires further research" or similar phrases (Audoloy et al, 2000;Bader et al, 2000;lake-Bruse and Sigmund, 2000;Fukamizu, 2000;Cvetkovic and Sigmund, 2000;Yagil and Yagil, 2001;Sugiyama et al, 2001;lavoie et al, 2004;Barbosa et al, 2005;lerman et al, 2005;McBride et al, 2006). the remaining 8 reviews (42%) were more critical and emphasised the limitations of the animal models when used to try to understand and treat human hypertension (Kurihara, 2001;Mullins and Mullins, 2003;takahashi and Smithies, 2004;Herrera and Ruiz-Opazo, 2005;Smithies, 2005;Bernstein et al, 2005;.…”