Abstract-The complex nature of hypertension makes identifying the pathophysiology and its genetic contributions a challenging task. One powerful approach for the genetic dissection of blood pressure regulation is studying inbred rat models of hypertension, as they provide natural allele variants but reduced heterogeneity (both genetic and etiologic). Furthermore, the detailed physiologic studies to which the rat is amenable allow for the determination of intermediate phenotypes.We have performed a total genome scan in offspring of an F 2 intercross between the Lyon hypertensive (LH) and Lyon normotensive rat strains to identify linkage of anthropometric, blood pressure, renal, metabolic, and endocrine phenotypes. Quantitative trait locus (QTL) regions involved in blood pressure regulation, end-stage organ damage, body and organ weight, and lipid metabolism in the LH rat were identified on chromosomes 1, 2, 3, 5, 7, 10, 13, and 17, with 2 phenotypes associated with the metabolic syndrome identified on chromosomes 1 and 17. Regions on chromosomes 2, 13, and 17 were revealed to be important for blood pressure regulation. Regions on chromosome 17 were found to significantly contribute to both metabolic homeostasis and blood pressure regulation; 2 aggregates of a total of 23 QTLs were identified, including several "intermediate phenotypes." These intermediate phenotypes may be used as closer surrogates to the mechanisms leading to hypertension and metabolic dysfunction in the LH rat. Key Words: genetics Ⅲ linkage analysis Ⅲ metabolism Ⅲ hypertension, genetic Ⅲ rats, inbred strains Ⅲ cardiovascular diseases H uman essential hypertension and associated cardiovascular diseases are multifactorial disorders with a complex etiology, resulting from the interaction between multiple genes and environmental factors. Despite development of new genetic and genomic technologies, the genetic determinants of multifactorial disorders remain unclear. The study of animal models in discovering pathophysologic and genetic determinants of polygenetic disorders such as hypertension provides a platform of reduced heterogeneity. Currently, there exist several different genetically hypertensive rat and mouse selection models. 1 Numerous linkage studies in rats have shown that each rat chromosome contains at least 1 blood pressure (BP) quantitative trait locus (QTL; http://rgd.mcw.edu/qtls).The Lyon hypertensive (LH) rat has many features common to the human metabolic syndrome, a group of metabolic risk factors including central obesity, atherogenic dyslipidemia, elevated BP, insulin resistance or glucose intolerance, and prothrombotic and proinflamatory states. 2 Interestingly, a control strain, the Lyon normotensive (LN) rat, has been simultaneously derived from a common ancestor of the LH; the LN is genetically quite similar to the LH (85% identical based on characterization of 4328 microsatellite markers; data not shown) but phenotypically very distinct. Compared with the LN, LH rats have mild salt-sensitive hypertension and reduced life ...

Aim To determine the independent and combined effects of three quantitative trait loci (QTL) for blood pressure in the Genetically Hypertensive (GH/Omr) rat by generating and characterizing single and combined congenic strains that have QTL on rat chromosomes (RNO) 2, 6, and 18 from the GH rat introduced into a hypertension resistant Brown Norway (BN) background.Methods Linkage analysis and QTL identification (genome wide QTL scan) were performed with MapMaker/EXP to build the genetic maps and MapMaker/QTL for linking the phenotypes to the genetic map. The congenic strains were derived using marker-assisted selection strategy from a single male F1 offspring of an intercross between the male GH/Omr and female BN/Elh, followed by 10 generations of selective backcrossing to the female BN progenitor strain. Single congenic strains generated were BN.GH-(D2Rat22-D2Mgh11)/Mcwi (BN.GH2); BN.GH-(D6Mit12-D6Rat15)/Mcwi (BN.GH6); and BN.GH-(D18Rat41-D18Mgh4)/Mcwi (BN.GH18). Blood pressure measurements were obtained either via a catheter placed in the femoral artery or by radiotelemetry in the single and combined congenics. Responses to angiotensin II (ANGII), norepinephrine (NE), and baroreceptor sensitivity were measured in the single congenics.Results Transferring one or more QTL from the hypertensive GH into normotensive BN strain was not sufficient to cause hypertension in any of the developed congenic strains. There were no differences between the parental and congenic strains in their response to NE. However, BN.GH18 rats revealed significantly lower baroreceptor sensitivity (β = -1.25 ± 0.17), whereas BN.GH2 (β = 0.66 ± 0.09) and BN.GH18 (β = 0.71 ± 0.07) had significantly decreased responses to ANGII from those observed in the BN (β = 0.88 ± 0.08). ConclusionThe failure to alter blood pressure levels by introducing the hypertensive QTL from the GH into the hypertension resistant BN background suggests that the QTL effects are genome backgrounddependent in the GH rat. BN.GH2 and BN.GH18 rats reveal significant differences in response to ANGII and impaired baroreflex sensitivity, suggesting that we may have captured a locus responsible for the genetic control of baroreceptor sensitivity, which would be considered an intermediate phenotype of blood pressure.

The aim of the present study was to identify the region within Chr 18 involved in the development of salt‐induced hypertension in the Dahl salt‐sensitive (SS) rat. Previous linkage and chromosomal substitution studies suggest the presence of a locus for salt‐sensitive hypertension in chr 18. Consomic SS‐18BN rats were backcrossed to the SS rat, and the offspring intercrossed to generate eight overlapping congenic strains covering the entire length of chr 18. Blood pressure and protein excretion were measured by telemetry in male rats during low salt and three weeks of high salt diet (8% NaCl) in parental (SS and SS‐18BN) and congenic strains. Mean arterial pressure (MAP) did not differ significantly between any of the strains studied during low salt diet. After three weeks of high salt, SS rats developed hypertension (MAP 1734 mmHg), while in the SS‐18BN consomics the development of hypertension was significantly attenuated (MAP 1485.5 mmHg). Characterization of the overlapping congenic strains suggests that there are at least five regions in chr 18 that are involved in the response of blodd pressure to a high salt diet in the SS rats.

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