Genetically Hypertensive Brown Norway Congenic Rat Strains Suggest Intermediate Traits Underlying Genetic Hypertension

摘要

Aim To determine the independent and combined effects of threequantitative trait loci (QTL) for blood pressure in the GeneticallyHypertensive (GH/Omr) rat by generating and characterizing singleand combined congenic strains that have QTL on rat chromosomes(RNO) 2, 6, and 18 from the GH rat introduced into a hypertensionresistant Brown Norway (BN) background.Methods Linkage analysis and QTL identification (genome wideQTL scan) were performed with MapMaker/EXP to build the geneticmaps and MapMaker/QTL for linking the phenotypes to the geneticmap. The congenic strains were derived using marker-assisted selectionstrategy from a single male F1 offspring of an intercross betweenthe male GH/Omr and female BN/Elh, followed by 10 generations ofselective backcrossing to the female BN progenitor strain. Single congenicstrains generated were BN.GH-(D2Rat22-D2Mgh11)/Mcwi(BN.GH2); BN.GH-(D6Mit12-D6Rat15)/Mcwi (BN.GH6); andBN.GH-(D18Rat41-D18Mgh4)/Mcwi (BN.GH18). Blood pressuremeasurements were obtained either via a catheter placed in the femoralartery or by radiotelemetry in the single and combined congenics. Responsesto angiotensin II (ANGII), norepinephrine (NE), and baroreceptorsensitivity were measured in the single congenics.Results Transferring one or more QTL from the hypertensive GH intonormotensive BN strain was not sufficient to cause hypertension in anyof the developed congenic strains. There were no differences betweenthe 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 fromthose observed in the BN (β = 0.88 ± 0.08).Conclusion The failure to alter blood pressure levels by introducingthe hypertensive QTL from the GH into the hypertension resistantBN background suggests that the QTL effects are genome backgrounddependentin the GH rat. BN.GH2 and BN.GH18 rats reveal significantdifferences in response to ANGII and impaired baroreflex sensitivity,suggesting that we may have captured a locus responsible for thegenetic control of baroreceptor sensitivity, which would be consideredan intermediate phenotype of blood pressure.