Dissociation of genetic hyperactivity and hypertension in SHR.

Abstract

The Wistar Kyoto strain of spontaneously hypertensive rat (SHR) has been characterized as behaviorally hyperactive as well as hypertensive. The relationship between these two inbred traits remains uncertain, and their coexistence in the SHR has complicated studies of central nervous system mechanisms underlying the hypertensive process. A breeding program was initiated to examine the possible genetic linkage of these two traits which, if separable, would allow us to develop substrains of SHR that are hypertensive without being hyperactive, or hyperactive without being hypertensive. We crossed SHR males with Wistar Kyoto, normotensive (WKY) female rats and produced F1 hybrids which were then randomly inbred to produce an F2 population. When tested at 12 weeks of age, F2 rats exhibited the expected wide range of mean systolic blood pressures (BP), from 111 to 174 mm Hg, as determined using indirect tail plethysmography. The BP in the parental rats at the time of breeding (16 weeks) was 187 +/- 4.5 mm Hg (SHR males, n = 7) and 111 +/- 2.4 (WKY females, n = 7). Locomotor activity was determined in an automated activity cage in F1 and F2 rats at 12 weeks of age. These strains exhibited a wide range of phenotypic distribution of locomotor activity scores, and the mean scores were intermediary between those of SHR rats and WKY rats of the same age. Among individual rats of both the F1 and F2 hybrid strains, there was no correlation between the activity score and the level of the BP at 12 weeks of age. These findings indicated that the genes responsible for the hypertensive trait and those responsible for the hyperactivity trait were not tightly linked in the hybrid populations, suggesting that different genetic factors were involved in the transmission of each of these traits. Accordingly, it should be possible to separate the two traits by further selective, recombinant inbreeding procedures.