GLUCOCORTICOID RECEPTOR POLYMORPHISM IN GENETIC-HYPERTENSION

The Milan hypertensive strain of rat (MHS) displays abnormalities in b oth renal function and adrenocortical activity. While the presser role of the former has been studied in detail, the role of the latter has not yet been clearly evaluated. In the present study, glucocorticoid r eceptor (GR) binding characteristics in liver cytosol from adult MHS a nd Milan normotensive controls (MNS) have been investigated. Dexametha sone, aldosterone and corticosterone were bound with lower affinity to cytosol of MHS rats compared with that of MNS rats. This pattern of b inding could explain the raised plasma corticosterone concentrations a nd adrenocortical hypertrophy previously noted in MHS. The coding sequ ence of MHS and MNS GR genes have been determined. The MHS gene differ ed in four respects from that of MNS: three silent point mutations and a polymorphic microsatellite region in exon 2. The latter polymorphis m has been used in cosegregation studies of F-2 hybrids of MHS x MNS. The MHS GR genotype was associated with hypercalciuria and lower blood pressure in female rats and lower body Tl;eight in male rats. Althoug h the effect on blood pressure is small, it is consistent with the aff inity data. MHS GR genotype cosegregated with lower blood pressure in F-2 rats and displayed a lower affinity in binding studies. In conclus ion, GR polymorphism may be responsible for differences of adrenocorti cal function between MHS and MNS. This may lead to a reduction in the blood pressure difference between the two strains.