MOLECULAR VARIANTS IN THE P450C11AS GENE AS DETERMINANTS OF ALDOSTERONE SYNTHASE ACTIVITY IN THE DAHL RAT MODEL OF HYPERTENSION

Dahl salt-sensitive (S) and salt-resistant (R) rats are widely used to study genetic determinants of salt sensitive hypertension. Difference s in blood pressure under a high sodium diet in these two strains may be due to differences in the synthesis of 18-OH-11-deoxycorticosterone (18-OH DOC). This difference in 18-OH-DOC synthesis is due to mutatio ns in the Dahl R rat's gene for P450c11 beta (11 beta-hydroxylase), an adrenal enzyme involved in the synthesis of both corticosterone and 1 8-OH DOC from 11-deoxycorticosterone. Aldosterone/renin ratios in plas ma and in the adrenals are greater in Dahl S than R rats, suggesting a n altered physiologic relationship between the renin-angiotensin and a ldosterone systems between these strains. We demonstrate that the mRNA for P450c11AS, (aldosterone synthase), an enzyme required for aldoste rone synthesis, is identical in the Dahl S rat and in normotensive Spr ague-Dawley rats, but that P450c11AS mRNA from the Dahl R rat contains 7 mutations that result in two amino acid substitutions, These two ch anges result in a form of P450c11AS that has a greater apparent V-max and lower apparent K-m, resulting in an enzyme that catalyzes the conv ersion of 11-deoxycorticosterone to aldosterone at a greater rate in D ahl R rats than the P450c11AS in Dahl S rats or Sprague Dawley rats, A lthough plasma and adrenal renin are lower in Dahl S versus R rats, th e regulation of P450c11AS mRNA expression in rats fed a low and high s alt diet are identical in these strains, The current findings may expl ain both the reduced aldosterone concentrations and increased aldoster one/renin ratios previously reported in the Dahl S versus Dahl R rat.