Vagal involvement in non-dipping phenotype of Hsd11b2 knockout rats

The Syndrome of Apparent Mineralocorticoid Excess (SAME) is a hypertensive disorder caused by deficiency of 11b-hydroxysteroid dehydrogenase type 2. Blood pressure is directly influenced by dietary salt intake, but the causes of salt-sensitivity are not fully resolved. We modelled SAME in Fischer 344 rats, using zinc finger nuclease targeting of the Hsd11b2 gene. The F344 genetic background showed modest salt sensitivity: blood pressure increased by [~]6mmHg when diet was switched from control (0.3% Na) to high salt (3% Na) diet. Homozygous knockout (Hsd2-/-) rats exhibited severe hypertension on control diet (mean arterial blood pressure of [~]180 mmHg compared to [~]115 mmHg in wild-types) and displayed no dipping in blood pressure in the inactive/sleep phase. They also displayed reduced heart rate (339 bpm versus 384 bpm in F344 controls). Low salt diet (0.03% Na) caused a dramatic fall in Hsd2-/- blood pressure (to [~]141mmHg), restoration of robust circadian variation in blood pressure, and an increase in heart rate (to 364bpm). This was mirrored by a restoration of circadian variation in the Poincare plot descriptor, SD1, suggesting involvement of parasympathetic dysfunction in the non-dipping phenotype. Alpha adrenoceptor blockade with prazosin treatment resulted in a further decrease in blood pressure (to [~]124mmHg), which blunted circadian rhythm, together with an increase in heart rate (to [~]394bpm). This rat model of human hypertension reveals clear links between dietary salt, autonomic nervous system dysfunction, and the non-dipping blood pressure phenotype.