Reprogramming development of experimental hereditary hypertension

Abstract

The aim of the studies described in this thesis was to investigate the development of experimental hereditary hypertension and to persistently ameliorate the development of hypertension due brief interventions during early development (perinatal treatment). We used two different models of experimental hereditary hypertension, namely the spontaneously hypertensive rat (SHR) and the fawn-hooded hypertensive rat (FHH). SHR and FHH dams and their offspring were supplemented with five different treatments during pregnancy and lactation. We found that in both models the perinatal manipulation on the balance between nitric oxide (NO) and reactive oxygen species, with L-arginine and antioxidants, resulted in a persistent decrease in blood pressure and prevented renal injury in the FHH. A similar effect was found after perinatal inhibition of the inflammatory transcription factor NF-kappaB. With micoarray analysis we investigated the transcriptome throughout life in SHR and we developed a new method to measure NO in vivo at a very young age (2-week-old). With the microarray studies we identified two pathways that were potential candidates for perinatal intervention, the citrulline-arginine pathway and the epoxyeicosatrienoic acid (EET) pathway. Therefore we perinatally supplemented SHR with citrulline to correct the decrease arginine synthesis and/or reabsorption or with an inhibitor of soluble epoxide hydrolase, AUDA, to increase EET. Both perinatal treatments resulted in a persistently lower blood pressure and perinatal citrulline increased renal NO. Taken together, it is very promising that brief dietary treatments and even supplementation of a single amino acid (citrulline) during development can cause long-lasting improvement of blood pressure regulation and renal protection in experimental hereditary hypertension. This raises the possibility that simple dietary interventions in the mother, might spare the next generation.