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Am J Physiol Renal Physiol (November 16, 2004). doi:10.1152/ajprenal.00314.2004
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Submitted on August 19, 2004
Accepted on November 15, 2004

Programming blood pressure in SHR by shifting the perinatal balance of NO and reactive oxygen species towards NO: the inverted Barker phenomenon

Simona Racasan1, Branko Braam2, Hein A. Koomans2, and Jaap A. Joles2*

1 Department of Nephrology and Hypertension, University of Medical Center Utrecht, Utrecht, The Netherlands; Deparment of Nephrology, University of Hospital, Cluj, Romania
2 Department of Nephrology and Hypertension, University of Medical Center Utrecht, Utrecht, The Netherlands

* To whom correspondence should be addressed. E-mail: j.a.joles{at}med.uu.nl.

The "programming hypothesis" proposes that adverse perinatal milieu leads to adaptation that translates into cardiovascular disease in adulthood. The nitric oxide/reactive oxygen species (NO/ROS) balance is disturbed in cardiovascular diseases including hypertension. Conceivably this balance is also disturbed in pregnancy, altering fetal environment; however, effects of perinatal manipulation of NO and ROS on adult blood pressure (BP) are unknown. In spontaneously hypertensive rats (SHR) NO availability is decreased and ROS increased as compared to normotensive WKY rats, and, despite the genetic predisposition, perinatal environment can modulate adult BP. Our hypothesis is that disturbed NO/ROS balance in the SHR dam persistently affects BP in her offspring. Dietary supplements, which support NO formation and scavenge ROS, administered during pregnancy and lactation resulted in persistently lower BP for up to 48 wk in SHR offspring. The NO donor molsidomine, and the superoxide dismutase mimic Tempol, induced comparable effects. Specific inhibition of inducible NOS reduces BP in adult SHR suggesting that inducible NOS is predominantly a source of ROS in SHR. Indeed inducible NOS inhibition in SHR dams persistently reduced BP in adult offspring. Persistent reductions in BP were accompanied by prevention of proteinuria in aged SHR. We propose that in SHR the known increase in AT1 receptor density during development leads to superoxide production, which enhances inducible NOS activity. Relative shortage of substrate and cofactors leads to uncoupling of inducible NOS, resulting in superoxide production activating transcription factors that subsequently again increase inducible NOS expression. This vicious circle probably perpetuates into adult life.




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