Catecholamine synthesising enzymes in the programming of hypertension by mild protein restriction during gestation

Abstract

The expression of TH and PNMT mRNA was analysed by Northern-blotting in the adrenal of female offspring born to dams fed either a diet mildly restricted in protein content (9% casein), but otherwise isocaloric, or fed a control diet (18% casein) throughout gestation. The blood pressure effects (measured by tail-cuff plethysmography) of twice daily, for a 7-day period, intraperitoneal administration of a PNMT inhibitor, versus vehicle, were analysed in low-protein and control male and female offspring. As previously described, offspring from dams fed the low-protein diet had significantly elevated blood pressure in postnatal life compared with the control of offspring. Levels of TH and PNMT mRNA expression in the adrenal of the low-protein offspring were not significantly different from those of the control offspring at either 2, 4, 8 or 12 weeks of age. At 16 weeks of age, low-protein offspring displayed a significantly greater adrenal TH mRNA expression than the controls. Blockade of central and peripheral adrenaline synthesis at 8 weeks of age with the PNMT inhibitor markedly reduced heart rate and tended to lower blood pressure in all offspring after 7 days compared with vehicle-treated offspring. Importantly, the PNMT inhibitor tended to exert a prolonged blood pressure reduction specifically in the low-protein female offspring, up to 3 weeks following withdrawal of the treatment. Adrenal PNMT activity was not different between low-protein and control offspring at 8 weeks of age. Therefore, the greater long-term blood pressure reduction in the low-protein female offspring following PNMT inhibition may be centrally mediated. The data suggest that the mechanisms by which hypertension is initiated may not depend on an increased synthesis of catecholamines from the adrenal. However, increased levels of adrenaline synthesis by PNMT in central adrenergic neurones may play a contributory role. Increased adrenal catecholamine synthesis may, once hypertension is established, participate in its maintenance.

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