Maternal Protein Restriction Increases Respiratory and Sympathetic Activities and Sensitizes Peripheral Chemoreflex in Male Rat Offspring

Background: Maternal protein restriction in rats increases the risk of adult offspring arterial hypertension through unknown mechanisms. Objectives: The aims of the study were to evaluate the effects of a low-protein (LP) diet during pregnancy and lactation on baseline sympathetic and respiratory activities and peripheral chemoreflex sensitivity in the rat offspring. Methods: Wistar rat dams were fed a control [normal-protein (NP); 17% protein] or an LP (8% protein) diet during pregnancy and lactation, and their male offspring were studied at 30 d of age. Direct measurements of baseline arterial blood pressure (ABP), heart rate (HR), and respiratory frequency (Rf) as well as peripheral chemoreflex activation (potassium cyanide: 0.04%) were recorded in pups while they were awake. In addition, recordings of the phrenic nerve (PN) and thoracic sympathetic nerve (tSN) activities were obtained from the in situ preparations. Hypoxia-inducible factor l alpha (HIF-1 alpha) expression was also evaluated in carotid bifurcation through a Western blotting assay. Results: At 30 d of age, unanesthetized LP rats exhibited enhanced resting Rf (P = 0.001) and similar ABP and HR compared with the NP rats. Despite their similar baseline ABP values, LP rats exhibited augmented low-frequency variability (similar to 91%; P = 0.01). In addition, the unanesthetized LP rats showed enhanced pressor (P = 0.01) and tachypnoeic (P = 0.03) responses to peripheral chemoreflex activation. The LP rats displayed elevated baseline tSN activity (similar to 86%; P= 0.02) and PN burst frequency (45%; P= 0.01) and amplitude (53%; P= 0.001) as well as augmented sympathetic (P= 0.01) and phrenic (P= 0.04) excitatory responses to peripheral chemoreflex activation compared with the NP group. Furthermore, LP rats showed an increase of similar to 100% in HIF-1 alpha protein density in carotid bifurcation compared with NP rats. Conclusion: Sympathetic-respiratory overactivity and amplified peripheral chemoreceptor responses, potentially through HIF-1a dependent mechanisms, precede the onset of hypertension in juvenile rats exposed to protein undernutrition during gestation and lactation.