The significant findings of the current investigation were that i) PPH did not exhibit alterations in baseline RSNA (contrary to our original hypothesis) and ii) PPH did display markedly exaggerated increases in RSNA, ABP and HR in response to physical stress (in concurrence with our original hypothesis). The latter finding supports a role for the sympathetic nervous system in the development of hypertension with prenatal programming and is in agreement with a growing body of evidence, albeit predominately indirect, that there is an alteration in sympathetic nerve activity in human adults born small for gestational age. For example, while an imperfect assessment of sympathetic tone, resting HR is higher in adults that were of low birth weight compared to controls 30
. Furthermore, the increases in blood pressure in response to psychological stresses such as public speaking were greater in offspring of mothers exposed to the Dutch famine during their first trimester of pregnancy than unexposed control subjects 31
. Direct measurement of sympathetic activity has been reported in adults who were small for gestational age and compared to those who were of normal weight at birth. While one study showed an increase in resting sympathetic nerve activity in adults who were small for gestational age 32
another did not 33
. However, the latter study found a significant increase over basal sympathetic nerve activity in response to the stress of breath holding in those who were born of low birth weight compared to controls 33
. These latter findings are comparable to our study where we demonstrated similar sympathetic nerve activity at baseline but an augmented RSNA response to physical stress.
The current study demonstrating that there is an enhanced RSNA response to physical stress in rats which were the offspring of mothers fed a low protein diet is consistent with previous studies examining the effect of renal denervation on blood pressure in this animal model 21, 24, 25
. In the previous studies, blood pressure was elevated in adult rats exposed to uteroplacental insufficiency 24, 25
or prenatal exposure of glucocorticoids 21
. The offspring of mothers exposed to uteroplacental insufficiency had greater renal norepinephrine content than controls at 6 weeks of age 25
. Renal norepinephrine content was also greater in offspring whose mothers were administered prenatal dexamethasone than control when studied at 3 weeks of age but not at 8 weeks of age 21
. While denervation did not affect blood pressure of control rats, blood pressure normalized to control levels in offspring of mothers that had a prenatal insult 21, 24, 25
. However, there are still some inconsistencies between these studies and our investigation that need to be resolved. In the current study, baseline RSNA was comparable in both groups of animals under anesthesia as well as after decerebration. An augmented increase in sympathetic activity in PPH was only noted in response to activation of the EPR, mechanoreflex and metaboreflex. It remains unknown if the conscious PPH rat would exhibit enhanced basal sympathetic activity and/or an exaggerated increase in RSNA in response to physical stress. In addition, baseline blood pressures significantly declined as compared to the conscious state in both control and PPH when the animals were placed on isoflurane anesthesia and/or decerebrated. One possibility for these reductions in pressure was the performance of the extensive surgery requisite for EPR testing. Another was the use of the pre-collicular decerebrate technique. For example, it has been suggested that portions of the hypothalamus (e.g. paraventricular nucleus) contribute to generating the elevated baseline SNA characteristic of hypertension34, 35
. Removal of such areas within the hypothalamus by pre-collicular decerebration may have abrogated baseline elevations in RSNA in PPH animals and/or produced the reductions in baseline ABP as compared to the conscious state. It has been proposed that utilizing a mid-collicular decerebrate procedure may be preferable when investigating EPR function 36, 37
although use of this technique would likewise remove the hypothalamus. These technical limitations must be taken into account when interpreting the results of the current study. Resolving these inconsistencies will only be answered by directly measuring blood pressure and sympathetic nerve activity in conscious unanesthetized rats, the latter of which is currently a technically difficult experimental endeavor.
It has been well documented that, in hypertension, the cardiovascular response to exercise is abnormally heightened and characterized by exaggerated increases in ABP, HR and vascular resistance 38–42
. To this end, our laboratory has previously demonstrated that selective activation of the EPR elicits greater increases in MAP, HR and RSNA in spontaneously hypertensive rats, a model of essential hypertension, compared to normotensive rats 43–45
. These findings provide evidence that the exaggerated cardiovascular response to exercise in hypertension is mediated, in part, by a dysfunctional EPR. There are differences between our findings in the spontaneously hypertensive rat and PPH rats compared to their respective controls. While the blood pressure was not different under anesthesia in the PPH compared to the control group, it was over 50 mm Hg higher in the SHR compared to their respective controls. In addition, the normalized heart weight was not different between PPH and control groups unlike previous studies in spontaneously hypertensive rats which exhibit significant cardiac hypertrophy 43–45
. Despite the possibility of PPH being a milder form of hypertension than that in the SHR model, the magnitude of the EPR overactivity was comparable 43–45
. Collectively, these studies suggest the EPR contributes significantly to the abnormally exaggerated sympathetically-mediated cardiovascular response to exercise in multiple forms of hypertension. Given that the accentuated cardiovascular response to physical activity is associated with elevated risks for myocardial ischemia, myocardial infarction, cardiac arrest and/or stroke during or immediately after a bout of exercise 46–48
it is clinically important to determine the mechanisms underlying EPR dysfunction in each etiology of the disease.
There are several viable possibilities for the enhanced cardiovascular and sympathetic responses demonstrated during activation of the EPR in this study. Since prenatal programming by maternal dietary protein deprivation results in a reduction in nephron number 13
it is possible that renal dysfunction or injury contributes to EPR overactivity in PPH. Renal sympathetic afferents can be activated by minor injury resulting in an increase in central sympathetic nerve activity and hypertension, which is prevented by renal denervation 49
. In patients with chronic kidney disease, there is an increase in muscle sympathetic nerve activity 50, 51
, which normalizes after bilateral nephrectomy 51
. Thus it is possible that the sympathetic overactivity may be initiated by renal afferents. However, prenatal programming can also have a primary effect on the brain 52, 53
, which may result in increased sympathetic nerve activity when animals are put under stress. The relative roles of the kidney and central nervous system in mediating EPR overactivity with prenatal programming will have to be resolved in future studies.