Transient Exposure of Enalapril Normalizes Prenatal Programming of Hypertension and Urinary Angiotensinogen Excretion

Abstract

Maternal low protein diet programs offspring to develop hypertension as adults. Transient exposure to angiotensin converting enzyme inhibitors or angiotensin II receptor blockers can result in improvement in hypertension. Male rats whose mothers received a low protein diet during the last half of pregnancy were given either vehicle, continuous enalapril (CE) in their drinking water or were given transient enalapril exposure (TE) after weaning at 21 days of age. The TE group had enalapril in their drinking water for 21 days starting from day 21 of life. All rats were studied at 6 months of age. Vehicle treated rats whose mothers were fed a low protein diet were hypertensive, had albuminuria, and demonstrated upregulation of the intrarenal renin-angiotensin system as evidenced by higher urinary angiotensinogen and urinary angiotensin II levels. In low protein rats both continuous and transient exposure to enalapril normalized blood pressure, urinary angiotensinogen and urinary angiotensin II levels at 6 months of age, but only continuous administration of enalapril decreased urinary albumin excretion. These data support the importance of the intrarenal renin-angiotensin system in mediating hypertension in programmed rats and transient exposure to enalapril can reprogram the hypertension and dysregulation of the intrarenal renin-angiotensin system.

Maternal Gestational Hypertension-Induced Sensitization of Angiotensin II Hypertension Is Reversed by Renal Denervation or Angiotensin-Converting Enzyme Inhibition in Rat Offspring

“…30 Washburn et al found increased plasma aldosterone levels in male adolescents born to mothers with preeclampsia. 8 In animal experiments, the offspring from dams with protein restriction, 11,12 diabetes 19 or inflammation 20 showed significant increases in intrarenal RAAS components such as angiotensinogen and ANG II, renal and arterial proinflammatory cytokines and pulmonary and plasma ACE activity, which were associated with higher BP in these offspring. However, not all studies involving treatments increasing the BP of pregnant dams have reported increased basal BP in the offspring.…”

“…RD or chronic blockade of the RAAS and inflammation has been demonstrated to reduce elevated BP through restoration of renal and arterial function in offspring of dams after different types of insult to the mother during pregnancy. 11,12,14–16,20 Mizuno et al demonstrated that the RAAS plays a significant role not only in the generation of increased basal BP but also in the development of the enhanced renal sympathetic and pressor responses to physical stress in prenatally programmed adult hypertensive rats. 17,18 Based on such observations, we investigated whether disrupting the integrity of the renal nerves or of the RAAS would alter the maintenance of sensitization of ANG II-induced hypertension in offspring of HT dams.…”

“…10 Consistent with the RAAS and SNA playing a role in mediating the fetal programming of hypertension, several studies have demonstrated that both captopril, an angiotensin converting enzyme (ACE1) inhibitor, and losartan, an angiotensin (ANG) II receptor blocker, administered in the drinking water reduced increased BP in the offspring of dams fed low protein diet, 11,12 and of spontaneously hypertensive rats, 13 while renal denervation (RD) abolished hypertension in the offspring from diabetic rats 14 or from pregnant rats with reduced uterine perfusion. 15,16 Moreover, Mizuno and colleagues demonstrated that the RAAS contributes to the enhancement of the renal sympathetic and pressor responses to physical stress in male offspring exposed to maternal protein restriction.…”

Effect of sex on glomerular filtration rate in programmed rats by prenatal dexamethasone

“…Rats were trained for four consecutive days by placing them in a large Lucite container and inflating a cuff around its tail several times (Mansuri et al. ; Mizuno et al. , ).…”

“…The investigator measuring the blood pressure (J.J.) was blinded as to whether the rat was from the vehicle or the dexamethasone group. Rats were trained for four consecutive days by placing them in a large Lucite container and inflating a cuff around its tail several times (Mansuri et al 2015;Mizuno et al 2014Mizuno et al , 2013. We then measured the blood pressure on the fifth day using a CODA Blood Pressure Non-Invasive Pressure Analyzer (Kent Scientific Corporation, Torrington, CT).…”