Programmed syndrome of hypernatremic hypertension in ovine twin lambs

An increased risk of adult hypertension, obesity, and coronary heart disease occurs in low birth weight or intrauterine growth-restricted newborn infants as a result of fetal programming. Human twins represent a natural model of low birth weight and intrauterine growth restriction because they are significantly smaller at birth than singleton infants because of both earlier delivery and reduced intrauterine growth. Increased blood pressure has been reported in several epidemiologic studies of human twin offspring, although this has not been confirmed in an animal model. Because the sheep pregnancy consists of singleton and twin litters, we sought to determine the impact of ovine twin gestation and twin nursing on the cardiovascular and renal function of the offspring.

Newborn lambs (n = 12) were studied at 21 +/- 2 day of life. Both singleton (n = 6) and twin lambs (n = 6) were born to ewes provided ad libitum water and food throughout gestation. After the delivery, ewes were provided ad libitum water and food, and newborn lambs were allowed ad libitum nursing with the maternal ewe. At 15 +/- 2 days of age, the lambs were prepared with vascular and renal catheters and studied at 21 +/- 2 days. After a 2-hour basal period, lambs received an intravenous infusion of hypotonic (0.075 mol/L) NaCl (0.15 ml/kg/hr) for an additional 2 hours. Newborn arterial blood pressure, heart rate, and urine flow were monitored continuously, and arterial blood samples were obtained before, during, and after the infusion.

At birth, twin lambs weighed 30% less than singleton lambs (3.5 +/- 0.1 kg vs 5.0 +/- 0.2 kg; P < .05), although 50% less at 21 days (5.2 +/- 0.6 vs 10.8 +/- 1.2 kg). There were marked differences in basal arterial blood values between twin and singleton lambs at 21 days, with twins having significantly increased plasma sodium and systolic, diastolic, and mean arterial pressures and reduced glomerular filtration rates, urine osmolality, osmolar excretion, and osmolar clearance (per kg body weight) compared with singleton lambs. In response to hypotonic saline solution infusion, the plasma composition and blood pressure differences between twin and singleton lambs persisted.

These results indicate that ovine twin gestation and nursing markedly reduced body weight at 21 days of age, with evidence of plasma hypernatremia, hypertension, and reduced glomerular filtration rates, which persisted throughout hypotonic saline solution infusion. Consistent with epidemiologic studies of humans, these results demonstrate that gestational/newborn nutrient stress may program hypertension in offspring.