Chronic exogenous hyperinsulinaemia-induced hypertension in pregnant rats: effect of chronic treatment with l-arginine

Abstract

Recent studies have shown that maternal hyperinsulinaemia is a risk factor for the development of hypertension in pregnancy. Experimentally, pregnant rats with chronic exogenously induced hyperinsulinaemia (P-INS rats) have increased blood pressure at the end of gestation. This is associated with a blunted elevation of the excretion of the urinary metabolites of nitrate (UNO(x)). In the present study, we aimed to evaluate the mechanism(s) of the increase in blood pressure in this model. Four groups were studied: normal pregnant rats (P rats), P-INS rats, P-INS rats treated with L-arginine (2 g/l in the drinking water) (L-ARG rats) and hyperinsulinaemic virgin rats (V-INS rats). Systolic blood pressure (SBP), UNO(x) excretion (on ingestion of a controlled low-nitrate diet), urine noradrenaline (norepinephrine) and plasma endothelin levels were evaluated. Rats were killed on day 22 of pregnancy. Five P-INS rats were not killed at this time, in order to measure SBP 30 and 60 days after delivery. Fetal number and fetal body weight were evaluated. At the end of pregnancy, a 10+/-3% increase in SBP was found in P-INS rats, contrasting with a fall of -15+/-4% in P rats (P<0.01). In the L-ARG group at the end of pregnancy, SBP values had fallen by -14+/-2%, to values comparable with those of P rats. The increase in UNO(x) excretion was 175+/-38% in P rats, 106+/-12% in L-ARG rats and 41+/-8% in P-INS rats (P<0.01 compared with P and L-ARG groups). No differences were found in the urinary excretion of noradrenaline or in the plasma levels of endothelin-1 between the pregnant groups. Fetal number was similar in all groups, but fetal body weight was lower for P-INS rats compared with P and L-ARG rats. Thus the blood pressure response to L-arginine strongly suggests that a decrease in NO availability may be the main pathogenic mechanism involved in the development of hypertension in this model.

Maternal insulin resistance and transient hyperglycemia impact the metabolic and endocrine phenotypes of offspring

“…Data are expressed as means Ϯ SE; n ϭ 4/group. mothers, and this is consistent with the results from studies using hyperinsulinemic pregnant rats created by exogenous insulin treatment (without causing hypoglycemia) (5,38). In the latter studies, fetuses of hyperinsulinemic rats were smaller than those of control mothers.…”

Adult Hypertension in Intrauterine Growth-Restricted Offspring of Hyperinsulinemic Rats

“…6 -8 On the other hand, the changes in the NO system documented previously in our model are similar to processes occurring in hypertension associated with pregnancy in humans. [5][6][7][8] …”

“…5 Several years ago, we developed an animal model 6 in which exogenous hyperinsulinemia in pregnant rats was consistently associated with IUGR. [7][8][9] In animal models studied so far, hypertension of the adult offspring is associated with renal abnormalities, such as reduced glomerular number and increased apoptosis. 3,4,10 In this study, we tested the hypothesis that IUGR resulting from maternal hyperinsulinemia will evolve into hypertension in the adult offspring, characterized by the renal abnormalities and investigated molecular events occurring in utero, which eventually lead to kidney damage.…”

Animal models of preeclampsia

“…As shown in Figure 3, BP increased close to term and pregnant hyperinsulinemic rats also exhibited mildly reduced blood serum glucose levels, hypertriglyceridemia, and a reduced fractional excretion of sodium although urinary protein excretion remained unchanged. 84,85 The normal increase in GFR (creatinine clearance) seen in pregnant rats was blunted in hyperinsulinemic pregnant rats. 85,86 Total NO production was diminished and systolic BP correlated directly with serum insulin levels and inversely with total NO production.…”

“…84,85 The normal increase in GFR (creatinine clearance) seen in pregnant rats was blunted in hyperinsulinemic pregnant rats. 85,86 Total NO production was diminished and systolic BP correlated directly with serum insulin levels and inversely with total NO production. Treatment with L-arginine normalized BP 85,86 and increased total NO production and also increased the renal eNOS protein levels.…”