Abstract 235: Chronic Endothelin Type A Receptor Blockade Abolishes Age-dependent Hypertension In Female Intrauterine Growth Restricted Rat Offspring.

Abstract

Birth weight is inversely associated with blood pressure. Placental insufficiency in the rat induces low birth weight indicative of intrauterine growth restriction (IUGR) associated with sex-dependent hypertension in IUGR offspring in young adulthood. However, placental insufficiency programs the development of age-dependent hypertension in the female IUGR rat by 12 months of age. Blood pressure increases with age and the prevalence of hypertension is significantly increased in low birth weight women at 60 relative to 50 years of age. Yet, the exact mechanisms that mediate age-dependent hypertension following a developmental insult are unknown. We previously noted that endothelin mediated via its endothelin type A receptor (ET_AR) plays a significant role in blood pressure regulation in hypertensive male IUGR but not in normotensive female IUGR rats in young adulthood. Thus, we hypothesized that endothelin mediated via its ET_AR would play a contributory role in the development of age-dependent hypertension in the female IUGR rat. Mean arterial pressure (MAP) was measured via arterial catheter in conscious female control and female IUGR offspring at approximately 12 and 18 months of age in animals that received vehicle or an ET_AR antagonist (ABT-627, 5 mg/kg BW, Abbott) in the drinking water for 4 days prior to measure of MAP. MAP was significantly increased in IUGR (135±2 mmHg; P<0.05,) relative to control (121±2 mmHg) at 12 months of age (N=9 per group). MAP was remained significantly elevated in IUGR (149±5 mmHg, P<0.05) relative to control (135±5 mmHg) at 18 months of age (N=5 per group) despite age-dependent increases in MAP in IUGR and control rats. Chronic ET_AR blockade significantly decreased MAP in treated IUGR (113±2 mmHg; P<0.05 vs. untreated IUGR, N=6) but blockade of the ET_AR had no impact on blood pressure in treated control (134±9 mmHg; N=5) at 18 months of age. Thus, these findings indicate that age augments the importance of endothelin via its ET_AR in the etiology of hypertension programmed by IUGR but does not contribute to the age-dependent increase in blood pressure in the female control. Furthermore, this study highlights the need for sex- and age-specific considerations in the management of hypertension following a developmental insult.