The role of the renin-angiotensin system in the fetal origins of hypertention

Abstract

Cardiovascular disease is a major cause of death throughout the world. Hypertension is a risk factor for cardiovascular disease, which is caused by a combination of genetic, environmental and lifestyle factors. It is hypothesised that maternal nutrition during pregnancy may also contribute to the risk of adult hypertension in her offspring. A rat model has been developed which supports this hypothesis. Rats are fed either a 9% casein (low protein) diet or an 18% casein (control) diet throughout pregnancy. The offspring of the low protein fed rats have elevated blood pressure in later life compared with controls. This thesis examines the role of the renin- angiotensin system in the development of the elevated blood pressure observed in this rat model. Feeding a 9% casein diet during pregnancy led to a decrease in weight gain compared to rats fed a control diet, but did not effect litter size. The offspring were of low to normal birthweight, and had a tendency to gain more weight than control rats in later life. Systolic blood pressure was significantly elevated fi-om 4 weeks of age in the rats exposed to a maternal low protein diet compared, with control rats. Plasma renin activity, angiotensin II and angiotensinogen concentrations were unchanged in the offspring of rats fed a low protein diet compared with rats fed a control diet. Pulmonary angiotensin converting enzyme (ACE) activity tended to be higher in the low protein exposed rats from early life, compared with control rats. This difference was statistically significant by 12 weeks of age. prostaglandin E2 (PGE2) excretion was elevated in the offspring of rats fed a low protein diet. Urinary PGE2 excretion was also measured in a group of children whose birth characteristics were known. PGE2 concentration was inversely correlated with head circumference and ponderal index, which are markers of fetal growth. Intervention with an ACE inhibitor (captopril) reduced the blood pressure in the low protein exposed rats to control levels during the treatment period. Early treatment with captopril or losartan (an angiotensin II receptor antagonist) prevented the onset of hypertension in this model and had no effect upon the blood pressures of the control rats. Treatment with an alternative anti-hypertensive drug (nifedipine), which does not target the renin-angiotensin system, had no effect upon the blood pressures of the low protein exposed rats. Urinary This thesis supports the hypothesis that maternal diet during pregnancy programmes blood pressure in her offspring. The results show that the renin-angiotensin system is altered in this model of matemal-diet-induced hypertension. The results of the intervention studies are suggestive of a role for the renin-angiotensin system in the development of the elevated blood pressure that is observed in the low protein exposed rats. These findings also show that the development of elevated blood pressure in this model is preventable. This may have implications for future public health.

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