Statin treatment depresses the fetal defence to acute hypoxia via increasing nitric oxide bioavailability

Abstract

In addition to lowering cholesterol, statins increase nitric oxide (NO) bioavailability, improving endothelial function. In the fetus, enhanced NO during acute hypoxia opposes the fetal peripheral vasoconstrictor response, part of the brain-sparing defence. This study tested the hypothesis that treatment with statins depresses the fetal circulatory response to acute hypoxic stress via increasing NO bioavailability. Under anaesthesia, 12 fetal sheep at 118 ± 1 days of gestation (term ca 145 days) were instrumented with vascular catheters and a femoral artery Transonic flow probe for chronic recording. Five days later, all animals were subjected to 30 min of acute hypoxia (fetal arterial partial pressure of O(2) ( ) reduced by ca 50%) before and 24 h after fetal treatment with pravastatin (25 mg i.v.). In half of the fetuses (n = 6), responses to hypoxia post-pravastatin were evaluated during NO synthesis blockade. Fetal exposure to pravastatin did not affect fetal basal cardiovascular function. Fetal was similarly reduced in all acute hypoxia experiments from ca 21 to 10 mmHg. Fetal exposure to pravastatin markedly diminished the fetal femoral vasoconstrictor (5.1 ± 0.9 vs. 2.5 ± 0.5 mmHg (ml min(-1))(-1)) and lactic acidaemic (4.4 ± 0.5 vs. 3.0 ± 0.3 mm) responses to acute hypoxia (both P < 0.05), without affecting plasma catecholamine responses. Post-pravastatin, the circulatory (5.8 ± 1.5 mmHg (ml min(-1))(-1)) and metabolic (3.9 ± 0.3 mm) responses could be restored to control levels during fetal treatment with NO synthase blockade. Pravastatin depresses the fetal cardiovascular and metabolic defences to acute hypoxia via increasing NO bioavailability. The use of statins during pregnancy should be viewed with extreme caution.

Pravastatin ameliorates placental vascular defects, fetal growth, and cardiac function in a model of glucocorticoid excess

“…Pravastatin, an HMG-CoA reductase inhibitor that reduces cholesterol biosynthesis, is currently contraindicated in pregnancy, because of its potential effects in altering NO bioavailability in the fetal circulation, with detrimental consequences for the fetal brain sparing response to acute hypoxia, as may happen intrapartum (35). However, pravastatin in various mouse models of preeclampsia appears to ameliorate preeclamptic pathology (23,36), and pravastatin is the subject of a randomized control trial to ameliorate severe preeclampsia (37).…”

Vasotrophic Regulation of Age-Dependent Hypoxic Cerebrovascular Remodeling

“…Because oxygen radicals can rapidly inactivate NO [107], any long-term change in anti-oxidant activity also changes NO action on adjacent smooth muscle. Statin treatment can also increase NO bioavailability in fetal sheep, most probably through an increased capacity for NO synthesis [221]. Equally important, the capacity for NO synthesis and release in most vascular beds increases with developmental age [222, 223], which helps explain certain age-related differences in reactivity to endothelium-dependent vasodilators [224] but also predicts that the role of NO in vascular remodeling strengthens with advancing postnatal age.…”

Pravastatin to prevent recurrent fetal death in massive perivillous fibrin deposition of the placenta (MPFD)

“…Recent animal experiments in offspring born to mothers with preeclampsia (generated by an adenovirus encoding sVEGFR-1 gene) who received pravastatin therapy during pregnancy reported improvement in blood pressure [75–77], post-weaning weight, concentrations of cholesterol and glucose [78,79], brain volume (especially in male fetuses) [80,81], and improved vestibular function, balance, and coordination [82]. One study raised a concern that pravastatin treatment might blunt a peripheral vasoconstrictor response to hypoxia, a fetal defense mechanism for the redistribution of blood flow to essential vascular beds, such as those that perfuse the brain and heart [83]. …”