Is prestroke use of angiotensin-converting enzyme inhibitors associated with better outcome?

BACKGROUND: There is evidence that angiotensin-converting enzyme inhibitors (ACEIs) reduce the risk of stroke. However, it is unclear whether ACEI use before stroke provides a vasoprotective effect resulting in less severe stroke. METHODS: We ascertained all strokes occurring in a defined population in Melbourne, Australia. Prestroke use of ACEIs and concomitant medications was obtained from medical records. Initial neurologic deficit was dichotomized according to a NIH Stroke Scale (NIHSS) score < 8 (less severe deficit) or > or = 8 (severe deficit). Logistic regression was used to assess the association between prestroke use of ACEIs and stroke severity (measured by severity of neurologic deficits and death at 28 days). RESULTS: Seven hundred sixteen first-ever ischemic stroke patients were included. Previous use of ACEIs was independently associated with a reduced risk of severe neurologic deficits (odds ratio [OR] 0.56; 95% CI 0.35 to 0.91) and death within 28 days (OR 0.46; 95% CI 0.24 to 0.87). Diuretics were associated with an increased risk of severe neurologic deficits (OR 1.81; 95% CI 1.13 to 2.90). Factors associated with a greater NIHSS score were older age, atrial fibrillation, heart failure, and use of diuretics. These factors and claudication were associated with an increased risk of 28-day mortality, whereas use of anticoagulants was associated with a reduced risk of severe neurologic deficits and death. CONCLUSION: Within this large community-based cohort, prestroke use of angiotensin-converting enzyme inhibitors was associated with a reduced risk of severe stroke.

Effect of finasteride on behavioural arousal and somatosensory evoked potentials in fetal sheep.

This study examines the effect of inhibiting the synthesis of gamma-aminobutyric acid(A) (GABA(A)) agonist steroids on behavioural activity and somatosensory evoked potentials (SEP) in late gestation fetuses. Pregnane steroid production was suppressed by infusion of the 5alpha-reductase inhibitor, finasteride in chronically catheterised fetal sheep, 130-135 days gestation. Finasteride treatment (160 mg in 10 ml of vehicle over 2 h) significantly increased the incidence of fetal arousal during the period 4-10 h after commencing the infusion (P<0.05, n=6), whereas other behavioural parameters were not effected. In three of four animals, finasteride produced an increase in the amplitude of the N22 peak of the SEP during high voltage electrocortical activity. We conclude that suppression of pregnane steroid synthesis, by inhibition of the 5alpha-reductase enzyme, increases arousal activity in the fetus which is consistent with a reduction in GABA(A) receptor mediated inhibition.

Effects of pregnanolone on behavioural parameters and the responses to GABA(A) receptor antagonists in the late gestation fetal sheep.

Placental progesterone metabolites may suppress fetal behaviour by interacting with GABA(A) receptors. In an initial study, the effect of 5beta-pregnan-3alpha-ol-20-one (pregnanolone) given as a bolus (2.5 and 5.0 mg) or infused at a rate of 25 mg/h was investigated in unanaesthetized, catheterized fetal sheep, 127-135 days gestation. The incidence of fetal breathing movements (FBM) and behavioural arousal activity, defined as nuchal muscle electromyographic (EMG) activity during low voltage electrocortical (LV ECoG) activity were suppressed by pregnanolone administered as a bolus, while the pregnanolone infusion produced a significant decrease in arousal and EOG activity, and an increase in the presence of HV ECoG. The effect of pregnanolone on fetal behaviour and arousal induced by the GABA(A) antagonist picrotoxin was also investigated. Picrotoxin was given as a bolus (approximately 300 microg/kg) and pregnanolone was subsequently administered as a bolus (5.0 mg), and behavioural parameters were recorded and analysed. The incidence of arousal and FBM were 1.1 +/- 1.6 min/10 min and 2.5 +/- 2.3 min/10 min, respectively, before picrotoxin treatment and increased during the 10-20 and 20-30 min epochs after picrotoxin treatment (arousal: 5.0 +/- 2.2 and 6.5 +/- 3.6 min/10 min, respectively, n = 6, P < 0.05; FBM: 7.3 +/- 3.2 and 9.3 +/- 1.2 min/10 min, respectively, n = 6, P < 0.05). The picrotoxin-induced increases in arousal and FBM were significantly suppressed (n = 6, P < 0.05) by pregnanolone treatment to 1.6 +/- 1.5 min/10 min and 4.6 +/- 2.3 min/10 min, respectively. We conclude that; (i) the GABA(A) active steroid pregnanolone suppresses basal and picrotoxin-induced fetal arousal and FBM; and (ii) steroid sensitive GABA(A) receptors may regulate fetal behaviour and breathing.

Effect of pregnane steroids on electrocortical activity and somatosensory evoked potentials in fetal sheep.

The effect of infusing the neuroactive steroids pregnanolone and iso-pregnanolone on somatosensory evoked potentials (SEP) and electrocortical (ECoG) activity was studied in unanaesthetised fetal sheep, 130-135 days gestation. Intravenous infusion of pregnanolone (6 mg/kg per h) significantly increased the proportion of high voltage ECoG (56.1+/-4.8% vs. control 43.5+/-3.2%, P < 0.05), and decreased low voltage ECoG (43.9+/-4.8% vs. control 56.6+/-3.2%, P < 0.05). Pregnanolone treatment decreased the amplitude of the N25 peak of the SEP (89.9+/-2.8% of control, P < 0.05) evoked following stimulation of the skin of the upper lip. In contrast, iso-pregnanolone treatment had no effect on ECoG activities, or on the amplitude and latency of peaks in the SEP. We conclude that 3alpha-hydroxy pregnane steroids are active at GABA(A) receptors in fetal sheep and can modulate sleep/wake activity before birth.

Effect of alteration of maternal plasma progesterone concentrations on fetal behavioural state during late gestation.

Placental progesterone synthesis exposes the fetus to high levels of progesterone and progesterone metabolites during late gestation which may influence fetal behaviour. To determine the role of maternal progesterone synthesis in the control of fetal arousal state and fetal breathing movements (FBM), the effect of raising and lowering maternal progesterone concentrations was examined in chronically catheterised fetal sheep. Fetal and maternal vascular catheters, fetal tracheal and amniotic fluid catheters as well as electrodes for recording fetal electrocortical (ECoG), electro-ocular (EOG) and nuchal muscle electromyographic (EMG) activity were implanted between 118 and 122 days gestational age (GA). Progesterone, 100 mg, administered twice daily i.m. for 3 days (130-133 days GA) resulted in a marked elevation in maternal plasma progesterone concentrations (370 +/- 121%, n = 5, P < 0.05), but had no effect on fetal plasma concentrations. Fetal EOG episodes and the duration of fetal behavioural arousal were significantly suppressed throughout the progesterone treatment period (74.4-81.1% and 58-65% respectively, P < 0.05, n = 5). Four ewes received Trilostane (25 mg i.v.), a 3 beta-hydroxysteroid dehydrogenase inhibitor, between 136 and 140 days GA. Maternal and fetal progesterone concentrations were significantly lowered by 60 min after treatment (19.8 +/- 8.0% and 39.5 +/- 24.3% respectively, P < 0.05). The incidence of fetal EOG activity increased from a pretreatment level of 26.8 +/- 1.5 min/h to 30.3 +/- 2.8 min/h at 1-6 h and to 35.0 +/- 1.7 min/h (P < 0.05) during the 7-12 h after Trilostane treatment. The duration of FBM episodes was significantly higher at 1-6 h and 7-12 h after Trilostane treatment (19.5 +/- 3.0 and 23.6 +/- 5.5 min/h respectively, P < 0.05) compared with pretreatment levels (11.2 +/- 1.2 min/h). We conclude that increasing maternal progesterone levels suppresses fetal EOG activity and behavioural arousal, whereas reducing maternal progesterone synthesis leads to an elevation of EOG activity and FBM.

Suppression of arousal by progesterone in fetal sheep.

The high rate of progesterone synthesis by the placenta in late gestation exposes the ovine fetus to high concentrations of progesterone and its metabolites that may affect activity of the fetal brain. The aim of this study was to determine the effect of inhibiting maternal progesterone synthesis on sleep-wake activity in fetal sheep. Fetal and maternal vascular catheters, a fetal tracheal catheter, and electrodes for recording fetal electrocortical (ECoG), electro-ocular (EOG) and nuchal muscle electromyographic (EMG) activity were implanted. At 128-131 days gestation, progesterone production was inhibited by an injection of trilostane (50 mg), a 3beta-hydroxysteroid dehydrogenase inhibitor. Vehicle solution or progesterone (3 mg h(-1)) was then infused into the ewe between 6 and 12 h after the trilostane treatment. Maternal progesterone concentrations were significantly reduced from 1-24 h after trilostane treatment (P < 0.05) when followed by vehicle infusion. Fetal breathing movements (FBM), EOG, nuchal muscle EMG, and behavioural arousal increased 12 h after trilostane treatment (P < 0.05). In contrast, there was no change in fetal arousal, EOG, EMG or FBM activities when progesterone was infused after the trilostane treatment. These findings show that progesterone can influence fetal behaviour, and indicates that normal progesterone production tonically suppresses arousal, or wakefulness in the fetus.