Gender-related effects of indomethacin on cerebrovascular CO2 reactivity

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Abstract

Prostaglandins are believed to play an important role in the regulation of resting cerebral blood flow and in the vasodilatory response to hypercapnia. Recently, we reported an increased CO2 reactivity (CR) in premenopausal women and, in the past, evidence has accumulated that estrogens might increase basal levels of prostaglandin secretion from endothelial cells. Therefore, one may speculate that gender differences in CR are possibly mediated by higher prostaglandin levels in women. Using transcranial Doppler sonography, we assessed CR before and 90 min after a single dose of 100 mg of indomethacin in 22 healthy volunteers (11 men, 11 women). Before intake of indomethacin, women had a significantly higher CR (4.53±0.49 vs. 3.61±0.74, P<0.01). Ninety minutes after indomethacin administration, CR decreased to 1.53±0.93 in women and 1.60±0.92 in men, respectively. The change of CR was 3.00±1.29 in women vs. 2.01±1.06 in men (P=0.07). For the entire study population, the decrease of CR was linearly correlated with the initial value of CR (rs=0.74, P<0.001). This gender-related difference possibly relates to higher prostaglandin levels as mediators of an increased CR in premenopausal women, although the exact features remain to be clarified.

Introduction

During the past few years, evidence has accumulated that prostaglandins are important both in the regulation of resting cerebral blood flow (CBF) and in the vasodilatory response to hypercapnia 12, 20, 26, 35. Prostacylin (PGI2) is formed by the vascular endothelium [11]and can be produced in vitro by cerebral blood vessels 3, 9. It is a potent endogenous vasodilator and inhibitor of platelet aggregation in man 25, 27.

In phencyclidine-anaesthetized baboons, Pickard and MacKenzie [28]first found that intravenous or intracarotid infusion of indomethacin (10 mg/kg and 0.04–0.2 mg/kg, respectively) reduced CBF by 38% at normocapnia, with no significant effect on the cerebral metabolic rate of oxygen (CMRO2). Indomethacin also markedly attenuated the increase in CBF during hypercapnia. Similar results have been reported since then in animals 6, 13, 32and humans 1, 15, 23, 29, 37.

Recently, we have reported an enhanced cerebrovascular CO2 reactivity in premenopausal women 16, 17. Estrogens have been shown to stimulate prostaglandin cyclooxygenase and prostacyclin synthetase activities of rat aortic smooth muscle cells 2, 5, 8, suggesting that estrogen might enhance basal levels of prostacyclin secretion from endothelial cells. Measuring prostacyclin levels using a bioassay technique, one group of investigators [24]found higher prostacyclin levels in young women compared to young men. The levels for women decreased markedly, beginning at the age 40 to 50, and there was little or no difference with men at older ages.

In view of these results, one may speculate that enhanced cerebrovascular reactivity to hypercapnia in premenopausal women is partially mediated by increased levels of prostaglandins.

If so, we hypothesized that inhibition of cerebrovascular reactivity to CO2 with indomethacin should be more pronounced in women compared to men. Therefore, the main objective of the present study was to assess gender related effects of a single dose of indomethacin (100 mg orally administered) on cerebrovascular CO2 reactivity (CR) using simultaneous bilateral transcranial Doppler sonography.

Section snippets

Subjects

Twenty-two healthy non-smoking neurology department staff members (11 women and 11 men) were studied after they gave their informed consent. The mean age was 28±2 years for women and 31±4 years for men. Each subject underwent a detailed interview and general physical and neurological examination and was ruled out as having anemia, hyper- or hypothyroidism, polycythemia, epilepsy or obstructive cerebrovascular disease, as shown by extracranial and intracranial ultrasound recordings. The

Results

The mean age of men and women was comparable and for the total population, there were no statistically significant side differences between left and right middle cerebral arteries in mean blood flow velocities and reactivity indices. Therefore, to investigate the influence of indomethacin on CR, the results of the right and left side were combined by averaging them.

In accordance with previous reports, the oral administration of 100 mg of indomethacin resulted in a variable reduction of mean

Discussion

Transcranial Doppler ultrasound (TCD) is a non-invasive, inexpensive and reproducible method for determining FVs in the basal intracranial arteries. However, several methodological considerations have to be considered. FV is considerably dependent on arterial carbon dioxide tension [10]. Consequently, very accurate PaCO2 determinations are indispensable for evaluating TCD data. In our study, direct measurement of PaCO2 requiring arterial puncture was avoided in favor of continuous on-line

Acknowledgements

The results of this project were completed during the course of Andreas Kastrup's fellowship of the Deutsche Forschungsgemeinschaft (DFG Ka 1419/1-1). We thank the volunteers for their participation in the study.

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