Effect of indomethacin on cerebral blood flow, carbon dioxide reactivity and the response to epoprostenol (prostacyclin) infusion in man.

Abstract

SUMMARY Cerebral blood flow (CBF) has been measured using a non-invasive Xenon'33 clearance technique in six normal subjects after 2 days pretreatment with oral indomethacin at a dose of 100 mg/day. The results were compared with placebo given in a double blind balanced cross-over design. Indomethacin was found to result in a reduction in resting CBF of about 25% but the reactivity of the cerebrovascular circulation to carbon dioxide was preserved at normal levels. Infusions of epoprostenol (prostacyclin, PGI2) at a dose of 5 ng/kg/min resulted in a reduction of CBF of about 10% after placebo but no significant change in CBF after indomethacin. The results suggest that prostaglandins are involved in the maintenance of cerebrovascular tone but not in the mechanism of cerebral vasodilation accompanying hypercapnia. The combination of indomethacin and PGI2 has been proposed as a treatment of cerebral artery spasm and the findings suggest that the combination therapy would not be accompanied by undesirable intracerebral steal.There is considerable evidence, recently reviewed by Pickard,' which suggests that prostaglandins and particularly prostacyclin (epoprostenol, PGI2) are involved in the control of cerebral blood flow (CBF). The evidence comes from two separate lines, firstly experiments on the effects of indomethacin used as an inhibitor of prostaglandin synthesis, and secondly animal experiments on the direct effects of PGI, both in vitro and in vivo. Pickard and Mackenzie2 first showed that in baboons intraarterial indomethacin reduced resting CBF, and almost abolished the rise in CBF that normally results from hypercapnia. Similar findings were recently reported in humans studied 1 hour after

Differential effect of three cyclooxygenase inhibitors on human cerebral blood flow velocity and carbon dioxide reactivity.

“…In one study no control group received hypercapnia; a significant increase in CBF was seen with a very modest increase in CO 2 concentration from 5.0 to 5.5 kPa, but this may represent a nonspecific response to the stress of the mask and the CO 2 . 13 Furthermore, without a control group it is unclear whether the response to hypercapnia was reduced compared with normal subjects, as the trend in our study suggested, or was unaltered as found by Pickles et al 14 However, other studies revealing conflicting results induced greater changes in end-tidal CO 2 concentrations, similar to those attained in our study, and used ade- Abbreviations as in Table 1. Standard deviations are shown in parentheses.…”

“…- 14 In addition, in some animal models indomethacin reduces the cerebral vasodilatory response to hypercapnia, 7 ' 810 although studies in humans have revealed conflicting results.…”

Influence of indomethacin on the ventilatory and cerebrovascular responsiveness to hypoxia

“…1). In contrast, Pickles et al (1984) reported a reduced basal CBF without any concurrent changes in cerebrovascular CO 2 reactivity in six participants following 2 days of INDO oral administration (100 mg day -1 ). However, in that study, participants were given 50 mg of INDO the morning of the experiment, whilst the present and other previous studies (Bruhn et al 2001;Eriksson et al 1983;Fan et al 2010;Ivancev et al 2009;Markus et al 1994;St Lawrence et al 2002;Wennmalm et al 1983;Xie et al 2006Xie et al , 2009 have assessed the effect of INDO on the cerebrovascular CO 2 reactivity following a single larger dose of INDO (100 mg) 90 min prior to measurement.…”

“…However, in that study, participants were given 50 mg of INDO the morning of the experiment, whilst the present and other previous studies (Bruhn et al 2001;Eriksson et al 1983;Fan et al 2010;Ivancev et al 2009;Markus et al 1994;St Lawrence et al 2002;Wennmalm et al 1983;Xie et al 2006Xie et al , 2009 have assessed the effect of INDO on the cerebrovascular CO 2 reactivity following a single larger dose of INDO (100 mg) 90 min prior to measurement. Accordingly, these methodological differences make it difficult to compare the findings of the Pickles et al (1984) study. Nishimura et al (1987) have previously found a reduction in the arterial-to-internal venous jugular PCO 2 difference during 5-15 min of hypoxic exposure in healthy humans.…”

Adverse Effects on Cerebral Perfusion of Prostacyclin Administered Directly into Patients with Fulminant Hepatic Failure and Acute Renal Failure

“…In addition, due to the reduction in arterial blood pressure, the net effect of prostacyclin in this study was a reduction in the cerebral perfusion pres sure. Other studies have shown that prostacyclin may cause both a reduction in cerebral blood flow [38] and cerebral perfusion pressure [39]. In this study, prostacyc lin caused a reduction in arterial oxygen tension and for the majority of patients studied a reduction in cardiac output.…”