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. 2006 Feb;231(2):181-5.
doi: 10.1177/153537020623100208.

Cyclooxygenase products stimulate carbon monoxide production by piglet cerebral microvessels

Alie Kanu  1 , David Gilpin, Alexander L Fedinec, Charles W Leffler
Affiliations

Cyclooxygenase products stimulate carbon monoxide production by piglet cerebral microvessels

Alie Kanu et al. Exp Biol Med (Maywood). 2006 Feb.

Abstract

Products of arachidonic acid (AA) metabolism by cyclooxygenase (Cox) are important in regulation of neonatal cerebral circulation. The brain and cerebral microvessels also express heme oxygenase (HO) that metabolizes heme to carbon monoxide (CO), biliverdin, and iron. The purpose of this study in newborn pig cerebral microvessels was to address the hypothesis that Cox products affect HO activity and HO products affect Cox activity. AA (2.0-20 microM) increased prostaglandin E2 (PGE2) measured by radioimmunoassay (RIA) and also CO measured by gas chromatography/mass spectrometry (GC/MS). Further, 10(-4) M indomethacin, which inhibited Cox, reduced both AA and heme-induced CO production. Conversely, neither exogenous 2 x 10(-6) M heme, which markedly increased CO production, nor the inhibitor of HO, chromium mesoporphyrin, altered PGE2 synthesis. Because AA metabolism by Cox generates both prostanoids and superoxides, we determined the effects of the predominant prostanoid and superoxide on CO production. Although PGE2 caused a small increase in CO production, xanthine oxidase plus hypoxanthine, which produces superoxide, strongly stimulated the production of CO by cerebral microvessels. This increase was mildly attenuated by catalase. These data suggest that Cox-catalyzed AA metabolites, most likely superoxide and/or a subsequent reactive oxygen species, increase cerebrovascular CO production. This increase seems to be caused, at least in part, by the elevation of HO-2 catalytic activity. Conversely, Cox activity is not affected by HO-catalyzed heme metabolites. These data suggest that some cerebrovascular functions attributable to Cox activity could be mediated by CO.

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Figures

Figure 1.
Figure 1.
Effect of arachidonic acid and indomethacin (10-4M) on prostaglandin E2 (PGE2) production by piglet cerebral microvessels. Means ± SE of 5 experiments * P< 0.05 compared with zero arachidonic acid, † P<0.05 compared with corresponding values without indomethacin.
Figure 2.
Figure 2.
Effect of arachidonic acid and indomethacin (10-4M) on CO production by cerebral microvessels of piglets. Means ± SE of 5 experiments. *p < 0.05 compared with zero arachidonic acid. † P < 0.05 Indomethacin compared to corresponding values without indomethacin.
Figure 3.
Figure 3.
Effect of HLL and indomethacin (10-4M) on CO production in piglet cerebral microvessels. Means ± SE of 5 experiments * P < 0.05 compared with no HLL. † P < 0.05 compared to no indomethacin.
Figure 4.
Figure 4.
Effect of HLL and Chromium mesoporphyrin (CrMP) (2×10-5M) on prostaglandin E2 (PGE2) production by piglet cerebral microvessels. Means ± SE of 5 experiments.
Figure 5.
Figure 5.
Effects of PGE2 and the superoxide generating system of xanthine oxidase (XO) (1U/ml) plus hypoxanthine (HX) (0.2mM), with and without catalase (CAT) (1200U/ml) on CO production by indomethacin (10-4M) treated piglet cerebral microvessels. n =11, 10, 10, and 7. Values are percentage change from vessels without either PGE2 or XO/HX. Means ± SE. * P < 0.05 compared to zero (no change) † P < 0.05 compared to no XO and HX.
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