Cerebrovascular responses to therapeutic dose of indomethacin in newborn pigs.

The aims of this study were 1) to compare the effects of low versus high doses of indomethacin on cerebral blood flow (CBF) responses to hypercapnia and 2) to investigate the effects of low-dose indomethacin on the cerebral vasculature during resting conditions and during vasodilator stimuli. In the first experiment, 27 piglets were randomized into three groups to receive 5 mg/kg indomethacin, 0.2 mg/kg indomethacin, or normal saline. Ninety minutes later, CBF was measured by radioactive microspheres at baseline, during hypercapnia [PaCO2 > or = 70 mm Hg (> or =9.3 kPa)] and normocapnia. Total CBF was comparable among the three groups at baseline. CBF increased during hypercapnia in all groups, but the hyperemic response was significantly attenuated in the high-dose indomethacin group compared with the saline group but not in the group treated with 0.2 mg/kg. CBF returned toward baseline during normocapnia in all piglets. In the second experiment, a closed cranial window was implanted over the parietal cortex of nine piglets. Cerebrovascular responses to hypercapnia and topical application of isoproterenol (10(-7) and 10(-6) M) and histamine (10(-6) and 10(-5) M) were investigated before and after administration of 0.2 mg/kg indomethacin. Within 10 min of indomethacin administration, pial arteriolar diameters decreased from 72 +/- 8 to 58 +/- 6 microm (p < 0.05), and 6-keto-PGF1alpha concentration decreased from 1440 +/- 250 to 570 +/- 30 pg/mL (p < 0.05). Two hours (138 +/- 21 min) later, pial arteriolar diameters had returned toward baseline values (65 +/- 5 microm), whereas 6-keto-PGF1alpha values remained considerably lower than preindomethacin values (530 +/- 30 pg/mL). Cerebrovascular responses to dilator stimuli were preserved after 0.2 mg/kg indomethacin. We conclude that 0.2 mg/kg indomethacin does not markedly affect the cerebral hyperemic responses to hypercapnia in contrast with a very prominent inhibition by 5 mg/kg indomethacin. Also, although indomethacin at a low dose constricts pial arterioles transiently and attenuates cerebral prostanoid production, it does not inhibit the pial arteriolar responsiveness to prostanoid-associated dilator stimuli. This observation may be due to the permissive role that prostacyclin plays in cerebral vasodilatory responses to some vasogenic stimuli such as hypercapnia and histamine.