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 do ses of indomethacin on cerebral blood flow (CBF) responses to hypercapnia a nd 2) to investigate the effects of low-dose indomethacin on the cerebral v asculature 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 minu tes later, CBF was measured by radioactive microspheres at baseline, during hypercapnia [Paco(2) greater than or equal to 70 mm Hg (greater than or eq ual to 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 indometha cin 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 pa rietal 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 a rteriolar diameters decreased from 72 +/- 8 to 58 +/- 6 mu m (p < 0.05), an d 6-keto-PGF(1 alpha) concentration decreased from 1440 +/- 250 to 570 +/- 30 pg/mL (p < 0.05). Two hours (138 +/- 21 min) later, pial arteriolar diam eters had returned toward baseline values (65 +/- 5 mu m), whereas 6-keto-P GF(1 alpha) values remained considerably lower than preindomethacin values (530 +/- 39 pg/mL). Cerebrovascular responses re, dilator stimuli were pres erved after 0.2 mg/kg indomethacin. We conclude that 0.2 mg/kg indomethacin does not markedly affect the cerebral hyperemic responses to hypercapnia i n 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 o bservation may be due to the permissive role that prostacyclin plays in cer ebral vasodilatory responses to some vasogenic stimuli such as hypercapnia and histamine.