Effects of Indomethacin upon Cerebral Hemodynamics of Newborn Pigs

Abstract

Treatment of unanesthetized newborn pigs with indomethacin trihydrate (5 +/- 1 mg/kg, intravenous) decreased cerebral blood flow uniformly throughout the brain by 18-28% without changing cardiac output, arterial pressure, or arterial blood gases and pH. Breathing 10% O2, 9% CO2 with the balance N2 (hypoxia/hypercapnia) caused cerebral blood flow to increase from 102 +/- 12 to 218 +/- 19 ml/100 g . min. Intravenous administration of indomethacin during hypoxia/hypercapnia caused a uniform decrease in cerebral flow throughout the brain to levels (94 +/- 5 ml/100 g . min) indistinguishable from those when the piglet was breathing ambient air. Further, 2.5 h later, the cerebral hyperemia caused by hypoxia/hypercapnia was attenuated markedly (129 +/- 19 ml/100 g . min). Vehicle treatment did not alter resting cerebral blood flow or cerebral hyperemia in response to hypoxia/hypercapnia. Measurements of 6-keto-prostaglandin F1 alpha, thromboxane B2, and prostaglandin E2 demonstrated that intravenously administered indomethacin crossed the blood-brain barrier of newborn pigs in sufficient quantity to inhibit prostanoid release into the cerebrospinal fluid passing over the surface of the brain. The mechanism by which indomethacin reduces cerebral blood flow and attenuates cerebral hyperemia cannot be determined from the present experiments. We conclude that intravenous administration of indomethacin decreases cerebral blood flow and attenuates cerebral hyperemia induced by severe, combined hypoxia/hypercapnia in newborn pigs.

Effects of Indomethacin on Myogenic Contractile Activation and Responses to Changes in O2 and CO2 in Isolated Feline Cerebral Arteries

“…To our knowledge, this ef fect of IND on the cerebrovascular response to the mixed gases has not been previously reported for adult animals. In unanesthetized neonatal piglets, Leffler et al (1985) found that the CBF increased if the animals breathed a hypoxic/hypercapnic gas mixture. However, after administering IND the CBF decreased to levels comparable to those mea sured while the animals breathed room air.…”

Role of prostacyclin signaling in endothelial production of soluble amyloid precursor protein-α in cerebral microvessels

“…[1][2][3][4] The endothelium is a major source of PGI 2 which is generated in response to a number of different stimuli including vascular injury.…”

“…Endothelium-derived PGI 2 is an essential molecule responsible for preservation of cerebrovascular homeostasis under pathological conditions when blood vessels are exposed to injury induced by stroke, inflammation, and brain trauma. [1][2][3]6,7,43,44 Indeed, PGI 2 has been identified as a major protective product of arachidonic acid metabolism within the vasculature. 6 In the cerebral circulation, elevated production of PGI 2 in response to vascular injury is designed to prevent aggregation of platelets, to preserve blood flow, and to inhibit aberrant remodeling of injured vascular wall.…”

Metaanalysis of the effect of antenatal indomethacin on neonatal outcomes

“…11 Similarly, by decreasing fetal cerebral blood flow, AI may cause fetal central nervous system hypoperfusion injury resulting in PVL. 12 The profound effects of indomethacin on platelet and neutrophil function may lead to increased incidence of IVH and sepsis. 13 AI is associated with in utero constriction of the fetal ductus arteriosus.…”