Thromboxane synthesis inhibitor in a beagle pup model of perinatal asphyxia.

Abstract

During perinatal asphyxia, cerebral blood flow is markedly reduced in the gray and white matter of the telencephalon. Since previous work has implicated prostaglandins in the control of blood flow, we tested the hypothesis that a thromboxane synthesis inhibitor would improve cerebral blood flow and blunt the metabolic alterations that accompany asphyxia. Forty-three newborn beagles 2-7 days old were anesthetized, ventilated, and randomized to insult (5 minutes of asphyxia) or no insult and received treatment with either the thromboxane synthesis inhibitor CGS 13080 (CIBA-GEIGY Corp.) (0.06 mg/kg/hr i.v. infusion) or saline. Cerebral blood flow was measured in 25 pups. Pups received treatment 30 minutes before insult or no Insult. In pups randomized to insult and receiving saline, cerebral blood flow increased during insult in the medulla but decreased elsewhere. Pups randomized to insult and treated with thromboxane synthesis inhibitor had increased cerebral blood flow during insult in all cerebral regions studied. In addition, these pups experienced a significantly higher incidence of intraventricular hemorrhage than did pups randomized to insult and receiving saline. In other experiments with 18 pups, brain extracts were prepared for proton nuclear magnetic resonance spectral analysis of high-energy phosphorylated compounds and lactate levels. In pups exposed to insult and receiving saline, mean±SD phosphocreatine concentration fell from 1.9±0.1 to 0.4±0.1 mmol/kg, lactate concentration increased from 2.0±0.5 to 3.3±0.4 mmol/kg, and the calculated pH fell 0.8 units. There were no differences between groups. Our findings suggest that therapeutic strategies for perinatal asphyxia must extend beyond blood flow maintenance to methods that may reduce cerebral metabolic needs. We can then hope to prevent neuropathologic changes. (Stroke 1989;20:809-814)

Augmented Vasoconstriction and Thromboxane Formation by 15-F 2t -Isoprostane (8-Iso-Prostaglandin F 2α ) in Immature Pig Periventricular Brain Microvessels

“…We speculate that 15-F 2t -IsoP may be a contributory factor in the hemodynamic compromise and periventricular brain injury in the premature neonate during oxidant stress; cyclooxygenase inhibitors, thromboxane synthase, and/or receptor blockers may attenuate the deleterious effects of oxidant stress. 47,48 …”

Molecular Mechanisms Regulating the Vascular Prostacyclin Pathways and Their Adaptation during Pregnancy and in the Newborn

“…Studies in a beagle pup model of perinatal asphyxia have shown that treatment with the TXAS inhibitor CGS-13080 (pirmagrel), which increases PGI 2 activity and CBF in early phases of neonatal HIE, failed to show improvement in the ischemic metabolic changes. In addition, the pups had an increased risk of developing IVH (Ment et al, 1989). Although PGI 2 is among the prostanoids that could contribute to increased CBF in the early reperfusion phase of cerebral ischemia in newborns with HIE, a delayed increase in PGI 2 production or activity in later stages of HIE may have more beneficial effects.…”

Increased platelet-activating factor-induced periventricular brain microvascular constriction associated with immaturity

“…We speculate that the markedly greater PAF-induced brain microvascular constriction in the younger subjects may contribute to the hemodynamic compromise and periventricular brain injury observed in premature neonates exposed to oxidant stress. PAF antagonists, thromboxane synthase inhibitor, and/or receptor blockers may attenuate the deleterious effects of oxidant stress (4,25,28).…”