Permissive role of prostacyclin in cerebral vasodilation to hypercapnia in newborn pigs.

Hypercapnic cerebral vasodilation in piglets is accompanied by increased cerebral prostanoid synthesis. Interventions that prevent the increased prostanoids also interfere with the vasodilation. However, the increased prostanoids may not produce vasodilation directly; instead, they may allow or enhance function of another mechanism. The present experiments examined the hypothesis that prostacyclin can allow, but may not directly produce, cerebral vasodilation to hypercapnia. Chloralose-anesthetized piglets were equipped with closed cranial windows for measurements of pial arteriolar diameters. Hypercapnia (arterial CO2 partial pressure approximately 70 mmHg) was administered before and after indomethacin (5 mg/kg iv) in all animals. Then artificial cerebrospinal fluid (aCSF) under the cranial window was replaced for the remainder of the experiment with aCSF containing vehicle, carbaprostacyclin (60 pM), iloprost (1 pM), prostaglandin E2 (PGE2; 1.7 and 3.3 nM), isoproterenol (10 and 100 nM), or sodium nitroprusside (1 microM), and hypercapnia was repeated. The two prostacyclin receptor agonists restored cerebral vasodilation to hypercapnia that had been blocked by indomethacin (to 92 +/- 31% and 76 +/- 11% of the before-indomethacin dilation for carbaprostacyclin and iloprost, respectively.) The highest dose of PGE2 partially restored the dilation (43 +/- 7% of the pre-indomethacin response). In contrast, neither isoproterenol nor sodium nitroprusside permitted significant dilation to hypercapnia following indomethacin treatment. These data indicate that prostacyclin can allow hypercapnic vasodilation to occur, but increasing levels do not appear to be necessary to cause the dilation directly. The short half-life of prostacyclin may explain why active prostanoid synthesis appears to be necessary for hypercapnia-induced cerebral vasodilation in newborn pigs.

Effects of indomethacin on newborn pig pial arteriolar responses to PCO2.

The present experiments were designed to determine whether hypocapnic cerebral vasoconstriction, like hypercapnic dilation, involves prostanoids and, if not, whether alternative mechanisms are related to the absolute arterial PCO2 (PaCO2) or the direction of change. We determined effects of indomethacin (5 mg/kg iv) on pial arteriolar responses to 1) increased PCO2 from normal, 2) decreased PCO2 from normal, and 3) increased PCO2 from hypocapnia to normocapnia in anesthetized newborn pigs. Pial arterioles constricted in response to hypocapnia (PaCO2 = 15-24 Torr) similarly before (-13 +/- 3%) and after (-16 +/- 2%) indomethacin. Cortical periarachnoid cerebrospinal fluid prostanoids were not increased by hypocapnia. As previously reported, cerebral vascular responses to hypercapnia (which increases cerebrospinal fluid prostanoids) were lost after indomethacin. To determine whether the failure of indomethacin to affect the responses to hypocapnia was due to the direction of change (decreasing) or the absolute level of PCO2, piglets were hyperventilated to approximately 15 Torr PaCO2. Increasing PaCO2 in these piglets to approximately 44 Torr caused pial arteriolar dilation (46 +/- 7%) that was not blocked by indomethacin (33 +/- 5%). Cortical periarachnoid prostanoids were not altered when PaCO2 was raised from hypocapnia to normocapnia. Therefore the relationship between CO2 and piglet cerebral vascular tone appears to involve multiple mechanisms. Specifically, dilation in response to CO2 above the normal range appears to involve prostanoids but changes in pial arteriolar diameter at low PaCO2 do not.

Fibroblast growth factor and culture in monolayer rescue mesoderm cells destined to die in the developing avian wing.

In an effort to elucidate control mechanisms for developmentally programmed cell death, conditions were sought that rescue the cells destined to die. Three areas of mesodermal cell death in the chick wing were examined: the posterior necrotic zone (PNZ), the opaque patch (OP), and apical mesoderm. The PNZ and OP are areas of normally programmed cell death, whereas the apical mesoderm undergoes cell death only after the overlying apical ectodermal ridge is excised. Cell death in vitro was quantitated using the chromium-release assay. While these tissues undergo apparently normal cell death in organ culture, in monolayer culture almost all are rescued. In addition, the cells are rescued by the addition of fibroblast growth factor to organ cultures. Since fibroblast growth factor is present in decreasing amounts in the limb at this stage of development, normal cell death may occur upon withdrawal of growth factor.