iloprost and Hypercapnia

In the middle cerebral artery (MCA), the presence of nitric oxide (NO) is responsible for maintaining a more dilated state than in its absence during increases in extracellular K(+) and osmolality. The purpose of the present study was to determine whether the involvement of NO was due to (a) a direct effect of the K(+)/osmolality (K(hyper)) on the endothelium or (b) a 'permissive' role of NO. MCAs (approximately 210 microm o.d.) were isolated, cannulated with glass micropipettes, and pressurized to 85 mmHg. When K(+) (KCl) in the extraluminal bath was increased to 21 mM, the diameter increased by 15-20% with the magnitude of dilation diminishing with further increases in K(hyper). The addition of N(G)-nitro-L-arginine methyl ester (L-NAME, 10(-5) mM), an inhibitor of nitric oxide synthase, had no significant effect on dilations at lower K(hyper) concentrations but constricted the arteries relative to the control at 51, 66, and 81 mM K(hyper). In the presence of L-NAME, the addition of an exogenous NO donor, S-nitroso-N-acetylpenicillamine (SNAP, 10(-8) M) or an analog of cGMP, 8-bromo-cGMP (6x10(-5) M), tended to restore the response of K(hyper)to near the original response. We conclude that the basal release of NO from the endothelium plays a permissive role in the K(hyper)-induced response.

Topics: Animals; Cerebrovascular Circulation; Cyclic GMP; Endothelium, Vascular; Enzyme Inhibitors; Hypercapnia; Iloprost; In Vitro Techniques; Male; Middle Cerebral Artery; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Penicillamine; Potassium; Rats; Rats, Long-Evans; S-Nitroso-N-Acetylpenicillamine; Vasodilator Agents

Specific cerebrovascular dilatory responses in newborn piglets are entirely prostanoid dependent, but require both nitric oxide (NO) and prostanoids in juveniles. We examined endothelial dependency and mechanisms of NO- and prostanoid-mediated cerebrovascular responses in anesthetized newborn and juvenile pigs implanted with closed cranial windows. Light/dye endothelial injury inhibited newborn and juvenile hypercapnic and bradykinin (BK) responses and inhibited dilation to acetylcholine in juveniles. Iloprost and NO act permissively in restoring light/dye inhibited newborn and juvenile responses, respectively. Differences in sensitivity to iloprost and sodium nitroprusside were not observed. Juvenile (not newborn) hypercapnic and BK cerebrovascular responses were sensitive to soluble guanylyl cyclase inhibition. Pial arteriolar diameter and cortical production of prostacyclin, cAMP, and cGMP in response to BK were measured under control conditions, after treatment with indomethacin and/or N(omega)-nitro-L-arginine methyl ester (L-NAME). Indomethacin inhibited BK responses in newborns. Juvenile responses were inhibited by L-NAME, and mildly by indomethacin. Cortical 6-keto-PGF(1 alpha), cAMP, and cGMP increased in response to BK in both age groups. Newborn cerebrovascular responses are largely NO independent, but NO becomes more important with maturation.

Topics: 6-Ketoprostaglandin F1 alpha; Acetylcholine; Age Factors; Animals; Animals, Newborn; Arterioles; Bradykinin; Cardiotonic Agents; Cardiovascular Agents; Cerebrovascular Circulation; Cyclic AMP; Cyclic GMP; Endothelium, Vascular; Enzyme Inhibitors; Epoprostenol; Female; Hypercapnia; Iloprost; Indomethacin; Isoproterenol; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitroprusside; Pia Mater; Swine; Vasodilation; Vasodilator Agents

The aim of the present study was to determine whether neuronal nitric oxide synthase (nNOS)-derived nitric oxide (NO) plays a permissive role in the regulation of cerebral blood flow (CBF) response to hypercapnia. To this end, we examined whether the administration of NO donors could reestablish the regional CBF (rCBF) response to hypercapnia after nNOS inhibition with 7-nitroindazole (7-NI). Rats were anesthetized with 1% halothane, and rCBF in the cortex was measured by laser-Doppler flowmetry. The administration of 7-NI (40 mg/kg ip) decreased resting rCBF by 17 +/- 5% (n = 6, P < 0.05) and attenuated the rCBF response to hypercapnia by 30 +/- 8% in comparison with the response seen in rats treated with the vehicle (peanut oil) alone. Intracerebroventricular administration of NO donors, sodium nitroprusside (SNP; n = 7) and (Z)-1-[N-methyl-N-[6(N-methylammoniohexyl)aminol]]diazen+ ++-1-ium-1,2-diolate (MAHMA NONOate; n = 6) in a dose of 0.1-1 nmol/min after 7-NI restored both resting rCBF to baseline and the vasodilatory response to hypercapnia. In contrast, intravenous infusion of SNP (0.05-0.5 nmol/min, n = 6) or intracerebroventricular administration of an NO-independent vasodilator, the stable prostaglandin I2 analog iloprost (0.01-0.1 nmol/min, n = 6), after 7-NI failed to restore the vasodilatory response to hypercapnia, despite the fact that it restored the resting rCBF to baseline. nNOS activity, assessed by the conversion of labeled arginine to citrulline, was inhibited by 70 +/- 7% after the administration of 7-NI. These findings confirm that the selective inhibition of nNOS decreases resting rCBF and attenuates the rCBF response of hypercapnia. They further indicate that the repletion of intraparenchymal NO allows the hypercapnic cerebrocortical vasodilation to occur. Therefore, it is suggested that the nNOS-derived NO plays a permissive role in the CBF response to hypercapnia.

Topics: Animals; Cerebrovascular Circulation; Enzyme Inhibitors; Epoprostenol; Hypercapnia; Iloprost; Indazoles; Laser-Doppler Flowmetry; Male; Neurons; Nitric Oxide; Nitric Oxide Synthase; Rats; Rats, Sprague-Dawley; Reference Values; Vasodilator Agents

Both light/dye endothelial injury and indomethacin treatment inhibit hypercapnia-induced cerebral prostacyclin synthesis and pial arteriolar dilation in newborn pigs. Topical iloprost can allow hypercapnia-induced dilation of pial arterioles to occur in piglets treated with indomethacin. We addressed the hypothesis that prostacyclin receptor activation with iloprost can return the ability of pial arterioles with endothelial injury to respond to hypercapnia. We also examined whether the endothelial dependence and the permissive role of prostacyclin extended to histamine-induced dilation or are specific for hypercapnia.. Experiments used chloralose-anesthetized piglets equipped with closed cranial windows. Hypercapnia (PaCO2 approximately 80 mm Hg) and topically applied histamine (10(-6) and 10(-5) mol/L) dilated pial arterioles. Dilations in response to both stimuli were abolished by light/dye treatment.. Simultaneous topical treatment with iloprost (10(-12) mol/L, which caused no residual dilation, returned dilation of pial arterioles to both hypercapnia and histamine. On removal of iloprost, responses were again absent and returned with readdition of iloprost to the cortical cerebrospinal fluid. Neither isoproterenol nor sodium nitroprusside returned responses to hypercapnia after light/dye treatment.. These data add further support to the hypothesis that prostacyclin represents an important endothelial-derived signal in the newborn pig cerebral circulation that can permit appropriate responses by adjacent smooth muscle in response to specific stimuli.

Topics: Animals; Animals, Newborn; Arterioles; Cerebral Arteries; Coloring Agents; Endothelium, Vascular; Histamine; Hypercapnia; Iloprost; Light; Receptors, Epoprostenol; Receptors, Prostaglandin; Swine; Vasodilation; Vasodilator Agents

The present study addresses the hypothesis that indomethacin, in addition to blocking prostaglandin synthesis, directly inhibits prostacyclin receptor-mediated cerebral vascular responses. To test this hypothesis, the effects of indomethacin on pial arteriolar dilation in response to the prostacyclin receptor agonist iloprost were investigated using a cranial window technique in newborn pigs. Topically applied iloprost resulted in dose-dependent pial arteriolar dilation and concomitant increases in cortical adenosine 3',5'-cyclic monophosphate (cAMP). Indomethacin (5 mg/kg iv + 10(-4) M topically) greatly reduced both the vasodilation and the increase in cortical cAMP in response to iloprost. In contrast, indomethacin did not attenuate beta-adrenoreceptor-mediated vasodilation and the increase in cortical cAMP in response to isoproterenol. Aspirin (50 mg/kg iv + 10(-3) M topically) did not affect pial arteriolar dilation or the increase in cortical cAMP in response to iloprost. Unlike indomethacin, aspirin was not effective in inhibiting prostanoid-associated cerebral vasodilation and increase in cortical cAMP in response to hypercapnia. The present data suggest that indomethacin selectively inhibits prostacyclin receptor-mediated responses in the newborn pig cerebral circulation. The combination of highly effective inhibition of prostaglandin H synthase and prostacyclin receptor-mediated vasodilation may contribute to the increased efficacy of indomethacin compared with other prostaglandin H synthase inhibitors in blocking certain vasodilator responses associated with prostanoids.

Topics: Animals; Animals, Newborn; Arterioles; Aspirin; Cerebrovascular Circulation; Hypercapnia; Iloprost; Indomethacin; Isoproterenol; Pia Mater; Receptors, Epoprostenol; Receptors, Prostaglandin; Swine

Cerebral vasodilation in response to hypercapnia involves prostanoids in newborn pigs. This study examines the hypothesis that endothelial injury in vivo inhibits cerebral vasodilation and prostacyclin synthesis in response to hypercapnia, thus suggesting prostacyclin is a primary endothelium-derived vasodilating factor in newborn pig cerebral circulation. Anesthetized piglets with closed cranial windows were studied before and after injury caused by light/dye or before and after dye-only sham control. Light/dye injury was produced by injecting sodium fluorescein intravenously and passing filtered light from a mercury arc lamp through the cranial window. Ultrastructural changes to endothelium of pial vessels were produced that were characterized by surface pits, vacuolar cytoplasmic inclusions, and mitochondrial injury. After the light/dye injury, dilation to hypercapnia was absent while dilations to iloprost, isoproterenol, and sodium nitroprusside and constrictions to norepinephrine and acetylcholine were retained. Before light/dye treatment, hypercapnia increased cortical periarachnoid 6-keto prostaglandin F1 alpha concentration approximately threefold. However, after treatment, 6-keto-prostaglandin F1 alpha was not increased significantly in response to hypercapnia. These findings are consistent with the hypothesis that endothelial prostacyclin synthesis induced by hypercapnia participates in dilation of adjacent smooth muscle.

Topics: Animals; Animals, Newborn; Arterioles; Carbon Dioxide; Fluorescein; Fluoresceins; Hypercapnia; Iloprost; Isoproterenol; Light; Muscle, Smooth, Vascular; Nitroprusside; Oxygen; Parietal Lobe; Partial Pressure; Pia Mater; Swine; Vasodilation

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.

Topics: Animals; Animals, Newborn; Cerebrovascular Circulation; Dinoprostone; Epoprostenol; Hypercapnia; Iloprost; Indomethacin; Prostaglandins, Synthetic; Receptors, Epoprostenol; Receptors, Prostaglandin; Swine; Vasodilation