Pial Artery Vasodilation Research Articles

The role of nitric oxide in opioid-induced pial artery vasodilation

The present study was designed to investigate the role of nitric oxide (NO) and the production of cGMP in the vasodilator response to opioid agonists in newborn pigs equipped with a closed cranial window. Methionine-enkephalin (10 −8, 10 −6 M), an endogenous μ opioid agonist, produced pial artery dilation that was attenuated by l-nitroarginine (LNA, 10 −6 M), an NO synthase inhibitor (10 ± 1 vs. 4 ± 1 and 16 ± 1 vs. 7 ± 1% for 10 −8, 10 −6 M methionine-enkephalin, respectively). Methionine-enkephalin-induced vasodilation was associated with increased cortical periarachnoid CSF cGMP and these changes in CSF cGMP were attenuated by LNA (354 ± 11 and 596 ± 32 vs. 278 ± 13 and 266 ± 19 fmol/ml for control and methionine-enkephalin 10 −6 M before and after LNA, respectively). Leucine enkephalin, an endogenous δ agonist, elicited similar changes in pial diameter and CSF cGMP while dynorphin, an endogenus k agonist, produced dilation associated with large increases in CSF cGMP (374 ± 18 vs. 1054 ± 45 fmol/ml for control and dynorphin 10 −6 M, respectively). Vascular and biochemical changes for these two opioids were similarly attenuated by LNA. The synthetic selective opioid receptor agonists, DAMGO, DPDPE, deltorphin, and U50,488H (10 −8, 10 −6 M) μ, δ 1, δ 2, and κ agonists, respectively, also elicited increases in pial artery diameter and CSF cGMP that were similarly attenuated by LNA. The coadministration of l-Arg (10 −3 M) with LNA partially restored opioid-induced pial artery dilation and associated changes in CSF cGMP whereas d-Arg (10 −3 M) coadministered with LNA did not restore opioid-induced vascular and biochemical changes. These data indicate that NO contributes to opioid-mediated pial artery vasodilation.

Activated oxygen species do not mediate hypercapnia-induced cerebral vasodilation in newborn pigs

In newborn pigs, vasodilation in response to hypercapnia is dependent on prostaglandin (PG) H synthase. We investigated the contribution of activated oxygen by-products to hypercapnia-induced PGH synthase-dependent dilation of pial arteries and arterioles in anesthetized newborn pigs. Activated oxygen species were generated on the cerebral surface using xanthine oxidase and hypoxanthine. Catalase, H2O2, and iron or N-(2-mercaptopropionyl)-glycine (MPG) were used to separate effects of superoxide anion and hydroxyl radical. All the activated oxygen species tested caused vasodilation of both arteries and arterioles. Vasodilation to all activated oxygen species was largely reversible with only the hydroxyl radical encouraging combination of xanthine oxidase, hypoxanthine, H2O2, and FeCl3, causing significant dilation 20 min after removal of treatment. Cotreatment with MPG blocked this residual dilation. Neither pretreatment with the extracellular superoxide anion radical scavenger, superoxide dismutase (SOD), the intracellular superoxide anion radical scavenger, Tiron, the H2O2 scavenger, catalase, nor hydroxyl radical scavengers, dimethyl sulfoxide (DMSO) and MPG, altered vasodilation of pial arteries or arterioles in response to hypercapnia. Furthermore, the increase in cerebral prostanoid synthesis in response to hypercapnia was not affected by pretreatment with SOD, Tiron, catalase, DMSO, or MPG. We conclude that the progressively reduced forms of oxygen that would be produced during PGH synthase metabolism of arachidonic acid can dilate pial arteries and arterioles of newborn pigs. However, these activated oxygen species are not responsible for the vasodilation to hypercapnia in the newborn pig, suggesting that eicosanoids cause the dilation.

Prostanoids in cortical subarachnoid cerebrospinal fluid and pial arterial diameter in newborn pigs.

These studies were designed to investigate the relationship between cerebral prostanoid synthesis and pial arterial caliber in chloralose-anesthetized newborn pigs with normal blood gases and pH and during combined arterial hypoxia and hypercapnia. Piglets less than 5 days old were equipped with closed cranial windows to allow direct observation of pial vessels, application of prostaglandin E2, and sampling of cortical subarachnoid cerebrospinal fluid. We found that prostanoids accumulate in cerebrospinal fluid on the cortical surface. The only prostanoid detected in arterial blood was 6-keto-prostaglandin F1 alpha [442 +/- 74 pg/ml (radioimmunoassay)]. Only small quantities of 6-keto-prostaglandin F1 alpha (214 +/- 53 pg/ml) and thromboxane B2 (122 +/- 18 pg/ml) were found in cerebrospinal fluid from the cisterna magna. Higher concentrations of 6-keto-prostaglandin F1 alpha (1056 +/- 159 pg/ml), thromboxane B2 (229 +/- 64 pg/ml), and prostaglandin E2 (4235 +/- 269 pg/ml) were found in cortical subarachnoid fluid. In contrast to arterial and cisternal concentrations, the concentrations of 6-keto-prostaglandin F1 alpha, thromboxane B2, and prostaglandin E2 in cortical subarachnoid fluid were increased reversibly by ventilation with 9% carbon dioxide, 10% oxygen, (6-keto-prostaglandin F1 alpha, 5436 +/- 1576 pg/ml; thromboxane B2, 694 +/- 122 pg/ml; and, prostaglandin E2, 12,455 +/- 3688 pg/ml). Further, pial arteries dilated in response to topical application of prostaglandin E2 at the concentration that was found in cortical subarachnoid fluid during combined hypoxia and hypercapnia. Systemic administration of indomethacin trihydrate (5 mg/kg) markedly reduced cortical subarachnoid fluid prostanoid concentrations and attenuated the pial artery vasodilation induced by combined hypoxia and hypercapnia.(ABSTRACT TRUNCATED AT 250 WORDS)