Cognitive functioning and cerebrospinal fluid concentrations of neuropeptides for patients with good neurological outcomes after aneurysmal subarachnoid hemorrhage.

OBJECTIVE: Many patients exhibit cognitive disturbances after aneurysmal subarachnoid hemorrhage (SAH). Structural and functional neuroimaging has failed to demonstrate any correlation with these complaints. This study was performed to investigate whether neuropeptide concentrations in cerebrospinal fluid could be related to cognitive disturbances after SAH. METHODS: Lumbar cerebrospinal fluid was obtained, 3 to 6 months after surgery, from 17 patients who experienced good outcomes after aneurysmal SAH. The samples were analyzed for various neuropeptides using radioimmunoassays, and the peptide concentrations were evaluated in relation to scores on standardized neuropsychological tests. RESULTS: The neuropsychological test results were normal for eight individuals, whereas the remaining nine patients exhibited various degrees of cognitive impairment. There was no correlation between the concentrations of arginine vasopressin or neuropeptide Y and test performance. However, significant correlations between cognitive impairment and elevated levels of beta-endorphins (P = 0.02), corticotropin-releasing factor (P = 0.004), and delta sleep-inducing peptide (P = 0.045) were noted. CONCLUSION: Patients with cognitive impairments after aneurysmal SAH exhibited higher cerebrospinal fluid concentrations of endorphins, corticotropin-releasing factor, and delta sleep-inducing peptide than did those with normal capacity. This is probably attributable to diffuse derangement of transmitter release in the brain, resulting from the insult or ensuing complications, although a secondary increase in corticotropin-releasing factor concentrations caused by increased stress during the testing because of reduced cognitive capacity cannot be excluded.

Effects of various cyclooxygenase and lipoxygenase metabolites on guinea-pig cerebral arteries.

1. The effects of some prostanoids, leukotrienes, lipoxins and lipoxin precursors (15-HETE, 15-HPETE) were examined in guinea-pig isolated basilar arteries. 2. The potency order among the prostanoids to elicit contraction was U44069 greater than prostaglandin B2 greater than prostaglandin F2 alpha greater than prostaglandin E2. Leukotriene C4 and D4 were approximately equipotent with prostaglandin B2. 3. Lipoxin A4 and B4 elicited small contractions (4% of the contractile response to 124 mM K+ at 3 x 10(-6) M), which were significantly (P less than 0.02) enhanced by indomethacin. The contractile responses to 15-HETE and 15-HPETE varied considerably (2-102% and 2-56% at 3 x 10(-6) M, respectively) between different vascular segments. 4. Among the leukotrienes, lipoxins and lipoxin precursors, only lipoxin A4 elicited a relaxation, albeit small and transient. 5. In summary, all examined eicosanoids contracted the guinea-pig basilar artery, although the responses to the lipoxins were small but significantly enhanced by cyclooxygenase inhibition.

Characterization of contraction-mediating prostanoid receptors in human hand veins: effects of the thromboxane receptor antagonists BM13,505 and AH23848.

The effects of prostaglandin F2 alpha, prostaglandin E1, prostaglandin E2 and the thromboxane A2 analogue U46619 were determined in ring segments of human hand veins. All prostanoids except prostaglandin E1 elicited contraction. The order of potency was U46619 greater than prostaglandin F2 alpha greater than prostaglandin E2. The thromboxane receptor antagonists BM13,505 and AH23848 both caused a parallel rightward displacement of the concentration-response curve for U46619 without depression of the maximum contraction, suggesting competitive antagonism. Schild plots for both antagonists yielded regression lines with slope indices not significantly different from unity. The pA2 values for BM13,505 and AH23848 were 7.9 and 8.4 respectively. Both antagonists also effectively inhibited prostaglandin F2 alpha-induced contractions. However, AH23848 significantly reduced the maximum response, and the results with BM13,505 gave no clear indication of the type of inhibition. In vein segments submaximally contracted by 5-hydroxytryptamine, prostaglandins E1 and E2 produced a biphasic response with a relaxation at low and a contraction at high concentrations. Prostaglandin F2 alpha and U46619 failed to elicit relaxation under these conditions. However, in the presence of either thromboxane receptor antagonist, prostaglandin F2 alpha but not U46619 produced a relaxation. The results are compatible with the presence of at least two prostanoid receptors in human hand veins, a contraction-mediating thromboxane receptor and an as yet unclassified receptor eliciting relaxation. U46619 was a potent agonist at the thromboxane receptor and prostaglandin E1 and E2 preferentially stimulated the relaxation-mediating receptor, whereas prostaglandin F2 alpha appeared to be active at both receptor sites.

Actions of platelet-activating factor on isolated feline and human cerebral arteries.

The effects of platelet-activating factor (PAF) were studied on isolated feline basilar arteries (BAs) and human pial arteries (PAs). PAF contracted the BAs by 67% of the contraction induced by 124 mM K+ and the PAs by 80%. The contraction in BAs was unaffected by both indomethacin and the thromboxane receptor antagonist AH23848. PAF relaxed prostaglandin F2 alpha-contracted arteries. In BAs 10(-6) M PAF reduced the contraction by 17% and in PAs by 47%. The relaxant effects in both arteries were unaffected by indomethacin. In conclusion, PAF can act both as a constrictor and as a dilator of isolated feline and human cerebral arteries. The effects are seemingly unrelated to vascular prostanoid production.

Influence of Bay K 8644 on vascular responses mediated by alpha 1- and alpha 2-adrenoceptors.

1. The calcium channel activator Bay K 8644 increased the potency of noradrenaline in cat middle cerebral (alpha 2-adrenoceptors) and mesenteric (atypical or mixed alpha 1- and alpha 2-adrenoceptor population) arteries, but not in rat middle cerebral and mesenteric arteries (alpha 1-adrenoceptors). 2. In cat arteries, exposure to 15 mM K+ solution shifted the noradrenaline concentration-response curve to the left in an almost identical manner as did Bay K 8644. 3. Bay K 8644 completely reversed the relaxation produced by nifedipine in K+-contracted cat middle cerebral arteries, whereas the relaxation induced by verapamil, diltiazem or flunarizine was only partially reversed. This suggests a specific interaction between Bay K 8644 and the dihydropyridine receptors on the calcium channels. 4. It is concluded that the degree to which noradrenaline promotes calcium influx through membrane channels is at least partly related to the alpha-adrenoceptor subtype mediating the response.

Further characterization of the contraction-mediating prostanoid receptors in feline cerebral arteries. Effects of the thromboxane-receptor antagonist AH 23848.

The effects of the thromboxane-receptor antagonist AH 23848 were investigated on isolated feline basilar arteries (BA). AH 23848 (10(-6) mol l-1) had no effect on contractions induced by 5-hydroxytryptamine or potassium, whereas the drug (10(-8)-10(-6) mol l-1) induced a parallel shift to the right in contractions induced by the thromboxane A2 mimic U46619. There was no depression of the maximum contraction, indicating competitive antagonism. The Schild plot revealed a slope index of unity with a pA2 value of 8.46. In contrast, 10(-6) mol l-1 AH 23848 depressed the maximum PGF2 alpha-induced contraction significantly from 100% to 13%. U46619 was able to induce a contraction amounting to 98% if the drug was added on top of the PGF2 alpha-induced contraction in the presence of 10(-6) mol l-1 AH 23848. The results provide strong support for previous suggestions that prostanoid-induced contractions in the feline BA are mediated by two receptor subtypes, one of which can be classified as a thromboxane-sensitive (TP) receptor.

Actions of some prostaglandins and leukotrienes on rat cerebral and mesenteric arteries.

The effects of some prostaglandins (PG's) and leukotrienes (LT's) on rat middle cerebral, basilar and mesenteric arteries were evaluated in vitro. The order of potency of some prostanoids with respect to their contractile effects in basilar arteries was: U44069 greater than PGF2 alpha greater than PGI2 approximately equal to PGE2 greater than 6-keto-PGE1 greater than 6-keto-PGF1 alpha, whereas 6,15-diketo-PGF1 alpha was inactive. Middle cerebral and basilar arteries were 3-5 times more sensitive than mesenteric arteries to PGF2 alpha. LTD4 and LTC4 were inactive in all three vessel types. PGI2 produced a concentration-related relaxation of similar potency in all three arteries contracted by PGF2 alpha. Arteries preactivated by other agents (K+, noradrenaline, 5-hydroxytryptamine) either failed to relax or inconsistently relaxed after PGI2 application. Among the PGI2 metabolites (6-keto-PGF1 alpha, 6,15-diketo-PGF1 alpha, 6-keto-PGE1), only 6-keto-PGE1 elicited relaxation in the PGF2 alpha-contracted basilar artery. However, the drug potency was significantly smaller than that of PGI2. Nifedipine inhibited the PGF2 alpha-induced contraction by 68% in middle cerebral arteries and by 80% in mesenteric arteries. Exposure to Ca2+-free medium for a time period which almost completely abolished the contractile response to K+ (less than 5% left), reduced the PGF2 alpha-induced contraction by 54, 61 and 85% in middle cerebral, basilar and mesenteric arteries, respectively. The PGF2 alpha-induced contraction of cerebral arteries in Ca2+-free medium was usually composed of a rapidly developing first phase, which levelled off after 1-2 min, and a second slowly developing tonic phase.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of the thromboxane-receptor antagonist L-636,499 on feline cerebral arteries.

The effects of the thromboxane-receptor antagonist L-636,499 on contractions induced by U46619 and prostaglandin (PG)F2 alpha were studied in the isolated feline basilar artery (BA). L-636,499 (10(-6)-3 X 10(-5) mol l-1) shifted concentration-response curves induced by U46619 to the right in a parallel manner. By contrast, concentration-response curves induced by PGF2 alpha were displaced only when L-636,499 concentrations of 10(-5) and 3 X 10(-5) mol l-1 were used. The Schild plot using U46619 as the agonist revealed a slope index (0.69) which was significantly less than unity. PA2-values calculated according to the method of van Rossum differed significantly between different concentration intervals of L-636,499. At 10(-6) to 3 X 10(-6) mol l-1 the PA2-value was 5.99, whereas at 10(-5) to 3 X 10(-5) mol l-1 it was 5.59. Using PGF2 alpha as the agonist the PA2-value at the L-636,499 concentration interval 10(-5) to 3 X 10(-5) mol l-1 was 5.69. It may be concluded that the feline BA contains two receptor sites mediating prostanoid-induced contraction, one of which may be characterized as a thromboxane-sensitive (TP) receptor. L-636,499 can interact with both receptor sites with highest affinity for the TP receptor site.

Cellular calcium and the contraction induced by prostaglandin F2 alpha in feline cerebral arteries.

The influences of different calcium-entry blockers, sialidase and caffeine on the biphasic contraction induced by prostaglandin (PG) F2 alpha in the feline basilar artery (BA) were studied in calcium-free medium. After incubation in calcium-free solution, PGF2 alpha induced a contraction of the BA amounting to 87% of the contraction in calcium-containing solution. The response was biphasic in 41 out of 42 vessel segments. PGF2 alpha-induced contractions were markedly attenuated in TRIS-buffered solutions as compared to contractions in Krebs solution. PGF2 alpha failed to induce a biphasic contraction (8 out of 9 preparations) in calcium-free HEPES-buffered solution. Calcium entry blockade with 1 mM manganese or 10(-5) M diltiazem abolished the second and major phase of the PGF2 alpha-induced contraction in calcium-free Krebs solution. The second contraction phase was also eliminated in four out of five preparations pretreated with sialidase (1 unit/ml for 30 min.), but was unaffected by a brief exposure to 20 mM caffeine in calcium-free medium. The present findings strongly support previous suggestions that a major part of the PGF2 alpha-induced contraction in calcium-free medium is mediated via the release of calcium bound to the exterior aspect of the cell membrane.

Some effects of the calcium promotor BAY K 8644 on feline cerebral arteries.

The proposed calcium promotor BAY K 86(44) contracted feline basilar arteries partially depolarized by 10 mmol X 1(-1) potassium in a concentration-dependent manner (EC50 value: (2.1 +/- 1.2) X 10(-9) mol X 1(-1)). The concentration-response curve for prostaglandin (PG) F2 alpha was displaced to the left after pretreatment with BAY K 86(44). PGF2 alpha induced a biphasic contraction in calcium-free medium as has been described previously. The second PGF2 alpha-induced contraction phase in calcium-free medium was abolished by pretreatment with nifedipine or diltiazem. BAY K 86(44) restored the second phase in arteries pretreated with nifedipine, but not in vessels pretreated with diltiazem. The findings suggest that BAY K 86(44) acts as a promotor of calcium-influx, probably by interaction with the 'dihydropyridine receptor' in the cell membrane, and also provide support for the view that PGF2 alpha releases membrane-bound calcium.

Characterization of the prostanoid receptors and of the contractile effects of prostaglandin F2 alpha in human pial arteries.

The contractile and relaxant effects of various prostanoids were studied on isolated human pial arteries. Contractions were elicited with the following order of potency: U46619 approximately equal to U44069 greater than PGB2 greater than PGF2 alpha greater than PGE2 approximately equal to PGD2 approximately equal to PGF1 alpha greater than or equal to TXB2, indicating that prostanoid-induced contractions probably are mediated by a thromboxane-sensitive receptor. Relaxation of PGF2 alpha-contracted arteries was induced with the order of potency: PGE2 greater than PGE1 greater than PGD2 approximately equal to PGD1. Vessels contrated by K+ were relaxed only by PGE1. Since PGI2 was previously found to be more potent than all the prostanoids tested in the present study, relaxant responses are probably mediated via a PGI2-sensitive receptor. The role of free extracellular and cellularly bound calcium for the contractile effects of PGF2 alpha and K+ were estimated by incubating the arteries for various times in calcium-free medium containing 10(-5) M EGTA. Incubation for 5-10 min abolished K+-induced contractions, whereas after 40 min of incubation PGF2 alpha still induced contractions that reached 70% of control. The PGF2 alpha-induced contraction was biphasic in 8 out of 10 preparations. The second phase could be eliminated by increasing the EGTA-concentration to 10(-4) M, as well as by nifedipine pretreatment. In calcium-free, high K+ medium calcium-induced contractions were elicited at lower concentrations in the presence of PGF2 alpha. The results suggest that PGF2 alpha-induced contractions in human pial arteries are relatively independent of free extracellular calcium. PGF2 alpha may promote trans-membrane influx of calcium, as well as release calcium from seemingly superficially located cellular stores.

Effects of prostanoids on isolated feline cerebral arteries. II. Roles of extra- and intracellular calcium for the prostaglandin F2 alpha-induced contraction.

The roles of extra- and intracellular calcium for the contractile effects of PGF2 alpha in the feline basilar artery (BA) were investigated. Comparisons were made with contractions induced by K+ and noradrenaline (NA). Addition of nifedipine to PGF2 alpha- or K+ (124 mM)-contracted arteries resulted in an incomplete relaxation, whereas NA-contracted vessels were completely relaxed. Incubation of the preparations in a calcium-free medium containing 10(-5) M EGTA for 5-10 min almost abolished contractions induced by K+ and NA. In contrast, 63% of the response to PGF2 alpha remained after pretreatment of the arteries in a calcium-free solution for 40 min; PGF2 alpha produced a biphasic contraction in 17 out of 20 preparations consisting of a rapidly developing initial phase followed by a second increase in tension after 1-6 min. The second phase was absent if the EGTA-concentration was increased to 10(-4) M, or if the arteries were pre-treated with nifedipine. After incubation of the arteries in a calcium-free medium for 40-120 min and K+-depolarization, re-addition of calcium elicited contractions at lower concentrations in the presence of PGF2 alpha than in controls. The results suggest that PGF2 alpha-induced contractions in the feline BA are considerably less dependent on extracellular calcium than contractions evoked by K+ or NA. PGF2 alpha appears to be able to release calcium from two cellular stores, and may also promote calcium influx through the cell membrane.

Effects of prostanoids on isolated feline cerebral arteries. I. Characterization of the contraction-mediating receptor.

The effects of various prostanoids on isolated feline basilar arteries (BA) were studied. Contractions were induced with the following order of potency: U 46619 approximately equal to U44069 greater than PGB2 greater than PGF2 alpha approximately equal to PGA2 approximately equal to PGB1 greater than or equal to PGA1 approximately equal to PGE2 = PGD2 greater than PGF1 alpha approximately equal to TXB2 approximately equal to PGE1 approximately equal to PGD1. Distinct bimodal responses with a relaxation at low concentrations followed by a contraction at high concentrations, were induced by PGA1, PGA2, PGD, and PGE2. None of the tested prostanoids relaxed K+-contracted arteries, and a sizable relaxant effect in PGF2 alpha-contracted arteries could be induced only by PGE1. As judged by the relative order of potency, PG-induced contractions of the feline BA seem to be mediated by a thromboxane sensitive receptor. PGF2 alpha-induced contractions apparently do not involve the release of noradrenaline from perivascular nerves since phentolamine failed to affect contractions induced by this agent.

Effects of prostaglandin E1, E2 and E2 alpha on isolated pial arteries of cat.

Responses to prostaglandin (PG), E1, E2, and F2 alpha were studied on isolated feline middle cerebral arteries. At resting state PGF 2 alpha produced strong dose-dependent contractions. PGE2 elicited weak relaxations at low concentrations, followed by powerful contractions at higher doses. PGE1 had little effect on resting pial vessels. The relative constrictory potency was PGF2 alpha greater than PGE2 greater than PGE1. During active tone, induced by administration of either potassium, norepinephrine, or 5-hydroxytryptamine, relaxations induced by PGE1 were enhanced, whereas PGE2-induced relaxations were unaffected. PGE1-induced relaxations were more pronounced when the active tension had been produced by administration of PGF2 alpha than with either of the vasoactive amines or potassium. This study demonstrates the importance of smooth muscle tone, and by what means this is achieved, when examining the response of PG's on cerebral blood vessels.