Tore Uski

Effects of nitrous oxide on human regional cerebral blood flow and isolated pial arteries.

BackgroundResults from previous studies on the effect of nitrous oxide (N2O) on the cerebral circulation are conflicting. Early reports claim N2O to have no effect whereas recent findings demonstrate a cerebral cortical vasodilatation during N2O inhalation, but the regional cerebral blood flow (CBF) in the subcortical structures is unknown. MethodsRegional CBF was measured three-dimensionally with single photon emission computer-aided tomography after injection of xenon 133 in 8 spontaneously breathing men (mean age 29.6 yr) during normocapnia and hypocapnia with and without inhalation of 50% N2O. 8 isolated human pial arterial segments were mounted in organ baths. The segments were contracted with prostaglandin F2α and subjected to 30% oxygen and 5.6% carbon dioxide in nitrogen or N2O. ResultsNormocapnic young men had a global CBF of 55 ± 4 ml · 100 g−1. min−1. Decreasing end-tidal CO2 tension by 1.3 kPa (9.3 mmHg) reduced CBF uniformly, with a decrease in global CBF to 45 ± 2 ml · 100 g−1. min−1 (P < 0.0001). During normocapnia, inhalation of 50% N2O increased mean CBF to 67 ± 7 ml · 100 g−1. min−1 (P < 0.0001). Inhalation of 50% N2O during hypocapnia increased mean CBF to 63 ± 5 ml · 100 g−1. min−1 (P < 0.0001). During N2O inhalation there was no significant difference in mean CBF between normo- and hypocapnia. However, during hypocapnia, but not during normocapnia, N2O inhalation significantly changed the distribution of regional CBF (P < 0.0001). Compared with hypocapnia without N2O, flow increased through the frontal (143%), parietal (140%) and temporal (133%) regions as well as through insula (151%), basal ganglia (145%) and thalamus (133%). In isolated human pial arteries, addition of N2O changed neither basal tension, nor the contraction elicited by prostaglandin F2α. ConclusionsInhalation of 50% N2O increased global CBF mainly by augmenting flow in frontal brain structures. In contrast, changes in carbon dioxide without N2O affected CBF uniformly in the brain. The uneven change in distribution of the CBF when N2O was added during hypocapnia, the reduced carbon dioxide response, and the lack of effect of N2O on isolated human pial arteries suggest that N2O may increase metabolism in selected brain areas.

Distribution of cerebral blood flow during anesthesia with isoflurane or halothane in humans

BACKGROUND: Halothane and isoflurane have been shown to induce disparate effects on different brain structures in animals. In humans, various methods for measuring cerebral blood flow (CBF) have produced results compatible with a redistribution of CBF toward deep brain structures during isoflurane anesthesia in humans. This study was undertaken to examine the effects of halothane and isoflurance on the distribution of CBF. METHODS: Twenty ASA physical status patients (four groups, five in each) anesthetized with either isoflurane or halothane (1 MAC) during normo- or hypocapnia (PaCO2 5.6 or 4.2 kPa (42 or 32 mmHg)) were investigated with a two-dimensional CBF measurement (CBFxenon, intravenous 133xenon washout technique) and a three-dimensional method for measurement of the regional CBF (rCBF) distribution with single photon emission computer-aided tomography (SPECT; 99mTc-HMPAO). In the presentation of SPECT data, the mean CBF of the brain was defined as 100%, and all relative flow values are related to this value. RESULTS: The mean CBFxenon level was significantly influenced by the PaCO2 as well as by the anesthetic used. At normocapnia, patients anesthetized with halothane had a mean CBFxenon of 40 +/- 3 (SE) ISI units. With isoflurane, the flow was significantly (P < 0.01, 33 +/- 3 ISI units) less than with halothane. Hypocapnia decreased mean CBFxenon (P < 0.0001) during both anesthetics (halothane 24 +/- 3, isoflurane 13 +/- 2 ISI units). The effects on CBFxenon, between the anesthetics, differed significantly (P < 0.01) also during hypocapnia. There were significant differences in rCBF distribution measured between the two anesthetics (P < 0.05). During isoflurane anesthesia, there was a relative increase in flow values in subcortical regions (thalamus and basal ganglia) to 10-15%, and in pons to 7-10% above average. Halothane, in contrast, induced the highest relative flow levels in the occipital lobes, which increased by approximately 10% above average. The rCBF level was increased approximately 10% in cerebellum with both anesthetics. Changes in PaCO2 did not alter the rCBF distribution significantly. CONCLUSIONS: There is a difference in the human rCBF distribution between halothane and isoflurane with higher relative flows in subcortical regions during isoflurane anesthesia. However, despite this redistribution, isoflurane anesthesia resulted in a lower mean CBFxenon than did anesthesia with halothane. (Less)

Responses of Isolated Feline and Human Cerebral Arteries to Prostacyclin and Some of its Metabolites

The effects of prostacyclin (PGI2) were studied in isolated cat basilar and middle cerebral arteries and in human pial arteries. In feline vessels with low resting tension, PGI2 had a contractile effect that reached a maximum of 132% (basilar artery) and 23% (middle cerebral artery) of the potassium-induced (127 mM) contraction. In potassium-contracted feline vessels, PGI2 caused a further contraction. When these vessels were contracted by PGF2α, PGI2 induced relaxation, which was most marked in the middle cerebral artery. PGI2 consistently relaxed the middle cerebral artery contracted by the prostaglandin endoperoxide analogue U-44069, whereas the basilar artery was almost unaffected. In human pial arteries with low resting tension, PGI2 had no effects in concentrations below 10−6 M, whereas higher concentrations induced contractions. In potassium-contracted (35 or 127 mM) preparations, PGI2 in concentrations below 10−6 M produced relaxation; in higher concentrations further contraction was induced. Human pial arteries contracted by PGF2α, U-44069, noradrenaline, or 5-hydroxytryptamine consistently relaxed in response to PGI2 (< 10−6 M). The PGI2 metabolite 6-keto-PGE1 had effects similar to those of PGI2, but proved to be less potent on human pial vessels. 6-Keto-PGF1α was ineffective, whereas 6, 15-diketo-PGF1α had minor relaxant effects. The results suggest that consideration must be given to regional as well as species differences concerning the cerebrovascular effects of PGI2.

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.

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

OBJECTIVEMany 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. METHODSLumbar 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. RESULTSThe 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 &bgr;-endorphins (P = 0.02), corticotropin-releasing factor (P = 0.004), and delta sleep-inducing peptide (P = 0.045) were noted. CONCLUSIONPatients 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.

Prostaglandin metabolism and prostacyclin in cerebral vasospasm

1. Contractions of isolated human pial arteries, induced either by exposition to hemorrhagic cerebrospinal fluid (CSF) from patients with subarachnoid hemorrhage and cerebral vasospasm or by exposition to noradrenaline, were markedly augmented after preincubation of the vessel segments with the cyclooxygenase inhibitor indomethacin, while serotonin-induced contractions were unaffected. 2. Prostacyclin relaxed human pial arteries contracted by either PGF2 alpha, noradrenaline, serotonin or hemorrhagic CSF. The same though less marked effects were obtained with 6-keto-PGE1. 3. The results support the contention that an intact vascular prostacyclin synthesis is important for the maintenance of a normal cerebrovascular tone, and that disturbances of the prostaglandin metabolism may be a prerequisite for the development of arterial spasm after aneurysmal subarachnoid hemorrhage. Tentatively. 4. a prostacyclin deficiency may be involved in the pathogenesis of delayed cerebral vasospasm after subarachnoid hemorrhage.

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 F2α-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 K8644 on vascular responses mediated by α1- and α2-adrenoceptors

Abstract 1. The calcium channel activator Bay K8644 increased the potency of noradrenaline in cat middle cerebral (α2-adrenoceptors) and mesenteric (atypical or mixed α1- and α2-adrenoceptor population) arteries, but not in rat middle cerebral and mesenteric arteries (α1-adrenoceptors). 2. In cat arteries, exposure to 15mM K+ solution shifted the noradrenaline concentration-response curve to the left in an almost identical manner as did Bay K8644. 3. Bay K8644 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 K8644 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 α-adrenoceptor subtype mediating the response.

Clinical Pharmacology of Calcium Channels

Calcium (Ca2+) influx through plasmalemmal channels, driven by the electrochemical gradient for Ca2+, is a crucial step in several biologic processes such as muscle contraction, neurotransmission, and hormone secretion. As regulators of transmembrane charge movements, Ca2+ channels may also be involved in electric events such as impulse generation and propagation. Ca2+ channels may be regarded as ion-selective pores composed of membrane-spanning glycoproteins, which allow Ca2+ to traverse the lipid bilayer in response to different stimuli.1 The best characterized plasmalemmal Ca2+ channels are those activated by membrane depolarization. These channels are the principal targets of the calcium antagonists presently used in clinical therapy. Ca2+ channels insensitive to changes in membrane potential, such as those activated by agonist-receptor interactions, represent another category of membrane channels.

Distribution of Cerebral Blood Flow During Anesthesia with Isoflurane or Halothane in Humans

Background Halothane and isoflurane have been shown to induce disparate effects on different brain structures in animals. In humans, various methods for measuring cerebral blood flow (CBF) have produced results compatible with a redistribution of CBF toward deep brain structures during isoflurane anesthesia in humans. This study was undertaken to examine the effects of halothane and isoflurane on the distribution of CBF. Methods Twenty ASA physical status patients (four groups, five in each) anesthetized with either isoflurane or halothane (1 MAC) during normo‐ or hypocapnia (PaCO2 5.6 or 4.2 kPa (42 or 32 mmHg)) were investigated with a two‐dimensional CBF measurement (CBFxenon, intravenous133 xenon washout technique) and a three‐dimensional method for measurement of the regional CBF (rCBF) distribution with single photon emission computer‐aided tomography (SPECT;99m Tc‐HMPAO). In the presentation of SPECT data, the mean CBF of the brain was defined as 100%, and all relative flow values are related to this value. Results The mean CBFxenon level was significantly influenced by the PaCO2 as well as by the anesthetic used. At normocapnia, patients anesthetized with halothane had a mean CBFxenon of 40 plus/minus 3 (SE) ISI units. With isoflurane, the flow was significantly (P < 0.01, 33 plus/minus 3 ISI units) less than with halothane. Hypocapnia decreased mean CBFxenon (P < 0.0001) during both anesthetics (halothane 24 plus/minus 3, isoflurane 13 plus/minus 2 ISI units). The effects on CBFxenon, between the anesthetics, differed significantly (P < 0.01) also during hypocapnia. There were significant differences in rCBF distribution measured between the two anesthetics (P < 0.05). During isoflurane anesthesia, there was a relative increase in flow values in subcortical regions (thalamus and basal ganglia) to 10–15%, and in pons to 7–10% above average. Halothane, in contrast, induced the highest relative flow levels in the occipital lobes, which increased by approximately 10% above average. The rCBF level was increased approximately 10% in cerebellum with both anesthetics. Changes in PaCO2 did not alter the rCBF distribution significantly. Conclusions There is a difference in the human rCBF distribution between halothane and isoflurane with higher relative flows in subcortical regions during isoflurane anesthesia. However, despite this redistribution, isoflurane anesthesia resulted in a lower mean CBFxenon than did anesthesia with halothane.