Regional cerebral metabolic rate (positron emission tomography) during inhalation of nitrous oxide 50% in humans.

BACKGROUND: Recent studies in man have shown that cerebral blood flow increases during inhalation of nitrous oxide (N2O), a finding which is believed to be a result of an increased cerebral metabolic rate (CMR). However, this has not previously been evaluated in man. METHODS: Regional CMR(glu) (rCMR(glu)) was measured three dimensionally with positron emission tomography (PET) after injection of 2-(18F)fluoro-2-deoxy-D-glucose in 10 spontaneously breathing men (mean age 31 yr) inhaling either N2O 50% in O2 30% or O2 30% in N2. RESULTS: Global CMR(glu) in young men was 27 (3) micromol 100 g(-1) min(-1) [mean (SD)]. Inhalation of N2O 50% did not change global CMR(glu) [30 (5) micromol 100 g(-1) min(-1)] significantly, but it changed the distribution of the metabolism in the brain (P<0.0001 analysis of variance). Compared with inhalation of O2 30% in N2, N2O 50% inhalation increased the metabolism in the basal ganglia [14 (17)%, P<0.05] and thalamus [22 (23) %, P<0.05]. There was a prolonged metabolic effect of N2O inhalation seen on a succeeding PET scan with oxygen-enriched air (P<0.0001) performed 1 h after the N2O administration. CONCLUSIONS: Inhalation of N2O 50% did not change global CMR(glu), but the metabolism increased in central brain structures, an effect that was still present 1 h after discontinuation of N2O.

Cerebral blood volume (CBV) in humans during normo- and hypocapnia: influence of nitrous oxide (N(2)O).

BACKGROUND: It is generally argued that variations in cerebral blood flow create concomitant changes in the cerebral blood volume (CBV). Because nitrous oxide (N(2)O) inhalation both increases cerebral blood flow and may increase intracranial pressure, it is reasonable to assume that N(2)O acts as a general vasodilatator in cerebral vessels both on the arterial and on the venous side. The aim of the current study was to evaluate the effect of N(2)O on three-dimensional regional and global CBV in humans during normocapnia and hypocapnia. METHODS: Nine volunteers were studied under each of four conditions: normocapnia, hypocapnia, normocapnia + 40-50% N(2)O, and hypocapnia + 40-50% N(2)O. CBV was measured after (99m)Tc-labeling of blood with radioactive quantitative registration via single photon emission computer-aided tomography scanning. RESULTS: Global CBV during normocapnia and inhalation of 50% O(2) was 4.25 +/- 0.57% of the brain volume (4.17 +/- 0.56 ml/100 g, mean +/- SD) with no change during inhalation of 40-50% N(2)O in O(2). Decreasing carbon dioxide (CO(2)) by 1.5 kPa (11 mmHg) without N(2)O inhalation and by 1.4 kPa (11 mmHg) with N(2)O inhalation reduced CBV significantly (F = 57, P < 0.0001), by 0.27 +/- 0.10% of the brain volume per kilopascal (0.26 +/- 0.10 ml x 100 g(-1) x kPa(-1)) without N(2)O inhalation and by 0.35 +/- 0.22% of the brain volume per kilopascal (0.34 +/- 0.22 ml x 100 g(-1) x kPa(-1)) during N(2)O inhalation (no significant difference). The amount of carbon dioxide significantly altered the regional distribution of CBV (F = 47, P < 0.0001), corresponding to a regional difference in Delta CBV when CO(2) is changed. N(2)O inhalation did not significantly change the distribution of regional CBV (F = 2.4, P = 0.051) or Delta CBV/Delta CO(2) in these nine subjects. CONCLUSIONS: Nitrous oxide inhalation had no effect either on CBV or on the normal CBV-CO(2) response in humans.

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.

Intracerebral microdialysis in clinical practice: baseline values for chemical markers during wakefulness, anesthesia, and neurosurgery.

OBJECTIVE: The study was undertaken to measure baseline values for chemical markers in human subjects during wakefulness, anesthesia, and neurosurgery, using intracerebral microdialysis. METHODS: Microdialysis catheters were inserted into normal posterior frontal cerebral cortex in nine patients who were undergoing surgery to treat benign lesions of the posterior fossa. The perfusion rate was 1.0 microl/min during anesthesia/neurosurgery and the early postoperative course and 0.3 microl/min during the later course. Bedside biochemical analyses of glucose, pyruvate, lactate, glycerol, glutamate, and urea were performed before, during, and after neurosurgery. After the bedside analyses, all samples were frozen for subsequent high-performance liquid chromatographic analyses of amino acids. RESULTS: The following baseline values were obtained during wakefulness (perfusion rate, 0.3 microl/min): glucose, 1.7+/-0.9 mmol/L; lactate, 2.9+/-0.9 mmol/L; pyruvate, 166+/-47 micromol/L; lactate/pyruvate ratio, 23+/-4; glycerol, 82+/-44 micromol/L; glutamate, 16+/-16 mmol/L; urea, 4.4+/-1.7 mmol/L. Marked increases in the levels of all chemical markers were observed at the beginning and end of anesthesia/surgery. CONCLUSION: The study provides human baseline levels for biochemical markers that can presently be measured at the bedside during neurointensive care. In addition, some changes that occurred under varying physiological conditions are described.

Effects of propofol on isolated human pial arteries.

BACKGROUND: The intravenous anaesthetic propofol has been reported to increase cerebral vascular resistance in vivo. The underlying mechanisms are not fully understood, but may include effects on metabolism and direct effects on the vascular smooth muscle. The present study was designed to evaluate the direct effects of propofol on human pial arteries. METHODS: We investigated the direct effect of propofol (10(-6)-10(-4) M) on isolated human pial arteries at basal tension as well as the influence on contractions induced by 5-hydroxytryptamine, prostaglandin F2alpha, noradrenaline and potassium chloride. RESULTS: Propofol did not change the basal tension. Propofol at 10(-6) and 10(-5) M did not affect the concentration-response curves of any of the contractile agents tested. Propofol at the supraclinical concentration 10(-4) M reduced the contractions induced by all contractile agents. CONCLUSION: Propofol reduces the tone of human pial arteries in vitro at supraclinical concentrations, but has no effect on the tone at clinically relevant concentrations.

Regional cerebral blood flow (SPECT) during anaesthesia with isoflurane and nitrous oxide in humans.

Nitrous oxide and isoflurane have different effects on absolute cerebral blood flow (CBF) and regional distribution of CBF in humans. In this study we examined the effects of isoflurane in combination with nitrous oxide on CBF. We studied 10 patients (two groups of five patients, ASA I) anaesthetized with 50% nitrous oxide and either 0.5 or 1.0 MAC of isoflurane during normocapnia (PaCO2 5.7 kPa) using two-dimensional CBF measurement (CBFxenon) (i.v. 133xenon washout technique) and a three-dimensional method for measurement of regional CBF (rCBF) distribution with SPECT (single photon emission computer-aided tomography with 99mTc- HMPAO). The results were compared with 1.0 MAC of isoflurane from a previous study performed in exactly the same way as the present investigation. During normocapnia, anaesthesia with 50% nitrous oxide and 0.5 MAC of isoflurane resulted in a mean CBFxenon of 45 (SEM 5) ISI units. Increasing the isoflurane concentration to 1.0 MAC had no significant effect on mean CBFxenon (53 (5) ISI units). Both flow values were significantly (P = 0.01) higher than the CBFxenon value obtained when 1 MAC of isoflurane was administered alone (33 (3) ISI units). There were no significant differences in rCBF distribution regardless of whether or not isoflurane was given alone or together with nitrous oxide at 0.5 or 1 MAC. In all situations there were higher relative flows in subcortical regions (thalamus and basal ganglia, 10%) and in the pons (7-10% above average). rCBF in the cerebellum was approximately 10% greater than average. In summary, we have found that mean CBF was greater with combined nitrous oxide and isoflurane anaesthesia than previously found with isoflurane alone; however, relative flow distribution was similar.

SPECT with technetium-99m-HMPAO in relation to late cognitive outcome after surgery for ruptured cerebral aneurysms.

Fifteen patients with a good neurological outcome after aneurysmal SAH and surgery were collected prospectively. Six months after surgery neurological examination and a SPECT study for evaluation of the three dimensional CBF distribution as well as an extensive neuropsychological test were performed. In all patients with pathological SPECT findings the location of the reduced regional CBF correlated with the location of the ruptured aneurysm and/or side of surgical approach. The volume of the brain tissue with reduced rCBF showed a great variety, from 9-112 cm(3) (mean: 33 cm(3)). Similarly, the maximum flow reduction in the affected areas also varied considerably from 17-95% (mean: 39%). In general, the neuropsychological functioning of the patients post SAH was favourable. Seven individuals had a presumably normal neuropsychological appearance with respect to estimates of premorbid levels of functioning. Another four patients were slightly impaired and the remaining four were moderately affected. Only in five cases did the location of SPECT pathology and the site of neuropsychological impairment appear to coincide, whereas this was not the case in the remaining 10 patients. In general, the extent of SPECT pathology did not differ in the three neuropsychological outcome groups (normal, slight and moderate disability).

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.

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

BACKGROUND: Results 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. METHODS: Regional 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 F2 alpha and subjected to 30% oxygen and 5.6% carbon dioxide in nitrogen or N2O. RESULTS: Normocapnic 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 F2 alpha. CONCLUSIONS: Inhalation 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.

Influence of halothane and isoflurane on the contractile responses to potassium and prostaglandin F2 alpha in isolated human pial arteries.

Volatile anaesthetics may modulate cerebrovascular resistance, but their direct actions on human cerebral arteries are unknown. In the present study, we have evaluated the effects of halothane and isoflurane at different MAC (0.4, 1.0 and 2.0) on contractions induced by depolarization (potassium) or receptor stimulation (prostaglandin F2 alpha) in isolated ring segments of human pial arteries. Neither halothane nor isoflurane had significant effects on potency (unaffected EC50 value) or the maximum response (Emax) in potassium-contracted arteries, even though there was a general tendency to attenuation of Emax. Similarly, the potency of prostaglandin F2 alpha was unchanged (unaffected EC50 value). However, the Emax value for prostaglandin F2 alpha at normocapnia (mean PCO2 4.3 (SEM 0.1) kPa, pH 7.41 (0.01)) and addition of halothane (0.4, 1.0 and 2.0 MAC) was significantly attenuated to 96 (2)%, 91 (3)% and 84 (4)% at the respective MAC concentrations. Isoflurane at 2 MAC and normocapnia also reduced Emax to 94 (3)%. During hypocapnia (PCO2 2.7 (0.1) kPa, pH 7.64 (0.01)), the vasodilator effect of halothane was reduced, whereas isoflurane at 0.4 and 1.0 MAC enhanced the contraction induced by prostaglandin F2 alpha.

Endothelium dependence of prostanoid-induced relaxation in human hand veins.

The endothelium dependence of prostanoid-induced relaxation was examined in human isolated hand veins precontracted by endothelin. Indomethacin (10(-6) mol l-1) and the thromboxane A2-receptor antagonist BM 13.505 (10(-6) mol l-1) were present throughout. The endothelium was removed by insufflating carbogen through the vessel lumen. Prostaglandin (PG) F2 alpha, PGE1, PGE2, and prostacyclin (PGI2) elicited concentration-dependent relaxant effects. Removal of the endothelium reduced the relaxation induced by PGF2 alpha and PGE2, but not that elicited by PGE1 and PGI2. The order of potency was PGE2 approximately PGE1 approximately PGI2 > PGF2 alpha regardless of the presence or absence of endothelium. The relaxation elicited by an acidified solution of NaNO2 (generating nitric oxide) was almost identical in intact and endothelium-denuded vein segments. The results are compatible with the existence of two prostanoid receptor populations mediating relaxation: (1) one located on the smooth muscle cells and; (2) another present on the endothelium or possibly on the smooth muscle and modulated by the endothelium. The latter receptor appears to be activated by PGF2 alpha and PGE2, but not by PGE1 and PGI2.

Modulation by carbon dioxide and pH of the contractile responses to potassium and prostaglandin F2 alpha in isolated human pial arteries.

Variation of PCO2 with concomitant changes in extracellular pH (pHo) may modulate cerebrovascular resistance, but the direct actions of carbon dioxide and pHo on human cerebral arteries are unknown. In this study, we have evaluated the effects of different carbon dioxide tensions (2.7, 4.2 and 7.2 kPa) with either fixed (pHo = 7.44) or concomitant changes in pHo, on contractions induced by depolarization (potassium) or receptor stimulation (prostaglandin F2 alpha) in isolated human pial arteries. Isolated changes in PCO2 had no significant effect on either potency (unchanged EC50 value) or the maximum response (Emax) in potassium-contracted arteries. Hypercapnia with uncompensated pHo significantly decreased both EC50 and Emax values, whereas uncompensated hypocapnia significantly increased the EC50 value without any effect on Emax. Concentration-response curves induced by prostaglandin (PG) F2 alpha were shifted significantly to the right (increased EC50 = decreased potency) during both hypo- and hypercapnia, independent of changes in pHo. The maximal responses were enhanced significantly during hypocapnia (Emax = 110 (SEM 2)%), but this enhancement was converted into a slight attenuation when pHo was compensated (Emax = 92 (4)%). Hypercapnia, with or without compensation of pHo, decreased the Emax values to 69 (16)% and 73 (9)%, respectively. We conclude that hypocapnia increases contractility in human pial arteries--an effect which is reversed by compensation of pHo. In contrast, the hypercapnic decrease of PGF2 alpha-induced contractions appears to be independent of pHo. The results confirm a relationship between contractility and pHo, but do not exclude a direct action of carbon dioxide in receptor-stimulated arteries.

Oxygen modulates contractile responses to potassium and prostaglandin F2 alpha in human pial arteries.

Oxygen may modulate cerebrovascular resistance, but its direct influence on human pial arteries is unknown. We have investigated the effects of varying oxygen tension (73, 30 and 8 kPa) in depolarized (potassium) and receptor stimulated (prostaglandin F2 alpha) isolated human pial arteries. Control responses were obtained at an oxygen tension of 30 kPa. Contractions induced by prostaglandin F2 alpha and potassium showed no significant difference in potency (unaffected EC50 values) at the different oxygen concentrations. In contrast, the maximum contractions (Emax) were dependent on the oxygen tension. Potassium-induced contractions were enhanced (Emax = 107 (SE 3)% of control contractions (P less than or equal to 0.01)) at an oxygen tension of 73 kPa, whereas a reduction in tension to 8 kPa had no significant effect (97 (2)%). Prostaglandin F2 alpha-induced contractions were enhanced at 73 kPa (115 (6)%) (P = 0.02) and depressed at 8 kPa (96 (2)%) (P = 0.02). Reduction in oxygen tension induced a relaxation in depolarized and in receptor stimulated arteries, regardless of whether or not oxygen was replaced by nitrogen or by helium. Low oxygen tension relaxed arteries despite pretreatment with 2,4-dinitrophenol, an agent which blocks oxidative phosphorylation. It is concluded that a reduction in oxygen tension exerted a direct, although small, depressant effect on human pial arteries, and that this effect was not mediated exclusively by hyperpolarization or by inhibition of oxidative phosphorylation.

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.

Characterization of contraction-mediating prostanoid receptors in human penile erectile tissues.

The effects of the thromboxane-receptor antagonist L-636,499 were studied on contractions induced by the thromboxane A2 mimic U44069 and by prostaglandin F2 alpha in isolated preparations of the human corpus cavernosum and corpus spongiosum. The objectives were to characterize prostanoid receptors and, in particular, to elucidate whether more than one receptor was involved in prostanoid-induced contraction of penile erectile tissues. L-636,499 at concentrations 10(-6) M to 3 x 10(-5) M induced a parallel shift to the right of the concentration-response curve to U44069 in both corpus cavernosum and corpus spongiosum suggesting competitive antagonism. Schild plots using U44069 as the agonist and L-636,499 as the antagonist revealed slope indexes near unity in both tissues, and the pA2 values were almost identical. In contrast, L-636,499 concentration-dependently reduced the maximum response to prostaglandin F2 alpha, indicating a non-competitive action. The results suggest that the main contraction-mediating prostanoid receptor in human penile erectile tissues is a thromboxane A2 sensitive receptor. However, the presence of more than one contraction-mediating prostanoid receptor cannot be excluded.

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)