Spinal cord stimulation and early experimental cerebral spasm: the "functional monitoring" and the "preventing effect".

BACKGROUND: Clinical and experimental data on cerebral blood flow (CBF) changes during spinal cord stimulation (SCS) were published since 1986. The aims of the present work are: 1. To find an experimental model of reliable, simple and in vivo monitoring of "early" basilar artery spasm after subarachnoid haemorrhage (SAH) and 2. To investigate the effects of cervical spinal cord stimulation (CSCS) on it. Vasospasm due to SAH is both "acute" and "recurrent". Early spasm occurs within minutes of the SAH. its duration is approximately 1 hour. The need of different morphological and haemodynamic methods to evaluate experimental early spasm is reported. To overcome intracranial surgical manipulations and biological effects of contrast and fixation media we designed a model that allows "in vivo" functional monitoring of basilar blood flow far away from the spasm without direct surgical and chemical interference. Subsequently we investigated the effects of CSCS on the new model of "functional monitoring" of the "early" cerebral vasospasm. METHOD: 29 adult Burgundy rabbits were studied. Group 1: under homeostatic monitoring, "on-line" carotid blood flow (carotid BF) changes produced by SAH in cisterna magna of 12 (plus 5 sham treated) animals were studied from the common carotid artery after external carotid artery occlusion before, during SAH and up to the end of the experiments. All the animals underwent digital subtraction cerebral panangiography (CPA) after SAH obtaining a significant increase of carotid BF only when basilar vasospasm was shown by CPA. Carotid BF increase during basilar vasospasm was defined "functional monitoring" of early spasm. Group 2: Twelve animals wearing a cervical epidural electrode underwent carotid BF "functional monitoring" of early basilar spasm before and during CSCS. FINDINGS: Carotid BF changes during CSCS occurred in 10 animals. No carotid BF changes (i.e. no basilar vasospasm) occurred after SAH up to the end of the experiments in all the stimulated animals. INTERPRETATION: CSCS is able to prevent "early spasm" due to SAH in all the animals studied with the new model of "functional monitoring" described, independently from the occurence and the sign for stimulation-induced carotid BF variations. The role and the limits of reversible functional sympathectomy in mediating the effect of CSCS on early vasospam are discussed.

Influenza vaccine in healthy preschool children.

BACKGROUND: Studies of influenza vaccination in healthy children have not definitely answered the question of their efficacy. METHODS: We have carried out a randomized trial in a well selected population of healthy preschool children in Sardinia, Italy. During October 1995, 344 children aged 1 to 6 years, were randomly assigned to receive influenza vaccine (n=177) or no treatment (n=167). Two doses of a trivalent subvirion vaccine, containing 15mg of highly purified surface antigens from the component strains A/Johannesburg/33/94-like, A/Singapore/6/86-like and B/ Beijing/184/ 93-like were administered. Follow-up data were collected from December 1, 1995 through April 30, 1996. RESULTS: Seroconversion was documented in 17 out of 17 children. No specific systemic symptoms or severe local reactions were observed after vaccination. Influenza-like episodes, defined by the presence of fever and cough or sore throat that lasted at least 72 hours, occurred in 63 (37.7%) of unvaccinated children and in 22 (12.4%) of vaccinated ones. The corresponding reduction in disease incidence was 67% (95% CI: 0.59-0.74). Three episodes of otitis were observed among children in the control group versus zero among vaccinated children (p=0.07). Mean duration of day care center absenteism was significantly reduced by vaccination (2.3 days in unvaccinated and 0.5 day in vaccinated children, p<0.001) CONCLUSIONS: Influenza vaccine is safe and effective in healthy preschool children. However the favourable implications of vaccination on disease rate in subsequent years have to be evaluated.

Neuropeptide Y-induced potentiation of noradrenergic vasoconstriction in the human saphenous vein: involvement of endothelium generated thromboxane.

1. We investigated the potentiating effect of low concentrations of neuropeptide Y (NPY) on the vasoconstriction induced by transmural nerve stimulation (TNS) and noradrenaline (NA) in human saphenous veins. The effects of (i) endothelium removal; (ii) the addition of the NO pathway precursor L-arginine; (iii) the ET(A)/ET(B) endothelin receptor antagonist Ro 47-0203; (iv) the cyclo-oxygenase inhibitor, indomethacin; (v) the selective thromboxane A2 (TxA2) receptor antagonists Bay u3405 and ifetroban, and (vi) the TxA2 synthase inhibitor, UK 38485, were studied in order to gain information about the mechanisms of NPY-induced potentiation. 2. Contractile response curves for TNS (0.5-8 Hz) and for exogenously administered NA (0.1-3 microM) were obtained in superfused saphenous vein rings. The contractions induced by both TNS and NA at all tested frequencies and concentrations, respectively, were significantly potentiated by 50 nM NPY in endothelium intact veins. Conversely, in endothelium-denuded vessel rings the contractile-response curves to TNS and NA overlapped both in the absence and presence of NPY, thus suggesting that a release of vasoactive substances from endothelial cells could account for the noradrenergic NPY-induced potentiation. 3. In vessels with intact endothelium, the potentiating action of NPY on TNS and NA was unaffected by the presence of high concentrations of the NO precursor L-arginine (3-10 mM) or the non-selective ET(A)/ET(B) endothelin receptor antagonist, Ro 47-0203 (10 microM). These data indicate that the NPY-induced effect does not involve either the endothelium-derived vasodilator nitric oxide or the vasoconstrictor endothelin. Conversely, in the presence of the cyclo-oxygenase inhibitor, indomethacin (30 microM), NPY failed to potentiate the vasoconstrictions produced by either nerve stimulation or by exogenous NA, thus providing evidence that arachidonic acid metabolites through the cyclo-oxygenase pathway are mainly responsible for the potentiation evoked by NPY. 4. When the TxA2 receptor antagonists, Bay u 3405 (1 microM) and ifetroban (1 microM) were added to the superfusing medium, NPY did not alter either the frequency- or the concentration-response curves for either TNS or NA. Accordingly, both TNS- and NA-induced contractions were not potentiated by NPY in the presence of the TxA2 synthase inhibitor, UK 38485 (10 microM). This clearly demonstrates the pivotal role of TxA2 in NPY-induced potentiation. 5. In superfused vein rings with endothelium, a subthreshold concentration (0.2 nM) of the TxA2 mimetic U 46619 potentiated both TNS- and NA-induced vasoconstrictions. This potentiation was higher at low stimulation frequencies and low NA concentrations, and resembled that produced by NPY. 6. Our results indicate that in the human saphenous vein NPY potentiates the contractions produced by sympathetic nerve stimulation acting at the postjunctional level, primarily on endothelial cells. In particular, the NPY-induced release of a cyclo-oxygenase metabolite, namely TxA2, may have a synergistic effect on the vasoconstriction induced by the noradrenergic mediator. Thus, such a mechanism may play a key role in the maintenance of the sympathetic tone of large human capacitance vessels.

Nitric oxide-dependent and -independent modulation of sympathetic vasoconstriction in the human saphenous vein.

The possible modulation by the endothelium of the contractile responses to sympathetic nerve stimulation was examined in isolated superfused human saphenous vein. Contractile response curves for transmural nerve stimulation and noradrenaline were higher in endothelium-denuded than in intact human saphenous vein rings. In vessels with endothelium, transmural nerve stimulation- and noradrenaline-induced contractions were unaffected by the cyclooxygenase inhibitor, indomethacin (10 microM), but were potentiated by the nitric oxide (NO) synthase inhibitor, L-N omega-nitro-L-arginine (L-NNA, 3 microM) even when combined with D-arginine (0.3 mM), but not with L-arginine (0.3 mM). As in the case of noradrenaline, contractile responses to 5-HT, but not to KCI, were enhanced by endothelium removal, L-NNA or L-NNA plus D-arginine, but were unaffected by L-NNA plus L-arginine. The guanylyl cyclase inhibitor, methylene blue (10 microM), potentiated both transmural nerve stimulation- and noradrenaline-induced contractions in endothelium intact rings, whereas it enhanced, although to a lesser degree, only the neurally evoked contractions in endothelium-denuded human saphenous vein. In the vessels without endothelium L-NNA failed to affect the vasoconstriction induced by both transmural nerve stimulation and noradrenaline. Our results suggest that at least two inhibitory factors are involved in modulating the sympathetic vasoconstriction in the human saphenous vein: (1) at a postjunctional level, NO, the release of which from endothelial cells is probably stimulated by the activation of specific receptors, and (2) at a prejunctional level, an unidentified vasodilator agent, which is unmasked by the removal of the endothelium layer and which is probably co-released along with noradrenaline, and which acts through the guanylyl cyclase pathway.

ETB receptor mediating pulmonary hypertension and bronchoconstriction induced by endothelin-1 in the guinea pig.

Endothelin (ET-1) caused dose-related contraction of isolated superfused bronchus and pulmonary artery and bronchoconstriction and pulmonary vascular hypertension of the heart lung preparation (HLP) of guinea pig. The specific ETA receptor antagonist BQ 123 completely blocked the responses of the pulmonary artery, but failed to affect those of bronchus and of HLPs. The specific ETB receptor agonist Sarafotoxin S6c caused contractions of bronchus, but not of pulmonary artery, and bronchoconstriction and pulmonary hypertension in HLPs. It is concluded that non-ETA subtype receptors, perhaps ETB, appear to be the main responsible for the potent pulmonary hypertensive effects of ET-1.

Mechanisms of pulmonary vasoconstriction and bronchoconstriction produced by PAF in the guinea-pig: role of platelets and cyclo-oxygenase metabolites.

1. The mechanisms of action of platelet activating factor (PAF) in the bronchial and cardiovascular systems have not yet been fully elucidated. In order to characterize better and to ascertain whether the effects of PAF in both these systems may be ascribed to the same mechanisms, we examined the actions of PAF in the heart-lung preparation of guinea-pig (HLP). The role of platelets and of cyclo-oxygenase metabolites was investigated. 2. In HLPs perfused with autologous blood, bolus injections of PAF (4-32 ng) produced major effects at the pulmonary vascular and bronchial levels. Both dose-related pulmonary vascular hypertension and bronchoconstriction produced by PAF were diminished to the same extent (46% and, respectively, 47%) when HLPs were perfused with a medium consisting of homologous red blood cells suspended in physiological solution containing 3.5% dextran (RBC). This suggests that the effects of PAF partially depend on the presence of formed elements. 3. When indomethacin (30 microM) was added to the perfusing blood, the dose-response curve for the pulmonary hypertensive responses produced by PAF was strongly reduced (90%) in comparison to control preparations, whereas the bronchoconstrictor effects of PAF were only partially diminished (23%). These data constitute direct evidence that products of the cyclo-oxygenase pathway exert a major role in the vascular, rather than in the bronchial actions of PAF. 4. In HLPs perfused with RBC containing indomethacin (30 microM), the pulmonary vascular hypertensive responses produced by PAF were almost completely abolished, thus indicating that cyclo-oxygenase products from tissues are involved in these effects. Conversely, PAF administration continued to cause dose-related bronchoconstrictor responses that were reduced only partially in comparison with HLPs perfused with RBC in the absence of the cyclo-oxygenase inhibitor. This implies that PAF also has direct action on the bronchoconstriction evoked.5. At the cardiac level, administration of PAF in HLPs perfused with blood caused a dose-related increase in right atrial pressure accompanied by a decrease in left atrial pressure and cardiac output,which were completely suppressed or attenuated by the absence of formed elements and the addition of indomethacin. This suggests that the progressive heart impairment is secondary to the severe pulmonary hypertension induced by PAF.6. The results of this study performed in the heart-lung preparation of the guinea-pig, which made it possible to simultaneously record cardiovascular and bronchial parameters, indicate that various components are involved in the responses produced by PAF. It is suggested that different mechanisms depending on the relative contribution of these components may account for the PAF-induced effects at the pulmonary vascular and airway levels.

Cardiopulmonary effects of endothelin-1 in the guinea pig: role of thromboxane A2.

The effects of endothelin-1 (ET-1) on the cardiovascular and bronchial systems were examined in a heart/lung preparation of guinea pig. The role of arachidonic acid metabolites through cyclo-oxygease (COX) and lipoxygenase (LOX) pathways was investigated. Bolus injection of ET-1 (25-400 ng) caused dose-related bronchoconstriction, pulmonary vascular hypertension, and cardiac output reduction. When indomethacin (30 microM) or the thromboxane receptor antagonist Bay u 3405 (1 microM) were added to the perfusing blood, the cardiopulmonary effects of ET-1 were almost completely abolished. Conversely, the presence of the LOX inhibitor Bay x 1005 (10 microM) did not affect the ET-1 produced actions. We concluded that ET-1 exerts both bronchial and pulmonary vascular effects through an indirect mechanism. COX products, most likely thromboxane A2 but not arachidonic acid metabolites via the LOX pathway, make the major contribution to the bronchoconstrictor and pulmonary vascular hypertensive effects of ET-1.

Postjunctional regulation by angiotensin II of alpha 1-adrenoceptor-mediated pressor responses in the rat.

The effects of angiotensin II on the vasopressor responses to the selective alpha 1-adrenoceptor agonist, phenylephrine, in intact and sympathectomized rats were investigated. Infusion of angiotensin II at subpressor doses significantly enhanced the pressor effects of phenylephrine in intact rats. We also found that in the chemically sympathectomized rat, where prejunctional sympathetic function is impaired, the effects of angiotensin II infusion on the pressor effects of phenylephrine were similar to those obtained in intact rats. Furthermore, pretreatment with valsartan ((S)-N-valeryl-N-([2'-(1H-tetrazol-5-yl)biphenyl-4-yl]-methyl)-val ine), a new selective angiotensin AT1 receptor antagonist, antagonized the effects of angiotensin II on phenylephrine-mediated pressor responses, whereas the administration of the selective angiotensin AT2 receptor antagonist, PD 123319 (1-[[4-(dimethylamino)-3-methylphenyl]-methyl]-5-(diphenylacetyl)- 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]-pyridine-6-carboxylic acid, ditriflouroacetate, monohydrate), injected in bolus doses of 100 micrograms/kg, did not antagonize the enhancing effect of angiotensin II. Collectively, these data suggest that angiotensin II modulates the response to phenylephrine primarily at a postjunctional level through the activation of angiotensin AT1 receptors and that the suggested prejunctional facilitation mediated by angiotensin receptors is quantitatively much less important in the intact animal.

HLA-DQB1*0305 and -DQB1*0304 alleles among Sardinians. Evolutionary and practical implications for oligotyping.

This study, performed in individuals of Sardinian descent, reports an epidemiologic and molecular analysis of the recently identified DQB1*0304 and DQB1*0305 alleles. These two alleles having a gene frequency of 0.017 and 0.005, respectively, are not uncommon in Sardinia and are distributed fairly uniformly on the island. The analysis of DQB1 second and third exons of the two alleles revealed that although they have always been found included within the same DRB1*0403-DQA1*03 haplotype, they had a different origin. The sequence pattern of DQB1*0305 confirmed that it originated from the DQB1*0302 "recipient" gene by the insertion of a DQB1*0402 nucleotide stretch, within its beta-sheet region, while that of DQB1*0304 suggested that it originated from the DQB1*0301 gene, either by a single point mutation at codon 57 (GCC instead of GAC) or, alternatively, by a segmental transfer of a DQB1*0302 motif, including codon 57, within its alpha-helic region. Independently from the mechanism of generation, the fact that DQB1*0304 originated from DQB1*0301 allele was intriguing considering that, in over 1500 HLA class II Sardinian haplotypes examined, neither the putative parental DRB1*0403-DQA1*03-DQB1*0301 haplotypes were found. Finally, since the assignment of DQB1*0305 may be inaccurate with the traditional panel of probes commonly used for DQB1 oligotyping, the use of an additional oligonucleotide probe is recommended.

Evidence for sympathetic neurotransmission through presynaptic N-type calcium channels in human saphenous vein.

1. The specific type(s) of voltage-sensitive calcium channels (VSCCs) involved in sympathetic neurotransmission have not yet been characterized in human vascular tissues. We therefore examined the functional role of the N- and L-type VSCCs in human saphenous veins. 2. Contractile response curves for transmural nerve stimulation (TNS) and for exogenously administered noradrenaline (NA) were obtained in superfused saphenous vein rings. The contractions induced by TNS, but not by NA, were inhibited by 1 microM tetrodotoxin and by 10 microM guanethidine. Both responses were substantially reduced by 1 microM phentolamine, indicating that the contractions evoked by TNS were mediated by endogenous NA released from noradrenergic nerves. 3. In the presence of 2 microM omega-conotoxin GVIA (omega Conus Geographus toxin, fraction VI A; omega-CgTx), a polypeptide with specific inhibitory activity on N- and L-type calcium channels, the neurally evoked contractions were almost completely abolished. In contrast, the responses induced by exogenous NA were not affected by the neurotoxin, thus providing evidence of the exclusive presynaptic action of omega-CgTx. 4. In the presence of the calcium antagonist verapamil (10 microM), which selectively blocks L-type VSCCs, the contractions induced by both TNS and NA were diminished to the same extent, suggesting that the organic calcium blocker is active only at the postjunctional level. 5. It is concluded that N-type calcium channels are the main pathway of calcium entry controlling the functional responses induced by activating sympathetic nerves; the role of L-type channels appears to be limited to the postjunctional level, modulating smooth muscle contractions.

Combinations of specific DRB1, DQA1, DQB1 haplotypes are associated with insulin-dependent diabetes mellitus in Sardinia.

The Sardinian population has an extremely high incidence of IDDM (30.2 of 100.000 in the age group of 0-14 years). This study reports the molecular characterization of HLA class II genes in 120 IDDM sporadic patients and 89 healthy subjects of Sardinian origin. Compared with other Caucasians, both Sardinian patients and controls had an unusual distribution of haplotypes and genotypes. In particular, there was a high gene frequency of the DRB1*0301, DQA1*0501, DQB1*0201 susceptibility haplotype both in patients (0.58) and controls (0.23) while a reduction of the DRB1*1501, DQA1*0102, DQB1*0602 protective haplotype (0.03) was observed in the healthy population. This distribution may partially explain the high incidence of IDDM reported in Sardinia. The analysis of the DQ beta 57 and DQ alpha 52 residues showed that the absence of Asp 57 and the presence of Arg 52 were associated with IDDM in a dose-response manner. On the other hand, we found that (a) a very similar distribution of these residues was found when comparing Sardinians with another healthy Caucasian population from the same latitude but with a lower rate of IDDM incidence; (b) several genotypes encoding the identical DQ alpha 52/DQ beta 57 phenotype carried very different relative risks; and (c) the DRB1*0403, DQA1*0301, DQB1*0304 haplotype (DQ beta 57 Asp-neg and DQ alpha 52 Arg-pos) was found in 40% of the DR4-positive controls but not in patients (p = 0.00034), while the DRB1*0405, DQA1*0301, and DQB1*0302 haplotype carrying the same residues at the same positions was found in 70% of the DR4-positive patients and in only one control (p = 0.00003). These findings suggest that IDDM susceptibility cannot be completely explained by the model in which only DQ alpha 52 and DQ beta 57 residues are taken into account.

In vivo metabolism of fluorescent ceramide in central nervous system myelin of adult rats.

The metabolism of sphingolipids in the central nervous system (CNS) has been studied in adult rats by intraventricular administration of fluorescent ceramide (CER). Rats were sacrificed at various time points post inoculation and the fluorescence of CER, cerebrosides (CB), sulfatides (SULF) and sphingomyelin (SPM) was determined in the CNS myelin and in the pellet, containing mainly microsomes, obtained by Norton myelin preparation. The incorporation of fluorescence was more in the pellet than in the myelin at all times studied. Initially the fluorescence present in the pellet was prevalently due to untransformed CER but an increase of fluorescent products with time was observed. CB was the main product up to 2 h post inoculation, then it decreased with concomitant increase of fluorescent SULF. In the myelin we did not observe differences in incorporation and transformation of fluorescent CER with time: CB was the main fluorescent product at all times studied. At 0.5 h post inoculation the fluorescence, observed by fluorescence microscope, was located in the cell lining the ventricles while after 24 h it appeared also in the paraventricular areas.

Thromboxane generation and pulmonary reactivity to arachidonic acid in heart-lung preparation of guinea-pig: modulation by PCO2.

A dose-related increase of pulmonary vasoconstrictive and bronchoconstrictive effects, as well as of the amounts in the perfusing fluid of TXB2, the stable metabolite of TXA2, was obtained through administration of arachidonic acid (AA) in normocapnic and deeply hypocapnic guinea-pig heart-lung preparations (HLPs) perfused with homologous red blood cells suspended in a modified Tyrode solution. Pulmonary hypertensive effects and the amounts of TXB2 detected in the perfusing fluid were reduced in hypocapnic preparations as compared with the normocapnic ones, while the bronchoconstrictive responses to AA were not affected by CO2 tension. It is concluded that: a) biosynthesis of TXA2 is reduced in hypocapnic group if compared with that observed in normocapnic one, b) the quantitative change of AA metabolism is responsible for hypocapnia reduction of pulmonary vasoconstrictive effects of AA, c) stability of bronchoconstriction due to AA infusions in normocapnic and hypocapnic HLPs might indicate an up regulation for TXA2 bronchial smooth muscle receptors by hypocapnia.

Effects of dihydrotestosterone treatment on adrenal gland function and morphology in adult female guinea-pigs.

The effect of chronic treatment of female guinea-pigs with dihydrotestosterone (DHT) on growth and function of the adrenal gland and, in particular, on the reticular zone is described. Two groups of 6 young adult, female guinea-pigs were treated with DHT (1 mg/kg dissolved in peanut oil and injected s.c.) for 30 and 60 days. Two other groups of animals, treated only with oil, were used as controls. At the end of treatment, animals were killed and adrenal glands were quickly removed. Plasma levels of pregnenolone, dehydroepiandrosterone (DHA) and its sulfate (DHA-S), 17 alpha-hydroxyprogesterone, androstenedione, testosterone, estradiol, 11-deoxycortisol, androstenedione, DHT and 3 alpha-androstanediol were determined by R.I.A. following celite microcolumn chromatography. Animals treated for 30 days showed only elevated DHT and 3 alpha-androstanediol plasma levels, whereas animals treated for 60 days also showed increased values of pregnenolone (251 +/- 62 vs 193 +/- 51 ng/dl; P less than 0.05), DHA-S (12,046 +/- 4110 vs 2780 +/- 888 ng/dl; P less than 0.001) and slightly increased values of DHA (110 +/- 31 vs 86.5 +/- 55.4). In the 30-day-treated animals no histological changes were observed, but in the 60-day-treated group the total size as well as cell volumes of the zona reticularis were significantly increased. Normal estrous cycles were observed in the 30-day-treated animals whereas the 60-day-treated animals showed a progressive acyclicity during the second month of treatment. These results indicate that in guinea-pigs, prolonged treatment with DHT induces a growth of the zona reticularis of the adrenal gland associated with increased levels of 5-ene steroids, particularly DHA-S. The mechanisms inducing these modifications are probably mediated by a DHT effect at the hypothalamic-pituitary level. A direct effect of DHT on the zona reticularis, however, cannot be excluded.

Hepatic uptake and metabolism of free cholesterol from different lipoprotein classes. An in vivo study in the rat.

Hepatic metabolism of [14C]cholesterol, vehiculated by LDL, HDL2 and HDL3 lipoprotein particles, has been studied in rats with a permanent biliary drainage. The lipoprotein fractions were infused individually by a jugular vein catheter and bile was collected for 180 min after the administration. At the end of this period, the animals were killed and the blood and livers were collected. The free cholesterol of the HDL2 fraction was secreted into bile, mainly as bile salt, preferentially to that associated with HDL3 and LDL fractions (11.7% vs. 2.3% and 0.3%, respectively). The free cholesterol of the HDL3 fraction, on the other hand, was taken up by liver more quickly and in a higher proportion than that associated with other lipoprotein fractions. The label incorporation in this lipoprotein fraction was secreted earlier and not transformed into bile. The contribution of LDL-vehiculated free cholesterol to bile secretion was small and the hepatic uptake amounted to no more than 12% of the injected label.

G6PD deficiency and breast cancer.

A study of the relative 2dG6P utilization in mononuclear cells from a group of 150 women with breast cancer was undertaken to evaluate a possible negative correlation between G6PD deficiency and cancer, as suggested by some authors. Twenty-one women (14.00%) were heterozygotes and 2 were homozygotes (1.33%). The prevalence found was not different from that expected. It would therefore seem that the G6PD Mediterranean allele does not play a protective role against the development of breast cancer.

Arachidonic acid and pulmonary function in heart-lung-preparation of guinea-pig: modulation by PCO2.

In normocapnic and deeply hypocapnic guinea-pig heart-lung-preparations (HLPs), dose-response relationships were estimated for the bronchoconstrictor and pulmonary hypertensive responses to histamine (H), 5 hydroxytryptamine (5HT), arachidonic acid (AA) and U-46619, a prostaglandin endoperoxide analogue acting on thromboxane (TXA2) receptors. Hypocapnia potentiated in a different way the bronchoconstrictor effects of AA (increased slope of dose-response curve) and of U-46619 (shift to the left of the curve). The pulmonary vascular effects of U-46619 were unaffected by CO2 tension, whereas a linear log dose-dependence of the pulmonary hypertensive responses to AA was present only in hypocapnic HLPs. The amount of TXA2-like material released in normocapnic HLPs was compatible with the AA/U-46619 potency ratio calculated for the bronchoconstrictor responses in normocapnic HLPs and for the pulmonary vascular responses in hypocapnic HLPs. The above described effects of hypocapnia were different from those produced on the bronchial and pulmonary vascular reactivity to H and 5HT, suggesting that specific mechanisms are involved in the modulating effect of PCO2. The inhibition by indomethacin of AA-induced pulmonary vasoconstriction was unaffected by changes in CO2 tension; conversely, the bronchoconstrictor effects of AA were more substantially reduced by indomethacin in normocapnic HLPs. It is concluded that: the relative contribution of different AA metabolites to the final response of the airway system to the precursor is affected by changes in CO2 tension; different receptorial or prereceptorial mechanisms are involved in the CO2-AA interaction taking place in the two components of the lung parenchyma; the pulmonary outflow of AA metabolites provides only circumstantial evidence of the functional meaning of this release.