Identification of α1-adrenoceptor subtypes in the dog prostate

Summary The ₁-adrenoceptor subtypes of dog prostate were characterized in binding and functional experiments. In saturation experiments, [³H]prazosin bound to ₁-adrenoceptors with high affinity. In the displacement experiments, unlabelled prazosin and WB4101 biphasically inhibited the binding of 400 pM [³H]prazosin, suggesting the presence of at least two distinct affinity sites for prazosin or WB4101. The proportion of high-affinity sites was approximately 10%. HV723 also recognized two distinct affinity sites but the proportion of high-affinity sites was approximately 20%. From these results the presence of three distinct ₁-adrenoceptor subtypes was suggested: presumably subtypes _1A (high affinity for prazosin and WB4101), _1N (high affinity for only HV723) and _1L (low affinity for the three antagonists) according to the recently proposed ₁-adrenoceptor subclassification. The density of subtype _1L was much higher than that of subtypes _1A and _1N subtypes. In the functional experiments, prazosin, WB4101 and HV723 competitively antagonized the contractile response to noradrenaline with low affinities close to those estimated for the _1L subtypes. These results suggest that the contractile response to noradrenaline in the dog prostate is mediated predominantly through _1L subtype -adrenoceptors.     

Serum α1-microglobulin and β2-microglobulin for the estimation of fetal glomerular renal function

As proteins cannot cross the placenta levels of the microproteins ₁-microglobulin (₁MG) and ₂-microglobulin (₂MG) can be used to assess fetal glomerular renal function. ₁MG, ₂MG and creatinine were routinely determined in cord and maternal blood of 133 newborns [gestational age (GA) 25–42 weeks]. Twenty-nine patients with suspected impaired maternal or fetal renal function were studied separately and two fetuses were studied in utero. The mean fetal ₂MG concentration fell from 3.87±0.56 mg/l in the 25–31 weeks GA group to 2.60±0.50 mg/l in the mature newborn group. ₁MG concentration fell from 3.10±0.51 to 2.25±0.49 mg/dl. In contrast, the mean maternal ₁MG concentration rose from 1.73±0.69 mg/l in the 25–31 weeks GA group to a mean of 1.83±0.48 mg/l in the mature newborn group; ₁MG rose from 3.96±0.58 to 4.33±1.6 mg/dl. Maternal and fetal creatinine levels were identical. Fetal microprotein levels fall during intra-uterine development as glomerular filtration rate (GFR) rises. There is no correlation between cord blood and maternal ₁MG or ₂MG concentrations. In 13 children with urological anomalies only 1 had elevated microprotein levels and he later developed renal insufficiency. Determination of microprotein levels in fetal serum can be used to detect severe renal function disturbances and to estimate GFR independently of maternal renal function.     

Effect of tumor necrosis factor-α and interferon-γ on the growth of human prostate cancer cell lines

Human recombinant tumor necrosis factor- (rTNF-, 10^-12–10^-8 M) inhibited the proliferation of androgen-dependent LNCaP cells by 32–56%. In contrast, proliferation of androgen-independent PC-3 and JCA-1 cells was only slightly inhibited, or not inhibited at all, respectively. Human recombinant interferon- (rIFN-, 500 U/ml) decreased proliferation of PC-3 and JCA-1 cells by 35% and 53%, respectively, but had no effect on LNCaP cells. Interestingly, the combination of rIFN- and TNF- had greater antiproliferative effects on JCA-1 cells than treatment with either cytokine alone. However, the antiproliferative effects of this combination were similar to those observed for PC-3 or LNCaP cells treated with rIFN- or TNF- alone, respectively. These data suggest that some forms of androgen-independent prostate cancer may benefit from a combination therapy of IFN- and TNF-, while the use of IFN- alone may be more efficacious in others.     

Bone-resorbing activities of 24-epi-1α-hydroxyvitamin D2 and 24-epi-1α,25-dihydroxyvitamin D2

Bone-resorbing activities of 24-epi-1-hydroxyvitamin D₂ [24-epi-1(OH)D₂], 24-epi-1,25-dihydroxyvitamin D₂ [24-epi-1,25(OH)₂D₂], and 1,24S,25-trihydroxyvitamin D₂ [1,24S,25(OH)₃D₂], which might be a metabolite of 24-epi-1,25(OH)₂D₂, were investigated. In an in vitro bone resorption test, the activity of 24-epi-1(OH)D₂ was similar to that of 1-hydroxyvitamin D₃ [1(OH)D₃] at 10^-9 M-10^-6 M. The activity of 24-epi-1,25(OH)₂D₂ was weaker than that of 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] at 10^-11 M-10^-8 M. On the other hand, the activity of 1,24S,25(OH)₃D₂ was similar to that of 24-epi-1,25(OH)₂D₂ at 10^-11 M-10^-9 M. In the formation assay of osteoclast-like cells, the activity of 24-epi-1(OH)D₂ was weaker than that of 1(OH)D₃ at 10^-7 M. The activity of 24-epi-1,25(OH)₂D₂ was almost similar to that of 1,25(OH)₂D₃ at 10^-11 M-10^-7 M. The activity of 1,24S,25(OH)₃D₂ was significantly weaker than that of 24-epi-1,25(OH)₂D₂ at 10^-11 M-10^-9 M. In the two experiments, the potencies of 24-epi-1,25(OH)₂D₂ were about 100 times higher than those of 24-epi-1(OH)D₂. In an in vivo/in vitro bone resorption test, the activity of 24-epi-1(OH)D₂ was almost similar to those of 1(OH)D₃ and 1,25(OH)₂D₃ and higher than those of 24-epi-1,25(OH)₂D₂ and 1,24S,25(OH)₃D₂. 24-epi-1-(OH)D₂ and 1(OH)D₃ were longer lasting than 24-epi-1,25(OH)₂D₂ and 1,25(OH)₂D₃ in this experiment. These results suggested that 24-epi-1(OH)D₂ as well as 1(OH)D₃ was converted into dihydroxy form in vivo.     

Neue Einblicke in die Rolle der Östrogene und ihrer Rezeptoren im Prostatakarzinom

Zusammenfassung In der vorliegenden Übersicht werden neue Befunde über die differenzielle Expression von Östrogenrezeptoren und östrogenregulierter Zielgene in der Prostata und im Prostatakarzinom zusammengefasst und ihre Bedeutung für die Tumorentstehung und Androgenresistenz diskutiert. Die beiden Östrogenrezeptoren und (ER, ER) werden in funktionell unterschiedlichen Kompartimenten des Prostataepithels exprimiert; der ER im Proliferationskompartiment (Basalzellschicht), der ER im Differenzierungskompartiment (sekretorisches Epithel).Bei der malignen Transformation des Prostataepithels (high-grade-prostatische intraepitheliale Neoplasie, HGPIN) verlagert sich die ER-Expression in das Differenzierungskompartiment und vermittelt als Onkogen kanzerogene Effekte auf das Prostataepithel. Der ER, ein potenzieller Tumorsuppressor, geht in der HGPIN partiell verloren, wodurch die protektive Wirkung der Phytoöstrogene auf das transformierte Prostataepithel abgeschwächt wird. Das Prostatakarzinom zeigt unabhängig von Grading und Staging hohe Expressoinsraten des ER. Erst im Stadium der Androgenresistenz geht der androgenregulierte ER partiell verloren. Im Gegensatz zum Mammakarzinom ist die Expression des klassischen ER und des Progesteronrezeptors im Prostatakarzinom ein spätes Ereignis in der Tumorprogression und ist maximal in Metastasen und hormonrefraktären Tumoren ausgeprägt. Etwa 30% der metastasierten und androgeninsensitiven Prostatakarzinome zeigen hohe Expressionsraten des ER regulierten Progesteronrezeptors. Das Antiöstrogen Raloxifen wirkt in androgeninsensitiven Prostatakarzinomzelllinien wachstumsinhibitorisch und induziert dosisabhängig den programmierten Zelltod.Aufgrund dieser Befunde sind Patienten mit androgeninsensitiven Prostatakarzinomen potentielle Kandidaten für eine Antiöstrogen- bzw. Antigestagentherapie. Klinische Studien müssen die Effizienz einer solchen Therapie prüfen.     

Receptor function studies in specimens from the proximal human urethra obtained by transurethral resection

Summary During transurethral resection (TUR) for prostatic hyperplasia, specimens were taken from the proximal urethra. Muscle strips thus obtained were mounted in an organ bath and muscle contraction was induced by adding increasing concentrations of noradrenaline (NA), methoxamine (₁-agonist) and clonidine (₂-agonist). NA and methoxamine induced a dose-dependent muscle contraction, but clonidine had no effect. The influence of prazosin (₁-antagonist) and yohimbine (₂-antagonist) on the NA-induced muscle contraction was also evaluated. Both antagonists had an inhibitory effect,which was much more potent with prazosin. The specimens taken during TUR were found to be suitable for in vitro receptor function studies. The -adrenergic receptor function in the proximal human urethra was found to be mainly of the -type.     

Influence of intravesical administration of tumor necrosis factor α and systemic γ-interferon on murine bladder cancer: Lack of dose response

Summary The effect of intravesical administration of high dose recombinant tumor necrosis factor- (rTNF) and in combination with systemic recombinant -interferon (rIFN) on murine bladder cancer was studied. RTNF was given at 12.5 g/mouse on days 7, 11 and 15 after tumor instillation or at 2.5 g/mouse on days 7, 9, 11, 13 and 15. Some groups were also injected i.v., 24-h prior to each rTNF treatment with rIFN at a dose of 1.3 g/mouse. RTNF treatment suppressed tumor growth up to 48% of control, although the difference was not statistically significant. Combined administration of rIFN did not provide additional benefit.     

Changes in the productivity of cytokines and active-oxygen in peripheral blood cells following surgery

An investigation was carried out on the productivity of cytokines and active-oxygen by peripheral blood cells during the pre- and post-operative periods. While the preoperative production of tumor necrosis factor (TNF) and interleukin-l (IL-1) was elevated, that of lymphotoxin (LT) and interferon- (IFN-) were slightly suppressed. In the postoperative period the peak TNF and IL-1 and active-oxygen productivity was elevated, while LT and IFN- productivity was suppressed in patients with an intraoperative bleeding volume of more than 1,000 ml compared to those with that of less than 1,000 ml. Thus, stress stimulates the TNF and IL-1 and active-oxygen producing system, that is, the macrophage-neutrophil system, and suppresses the LT and IFN- system, being, the inflammatory helper T cell system, in the early postoperative period.     

Urinary unconjugated 5α-androstane-3α, 17β-diol in patients with prostatic tumours

Summary A sensitive and reliable radioimmunoassay (RIA) for urinary unconjugated 5-androstane-3, 17-diol is described. The mean overall recovery of unconjugated 5-androstane-3, 17-diol was found to be 57.4%. The sensitivity of the assay was 79 fmol per assay tube and the intra and inter-assay variations ranged between 7.2% and 11.4%. The mean ± SEM for the concentration of this androgen in the urine of normal men was 339.6±66.8 nmol/24h. The corresponding values for patients with benign prostatic hypertrophy (BHP) and carcinoma of the prostate (Ca) were 297.8±44.7 and 1592.1±622.7 respectively. The mean value for Ca patients was significantly higher than either BPH (p<0.05) or normal subject (p<0.02), suggesting a differential urinary excretion pattern for unconjugated 5-androstane-3, 17-diol between BPH and Ca patients. It is concluded that the combined measurement of this androgen in the plasma and urine provides a more accurate assessment of the profile of this hormone than a single plasma estimation.     

Natural human IgG inhibits the production of tumor necrosis factor-α and interleukin-1α through the Fc portion

The overproduction of cytokines such as the tumor necrosis factor- (TNF-) and interleukin-1 (IL-1) may cause further deterioration in the already critical condition of patients with shock, sepsis, and acute inflammation. The effectiveness of infusion therapy of natural human IgG to such patients is suggested to depend partly upon the inhibition of the productivity of these cytokines. In this study, we investigated the modulation effects of IgG and its fragments on the production of TNF- and IL-1, on human peripheral blood mononuclear cells (PBMC). The production of TNF- and IL-1 was found to be dose-dependently inhibited by IgG when stimulated by lipopolysaccharide (LPS), phytohemagglutinin (PHA), concanavalin A (Con A), and interleukin-2 (IL-2). However, no inhibition was seen when stimulated by phorbormyristate acetate (PMA). The F(ab)₂ fragment showed enhancing effects on cytokine production by LPS, while the Fc fragment showed not as much inhibitory effect as whole intact IgG. IgG showed no direct cytotoxic effect on PBMC. These data suggest that natural human IgG inhibits TNF- and IL-1 production by PBMC through the Fc portion. The results of this study led us to conclude that whole intact IgG may be the best form of therapeutic delivery.     

The Normal and Malignant Mammary Gland: A Fresh Look with ERβ Onboard

Estrogens are important for the development and function of the normal mammary gland as well as for development of mammary cancer. The frontline therapy for treatment of estrogen receptor (ER)⁴ positive breast cancer is antiestrogens. A second estrogen receptor (ER) is also expressed in the breast but it has not been measured because it is not detected by the immunoassays used to detect ER. In many cell systems ER has actions which are opposite to those of ER and this finding has raised questions about the role of ER in the development and treatment of breast cancer.     

G-Proteins in alpha1-adrenoceptor mediated prostatic smooth muscle contraction

The role of signal transducing guanine-nucleotide binding proteins (G-proteins) in ₁-receptor mediated smooth muscle contractions was investigated in human hyperplastic prostatic tissue. The selective ₁-receptor agonist phenylephrine (PE) evoked dose dependent contractions antagonized by the ₁-receptor blockers prazosin (EC₅₀ 10 nM) and YM 617 (EC₅₀ 3 nM). Application of nifedipine (1–10,000 nM), a blocker of voltage-dependentl-type Ca^2--channels (VDCC), inhibited the PE evoked contraction up to 65.4%. Pretreating the tissue strips with pertussis toxin (PTX, exotoxin from Bordetella pertussis; 5–25 g/ml), inactivating a subpopulation of G-proteins, inhibited the PE induced contractions up to 73.9%. PTX pretreatment had no effect on contractions elicited by 125 mMK^-. Application of nifedipine to PTX pretreated tissue led to an additional inhibition of 13.7%. Our findings demonstrate the involvement of PTX-sensitive G-proteins in the signal transduction pathway of ₁-receptor induced contractions of prostatic smooth muscle. The remaining contractility of PTX pretreated tissue suggests additional participation of PTX insensitive mechanisms in ₁-receptor mediated prostatic smooth muscle contractions.     

Hyperthermic Isolated Perfusion With Low-Dose Tumor Necrosis Factor α and Doxorubicin for the Treatment of Limb-Threatening Soft Tissue Sarcomas

Background Tumor necrosis factor (TNF)-–based hyperthermic isolated limb perfusion (HILP) is one of the most active available approaches for locally advanced soft tissue sarcomas (STS) of the limbs. The aim of this study was to investigate the anticancer activity of a novel drug regimen including doxorubicin (DXR) and low-dose TNF-.Methods HILP with low-dose TNF- (1 mg) and DXR (8.5 mg/L of limb volume) was given to 21 patients with limb-threatening STS: 14 had primary and 7 had recurrent STS, most of which were high grade (grade 1, n = 3; grade 2, n = 6; grade 3, n = 12). Resection of the tumor remnant was performed 6 to 8 weeks after HILP. TNF- concentrations in plasma and perfusate were measured throughout perfusion.Results A major tumor response was observed at histology and clinical evaluation in 90% and 62% of patients, respectively. After a median follow-up of 30 months, limb salvage and local disease control were achieved in 71% and 81% of cases, respectively. Fourteen patients had moderate regional toxicity, which was resolved in all cases. One patient had severe limb toxicity, which did not require amputation. Systemic side effects were minimal, and there were no postoperative deaths. The perfusate/plasma area under the curve ratio for TNF- was 56.Conclusions HILP with low-dose TNF- and DXR seems to be an active neoadjuvant drug regimen against limb-threatening STS. This therapeutic approach can achieve high limb-sparing surgery rates with acceptable local and negligible systemic toxicity.     

Fibrinogen osaka IV: A congenital dysfibrinogenemia found in a patient originally reported in relation to surgery,now defined to have an Aα arginine-16 to histidine substitution

We discovered a congenital heterozygous dysfibrinogen in a patient and reported this case in relation to surgery some time ago (Jpn J Surg (1988) 18:43–46).³ Further studies on the isolated abnormal population of fibrinogen derived from this patient have revealed that fibrinopeptide A was not cleaved by ancrod, a snake venom-derived thrombin-like enzyme, but by thrombin, slowly but completely. The released fibrinopeptide A components, being the A, AY, and AP peptides, were all found to be abnormal, as evidenced by slightly earlier elution positions on high-performance liquid chromatography, compared with the normal counterparts. By analyzing their amino acid sequence, we have identified an arginine to histidine substitution at position 16 of the A chain, the thrombin cleavage site. Utilizing insolubilized abnormal fibrinogen, we confirmed that the polymerization site assigned to the central E domain, the A site, was exposed by thrombin, but not by ancrod. This dysfibrinogen, designated as fibrinogen Osaka IV, is the second abnormal molecule with an A arginine-16 to histidine substitution identified among Japanese families.     

Pied plat réductible traité par la vis d’expansion du sinus du tarse. À propos de 30 cas

Résumé: Dans un pied plat, lobjectif de larthrorise subtalaire est de rétablir des rapports appropriés entre le talus et le calcanéum par limplantation dun espaceur. Le but de cette étude est dévaluer les résultats de la vis dexpansion du sinus du tarse ainsi que le devenir des pieds au recul. Matériel: Trente patients porteurs de pied plat réductible et symptomatique ont participé à cette étude. Il sagissait de 28 hommes et de 2 femmes. Lindication opératoire a été posée sur la coexistence dun handicap fonctionnel liée à la douleur et de léchec du traitement orthopédique. Lâge moyen au moment de lintervention était de 21 ans. Langle de Djian-Annonier était de 134°. Méthodes: Il sagissait dune étude rétrospective. Létat fonctionnel global était évalué au moyen du score de Kitaoka. Résultats: Le recul moyen était de 4 ans. Plus aucun patient ne portait de chaussure orthopédique. Nous navons pas de remaniements articulaires dégénératifs au recul. Le résultat global était: 20 très bien, 4 bien, 2 passable, 4 mauvais. Discussion: Larthrorise par espaceur du sinus du tarse est un geste techniquement simple permettant une correction podoscopique significative du pied plat qui se maintient à la révision. Conclusion: Cette technique simple permet dobtenir des résultats anatomiques et fonctionnels satisfaisants.* Les figures de cet article sont disponibles en couleur sur le site springerlink.com     

TNFα-stimulated gene product (TSG-6) and its binding protein, IαI, in the human intervertebral disc: new molecules for the disc

Inflammation and irritation of the nerve roots has been indicated as an important factor in the pain associated with symptomatic disc herniations. Tumour necrosis factor (TNF) is now believed to be involved in this pathway. TNF causes connective tissue cells in culture to synthesise a glycoprotein, TNF-stimulated gene-6 (TSG-6). TSG-6 is found in inflammatory diseases of related connective tissues, such as articular cartilage in rheumatoid arthritis, but is not present in unaffected individuals. In order to determine if TSG-6 occurred in intervertebral disc (and cartilage endplate), we have investigated the presence of TSG-6 and its binding protein, inter--inhibitor (II), in 58 herniated and 15 non-herniated discs. Immunostaining for the cytokines, IL-1, IL-1 and TNF, has also been carried out. We have demonstrated that both TSG-6 and II occur commonly in human intervertebral disc matrix with at least some TSG-6 in 98% of discs studied and II in all of them. Staining for TSG-6 was greatest in herniated discs, particularly close to blood vessels. II immunostaining was frequently widespread throughout the disc but there was little in the cartilage endplate. It has been proposed that these molecules have widespread effects, including extracellular matrix stabilisation, down-regulation of the protease network and reduction of inflammation. Hence, the occurrence of TSG-6 and II in disc tissue could have implications in the aetiopathogenesis and future therapeutics of intervertebral disc disease.     

Functional Down-Regulation of β1 and β2 Integrins on Lamina Propria Lymphocytes (LPL) and Tumor-Infiltrating Lymphocytes (TIL) in Colorectal Cancer Patients

Integrins play an important role in various lymphocyte functions. In this study, we isolated lamina propria lymphocytes (LPL) and tumor-infiltrating lymphocytes (TIL) from normal and malignant tissues in patients with colorectal cancer, and examined the expression of 1 and 2 integrins on these lymphocytes quantitatively with two-color flow cytometry. Both LPL and TIL expressed a lower level of common 1 chain (CD29) in CD4 and CD8 subpopulations than did peripheral blood lymphocytes (PBL). Among the associated chains, the expression levels of 1 (CD49a) and 2 (CD49b) were slightly higher, whereas those of 4 (CD49d) and 6 (CD49f) were markedly reduced in LPL and TIL. No significant differences were observed in expressions of any 1 integrin chains between these two lymphocytes populations. Similarly, both L (CD11a) and 2 (CD18) were down-regulated in TIL and LPL with CD8⁺ cytotoxic phenotype, but not in those with CD4⁺ phenotype. CD8⁺ TIL expressed a slightly but significantly higher level of L2 than did CD8⁺ LPL. CD8⁺ LPL and CD8⁺ TIL consistently showed significantly decreased binding to purified ICAM-1, VCAM-1 and HT29 colon cancer cells as compared with CD8⁺ PBL. Although CD8⁺ TIL showed a slightly higher level of adhesion to these substrates than did CD8⁺ LPL, the level was much lower than that in PBL. The expression pattern and functional down-regulation of these integrins may be one of the reasons why TIL cannot eradicate the cancer cells in colorectal cancer.     

The association between transforming growth factor-β gene promoter C-509T polymorphism and Chinese children with Henoch-Schönlein purpura

Many cytokines, including transforming growth factor- (TGF-) and tumor necrosis factor- (TNF-), are involved in the inflammatory process of Henoch-Schönlein purpura (HSP). The objective of this study was to investigate whether TGF- C-509T and TNF- G-308A polymorphisms are associated with childhood HSP. The loci of interest were amplified from genomic DNA using specific primers and polymerase chain reaction, and these two polymorphisms were compared between Chinese children with HSP and healthy controls. The disease severities evaluated and expressed as symptom score of patients with different genotypes were also compared. The TGF- -509 TT genotype was more common in children with HSP than controls (31% vs. 8%, P =0.03, odds ratio=4.95). The allelic frequencies of TGF- -509, genotypic and allelic frequencies of TNF- -308 were not significantly different. Patients with the TT genotype had more severe clinical presentations than non-TT (TC+CC) patients (4.1±0.42 vs. 2.7±0.31, P =0.018). These results suggest that the TT genotype of the C-509T polymorphism of the TGF- gene might be related to the susceptibility of Chinese children to HSP and to the severity of this disease.     

Intratumoral IL-12 and TNF-α–Loaded Microspheres Lead To Regression of Breast Cancer and Systemic Antitumor Immunity

Background: Local, sustained delivery of cytokines at a tumor can enhance induction of antitumor immunity and may be a feasible neoadjuvant immunotherapy for breast cancer. We evaluated the ability of intratumoral poly-lactic-acid-encapsulated microspheres (PLAM) containing interleukin 12 (IL-12), tumor necrosis factor (TNF-), and granulocyte-macrophage colony stimulating factor (GM-CSF) in a murine model of breast cancer to generate a specific antitumor response.Methods: BALB/c mice with established MT-901 tumors underwent resection or treatment with a single intratumoral injection of PLAM containing IL-12, TNF-, or GM-CSF, alone or in combination. Two weeks later, lymph nodes and spleens were harvested, activated with anti-CD3 monoclonal antibodies (mAb) and rhIL-2, and assessed for antitumor reactivity by an interferon (IFN) release assay. Tumor-infiltrating lymphocyte (TIL) analysis was performed on days 2 and 5 after treatment by mechanically processing the tumors to create a single cell suspension, followed by three-color fluorescence-activated cell sorter (FACS) analysis.Results: Intratumoral injection of cytokine-loaded PLAM significantly suppressed tumor growth, with the combination of IL-12 and TNF- leading to increased infiltration by polymorphonuclear cells and CD8⁺ T-cells in comparison with controls. The induction of tumor-specific reactive T-cells in the nodes and spleens, as measured by IFN- production, was highest with IL-12 and TNF-. This treatment resulted in resistance to tumor rechallenge.Conclusions: A single intratumoral injection of IL-12 and TNF-–loaded PLAM into a breast tumor leads to infiltration by polymorphonuclear cells and CD8⁺ T-cells with subsequent tumor regression. In addition, this local therapy induces specific antitumor T-cells in the lymph nodes and spleens, resulting in memory immune response.     

A Prostacyclin Analogue,OP-41483α-CD,Restores the Ability of a β<Subscript>2</Subscript>-Adrenergic Agonist to Stimulate Alveolar Fluid Clearance in Rats

Purpose. It is not yet known whether a prostacyclin analogue can affect alveolar fluid clearance. According to recent studies, high-dose (10^–3M) terbutaline, a ₂-adrenergic agonist, failed to increase alveolar fluid clearance. Therefore, we examined the effects of OP-41483-CD, a prostacyclin analogue, on alveolar fluid clearance in the presence of high-dose terbutaline in rats.Methods. Albumin solution containing Evans blue dye and various drugs was instilled into the alveolar airspaces of isolated rat lungs, which were then inflated with 100% oxygen at an airway pressure of 8cmH₂O. Alveolar fluid clearance was measured by the progressive increase in dye concentrations over 1h.Results. Although 10^–5 and 10^–4M terbutaline increased alveolar fluid clearance, 10^–3M terbutaline did not. OP-41483-CD restored the ability of 10^–3M terbutaline to stimulate alveolar fluid clearance. The effect of OP-41483-CD was consistent with the effect of atenolol, a ₁-adrenergic antagonist. The effect of OP-41483-CD on alveolar fluid clearance was unchanged in lungs inflated with nitrogen. Prostaglandin E (PGE)₁ and PGE₂ analogues had similar effects to OP-41483-CD on alveolar fluid clearance.Conclusion. These results indicate that a prostacyclin analogue restores the ability of high-dose terbutaline to stimulate alveolar fluid clearance.