班布特罗对豚鼠支气管收缩反应的扩张作用

观察班布特罗对豚鼠支气管收缩反应的影响。方法：用哮喘发作潜伏期,肺机械功能及离体气管平滑肌松弛试验观察班布特罗的支气管扩张作用。结果：班布特罗ｉｇ后１ｈ,４ｈ和２４ｈ均能延长组胺诱导的豚鼠哮喘潜伏期,ＥＤ５０分别为０．７４,０．７５,１．００ｍｇ．ｋｇ＾－１,其作用持续时间明显长于特布他林。     

Peptide leukotriene antagonistic activity of AS-35, a new antiallergic drug.

The effects of 9-[(4-acetyl-3-hydroxy-2-n-propylphenoxy) methyl]-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (AS-35), a newly synthesized compound, on leukotrienes (LTs) antagonistic activities were investigated in vitro and in vivo. In isolated guinea pig preparations, AS-35 antagonized LTC4-, LTD4- and LTE4-induced contractions of the ileum with IC50 values of 8 nM, 4 nM and 3 nM, respectively. In the trachea, the agent also antagonized LTD4- and LTE4-induced contractions with IC50 values of 10 nM and 20 nM, respectively. However, LTC4-induced tracheal contraction in the presence of L-serine borate was not antagonized by AS-35. Histamine-, acetylcholine-, serotonin- and bradykinin-induced contractions of the ileum, carbachol-, prostaglandin D2-, prostaglandin F2 alpha-induced contractions of the trachea and LTB4-induced chemotaxis of rat polymorphonuclear leukocytes were not inhibited by AS-35. As to the in vivo models, AS-35 (i.v.) dose-dependently antagonized bronchoconstriction induced by i.v.-injection of LTC4 and LTD4 in anesthetized guinea pigs, but did not inhibit histamine-induced bronchoconstriction. Oral administration of AS-35 also antagonized LTD4- as well as antigen-induced LT-mediated bronchoconstriction. In addition, LTD4-induced increase in the cutaneous vascular permeability of guinea pig was inhibited by the drug (p.o.). These results indicate that AS-35 is an orally effective, potent and selective peptide LT antagonist.     

Synthesis and antiallergic activity of a novel series of 5-lipoxygenase inhibitors

A series of novel substituted [[(phenoxymethyl)phenyl]amino]oxoalkanoic acid esters have been synthesized. These compounds were tested in vitro for their ability to inhibit the synthesis of 5-hydroxyeicosatetraenoic acid and leukotriene (LT) B4 from rat polymorphonuclear leukocytes (PMN) and in vivo as inhibitors ovalbumin- (OA) and LTD4-induced bronchospasm in the guinea pig. Compounds 5-12 and 25 had IC50's between 1 and 5.6 microM in the rat PMN 5-lipoxygenase assay. Compounds 1, 3, and 16 inhibited OA-induced bronchoconstriction (61%, 64%, and 57%, respectively), but only 1 showed activity against LTD4-induced bronchoconstriction. When tested against LTD4-induced contraction of isolated guinea pig tracheal spiral strips, 1 was a competitive inhibitor with a pKB of 4.94.     

Quinones. 4. Novel eicosanoid antagonists: synthesis and pharmacological evaluation

A new series of omega-phenyl-omega-quinonylalkanoic acids and related compounds was synthesized. The compounds were tested for their inhibitory effects on U-44069-induced contraction of the rabbit aorta. (+/- )-7-(3,5,6-Trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptanoic acid (4d) (AA-2414) with pA2 value of 8.28 was one of the most potent compounds. Compound 4d inhibited U-46619-induced contraction of the guinea pig lung (pA2 = 8.29) and U-44069-induced aggregation of the guinea pig platelet (IC50 = 3.5 x 10(-7) M). Compound 4d displaced the binding of [3H]U-46619 to guinea pig platelets (IC50 = 7.4 x 10(-9) M). Compound 4d also showed very potent inhibitory effects with an MED of 0.3 mg/kg (po) on U-46619-, LTD4-, PAF-, or IgG1-induced bronchoconstriction in guinea pigs. The enantiomers of 4d were prepared. The R-(+) isomer 8a was active in both in vitro and in vivo tests, but the S-(-) isomer 8b was much less active. We concluded that the antiasthmatic effects of 4d were based mainly on the TXA2 receptor antagonistic action. In addition, compound 4d showed potent inhibitory effects on PGD2-, PGF2 alpha-, and 11-epi-PGF2 alpha-induced contraction of the guinea pig tracheal strips. The diverse inhibitory effects might be expressed in terms of eicosanoid-antagonistic activity.     

Red wine polyphenolic compounds inhibit tracheal smooth muscle contraction during allergen-induced hyperreactivity of the airways

The aims of the study were to investigate the short and long-term effects of Provinol (red wine polyphenolic compounds) on tracheal smooth muscle reactivity using an in-vitro model of ovalbumin-induced airway inflammation in guinea-pig trachea, and to evaluate the role of nitric oxide (NO) in the bronchodilatory effect of Provinol. The amplitude of tracheal smooth muscle contraction in response to mediators of bronchoconstriction - histamine (10 nM-1 mM), acetylcholine (10 nM-1 mM) and to allergen (ovalbumin 10(-5)-10(-3) g mL(-1)) was used as a parameter of tracheal smooth muscle reactivity. To test the short-term effects of Provinol, isolated tracheal strips were pre-treated for 30 min with Provinol (10(-4) mg mL(-1)) alone or in combination with Nomega-nitro-L-arginine methyl ester (L-NAME; 10(-6) mol L(-1)). To test the long-term effects of Provinol, isolated tracheal strips were prepared from guinea pigs that had been treated for 14 days with Provinol (20 mg kg(-1) per day) alone or in combination with L-NAME (40 mg kg(-1) per day). Incubation of tracheal smooth muscle with Provinol decreased the amplitude of contraction in response to ovalbumin, histamine and acetylcholine. The non-selective NO synthase inhibitor L-NAME partially abolished the effect of Provinol on acetylcholine and ovalbumin-induced but not histamine-induced bronchoconstriction. A similar profile was observed after 14 days' oral administration of Provinol. In conclusion, Provinol inhibited the allergen- and spasmogen-induced contraction of tracheal smooth muscle in ovalbumin-sensitized guinea pigs via a mechanism that was mediated at least partially through the metabolism of NO.     

Inhibitory effect of dendroaspis natriuretic peptide on spontaneous contraction in gastric antral circular smooth muscles of guinea pigs

Aim： To determine whether the natriuretic peptide receptor （NPR） is present in the stomach of guinea pigs and to investigate the effect of dendroaspis natriuretic peptide （DNP） on the gastric motility of guinea pigs and its mechanism. Methods： The distribution of the NPR was analyzed by autoradioimmunography. The spontaneous contraction of gastric antral circular muscles of guinea pigs was recorded by a 4-channel physiograph. The whole cell patch-clamp technique was introduced to record calcium-activated potassium currents in the gastric myocytes isolated by collagenase. Results： The NPR existed in the gastric fundus, gastric body, and gastric antrum of guinea pigs, and its density was largest in the gastric antrum. DNP inhibited spontaneous contraction and exhibited a dose-dependent manner. The DNP-induced inhibition was diminished by LY83583 （a guanylate cyclase inhibitor） and was potentiated by zaprinast （a cGMP-sensitive phosphoesterase inhibitor）. The inhibitory effect of DNP on spontaneous contraction was also inhibited by tetraethylammonium （a non-selective potassium channel blocker）; 10 nmol/L DNP increased the calcium-activated potassium currents in the gastric circular myocytes of guinea pigs. Conelusion： The NPR is most common in the gastric antrum of guinea pigs. DNP significantly inhibits gastric motility in the gastric antrum of guinea pigs. The inhibitory effect occurs via a cGMP-dependent pathway, and a calcium-activated potassium channel may be also involved in the relaxation induced by DNP in gastric antral circular smooth muscles.     

海群生对豚鼠离体气管条平滑肌收缩的影响

目的研究海群生（枸橼酸乙胺嗪,ＤＥＣ）对豚鼠离体气管条平滑肌收缩反应的影响及其作用机制。方法取气管条放入３７℃浴管的Ｋｒｅｂｓ溶液中,分别在浴液中加入药物,测定ＫＣＩ和５－羟色胺（５－ＨＴ）收缩气管条的作用和量效反应以及ＤＥＣ和维拉帕米对ＫＣｌ和５－ＨＴ作用的影响。结果ＤＥＣ能使ＫＣＩ或５－ＨＴ引起的气管条平滑肌收缩显著抑制,其ＩＣ５０值分别为５．０３ｍｍｏｌ·Ｌ－１和９．５４ｍｍｏｌ·Ｌ－１,与维拉帕米的作用相似。ＤＥＣ使ＫＣｌ和５－ＨＴ的量效曲线右移,最大反应降低,呈非竞争性拮抗,其ｐＤ２值分别为１．５５４和１．８５１,并对细胞内Ｃａ２＋释放和细胞外Ｃａ２＋内流引起的收缩有抑制作用。结论ＤＥＣ可抑制ＫＣｌ和５－ＨＴ引起的气管条平滑肌收缩,其机制可能是通过其钙拮抗作用所致。     

Effects of flutropium bromide, a new antiasthma drug, on mediator release from mast cells and actions of mediators

The effects of flutropium bromide (Ba598Br), a new antiasthma drug possessing the quarternary ammonium structure of atropine derivatives, on mediator release from mast cells and on actions of leukotriene (LT) D4 and serotonin were investigated. Flutropium bromide (3 and 10 mg/kg, i.v.) showed an inhibitory action on the 48 hr homologous PCA in guinea pigs. Atropine showed no inhibitory effect. Flutropium bromide also inhibited the release of histamine from isolated rat mast cells stimulated by antigen, although the inhibitory action was weaker than that of disodium cromoglycate. Atropine also had no inhibitory action in this case. Flutropium bromide and atropine showed no antagonistic action against LTD4-induced contraction of isolated tracheal smooth muscle of guinea pigs. Inhalation of flutropium bromide (0.3%) also showed no antagonistic action against serotonin-induced bronchoconstriction in dogs. From the above results, it is indicated that flutropium bromide has a weak mast cell stabilizing action, but no antagonistic action against LTD4 and serotonin.     

Inhibition of cysteinyl-leukotriene production by azelastine and its biological significance

Azelastine is a phthalazinone derivative with a wide spectrum of pharmacological activities. Actively sensitized guinea pigs were used to examine the broncholytic effect of azelastine in vivo. Furthermore, the influence of azelastine on the production of arachidonic acid (AA) metabolites was investigated in vitro and compared to the effects of nordihydroguaiaretic acid (NDGA), indomethacin and ketotifen. In vivo, azelastine protected actively sensitized guinea-pigs against ovalbumin-induced bronchospasm with an ID50 of 0.08 mg/kg orally. Ketotifen was similarly active (ID50 = 0.05 mg/kg). Antigen-induced contraction of isolated tracheal rings of sensitized guinea-pigs was concentration-dependently inhibited by azelastine and NDGA with IC50-values of 94.1 and 34.2 mumol/l, respectively. Ketotifen exerted only weak inhibitory activity (18% at 100 mumol/l). The arachidonic acid-induced contraction of isolated guinea-pig tracheal rings was also inhibited both by azelastine (IC50 = 92.6 mumol/l) and NDGA (IC50 = 20.4 mumol/l). Ketotifen was inactive on this model. Antigen challenge of chopped lung tissue from sensitized guinea-pigs resulted in the release of cysteinyl-leukotrienes (LT) which were identified by reversed phase high pressure liquid chromatography (HPLC) as LTD4 and LTE4. The release of cysteinyl-LT from sensitized guinea-pig lung tissue induced by antigen challenge was concentration-dependently inhibited by azelastine (IC50 = 35.2 mumol/l) and NDGA (IC50 = 8.4 mumol/l) but not by ketotifen and indomethacin. By contrast, indomethacin caused a pronounced augmentation of cysteinyl-LT release. The concentration of indomethacin, which augmented cysteinyl-LT release by 50% was 0.19 mumol/l.(ABSTRACT TRUNCATED AT 250 WORDS)     

Inhibitory effects of OKY-046 on spasmogen-induced bronchoconstrictions in sensitized and non-sensitized guinea pigs

We examined the effect of thromboxane A2 (TXA2) synthetase inhibitor, OKY-046, on bronchoconstriction induced by antigen and various spasmogenic mediators in guinea pigs in vivo. Further, inhibitory activities of OKY-046 on contractions of isolated tracheae and lung parenchymal strips induced by various contractile agents were also investigated in vitro. OKY-046, but not indomethacin, significantly inhibited antigen-induced bronchoconstriction in a dose-dependent manner. Moreover, OKY-046 attenuated bronchoconstrictions induced by peptide leukotrienes (LTs) and platelet activating factor (PAF), but not those by histamine, prostaglandin D2 (PGD2) and STA2 (a stable TXA2 mimetic agent). Although contractile responses induced by spasmogens such as peptide LTs, PAF and histamine were not influenced by OKY-046 in isolated tracheae, OKY-046 elicited significant and concentration-dependent inhibitions against contractile responses induced by peptide LTs and PAF in isolated lung parenchymal strips. These results suggest the possible involvement of TXA2 in the development of anaphylactic bronchoconstriction in sensitized guinea pigs.     

9,11-epoxy-9-homoprosta-5-enoic acid analogues as thromboxane A2 receptor antagonists

A novel bicyclic prostaglandin analogue, (1S)-[1 alpha, 2 alpha(Z),3 alpha(1E,3S*,4R*),4 alpha]-7-[3-(3-hydroxy-4-phenyl-1-pentenyl)-7- oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (4), was found to be a potent and selective thromboxane A2 (TxA2) receptor antagonist. Alcohol 4 was the only member in a series of allylic alcohols which did not display direct contractile activity in the rat stomach strip model. Alcohol 4 was effective in the inhibition of (a) arachidonic acid induced platelet aggregation of human platelet-rich plasma (I50 = 0.65 +/- 0.1 microM); (b) 11,9-epoxymethano-PGH2 induced contraction of guinea pig trachea (pA2 = 8.0 +/- 0.2) or rat aorta (pA2 = 8.1 +/- 0.2); and (c) arachidonic acid induced bronchoconstriction in the anesthetized guinea pig (1 mg/kg iv). A radioiodinated analogue of 4 bound in a specific and saturable manner to human platelet membranes with a Kd = 2.3 +/- 0.9 nM. Modification of the alpha-chain, in an attempt to minimize in vivo metabolism, resulted in TxA2 receptor antagonists of reduced in vitro potency.     

速激肽受体拮抗剂抗豚鼠过敏性哮喘的作用

实验目的是研究速激肽与哮喘的关系,评价速激肽受体拮抗剂对哮喘的治疗作用。结果表明,ip速激肽NK-1受体拮抗剂CP-96345,NK- 2受体拮抗剂SR-48968或两药合用,均可有效减少清醒致敏豚鼠吸入抗原引起的喘息反应,降低过敏性休克死亡率。SR-48968减轻麻醉豚鼠抗原引起的气道收缩,并浓度依赖性降低抗原引起的气管和支气管平滑肌收缩幅度。CP-96345可抑制抗原诱导的支气管和肺叶伊文思蓝渗出,仅对支气管平滑肌收缩有部分抑制作用。结果提示,速激肽参与哮喘发病,速激肽受体拮抗剂可抑制抗原诱导的气道平滑肌收缩(NK-2受体)和微血管渗漏(NK-1受体)而减轻哮喘反应。     

Thromboxane A2 mediated bronchoconstriction in the anesthetized guinea pig

Arachidonic acid-induced platelet aggregation has been shown to be selectively antagonized by the thromboxane A₂ synthetase inhibitor SQ 80,338 or by the thromboxane A₂ receptor antagonist SQ 24,775. Experiments were done to see what effect these two compounds would have on the bronchoconstrictor response to various agents in the anesthetized guinea pig. Increases in pulmonary resistance and decreases in dynamic compliance were taken as an index of bronchostriction. Both SQ 80,338 (0.3–10.0 mg/kg) and SQ 24,775 (0.1–1.0 mg/kg) administered i.v. caused dose-related inhibitions of arachidonate-induced bronchoconstriction. SQ 80,338 (3.0 and 10.0 mg/kg) also inhibited bradykinin-induced bronchoconstriction in the presence of β-adrenergic blockade. These same doses of SQ 80,338 and SQ 24,775 did not alter either histamine- or antigen-induced bronchoconstriction. SQ 80,338 (10.0 μg/ml) prevented arachidonate-induced release of TXA₂ from the isolated perfused guinea pig lung while SQ 24,775 (1.0 μg/ml) antagonized the contraction of the isolated rat aorta induced by 9,11,AZO-PGH₂. These results suggest that both arachidonate- and bradykinin-induced bronchoconstriction are mediated through the generation of TXA₂, while histamine- and antigen-induced bronchoconstriction are not.     

Diminished inibitory action of ethanol on the contraction of gallbladder isolated from chronically ethanol-fed Guinea pigs

Ethanol is known to decrease the gallbladder contractility. The purpose of this study was to clarify the mechanism of tolerance to the inhibitory action of ethanol on the gallbladder contractility. Male guinea pigs were fed ethanol (3%) or calorie-matched sucrose in the drinking water for 4 weeks. Then, the gallbladder was isolated, and its isometric tension was measured. The contractile responses to KCl, BAY K8644, histamine, and phorbol 12,13-dibutyrate in the normal medium were not different between the gallbladder strips from ethanol-fed and control guinea pigs. Ethanol at 25 mmol/l in vitro did not affect the contractile responses to KCl and BAY K8644 in the gallbladder strips from both ethanol-fed and control guinea pigs. On the other hand, ethanol at 25 mmol/l in vitro significantly inhibited the contractile responses to histamine and phorbol 12,13-dibutyrate in the gallbladder strips from the control guinea pigs, but it did not affect the contractile response to histamine and significantly augmented that to phorbol 12,13-dibutyrate in the strips from the ethanol-fed guinea pigs. Diphenhydramine, a selective H(1) receptor antagonist, abolished the histamine contraction in gallbladder strips from both control and ethanol-fed guinea pigs, while cimetidine, a selective H(2) receptor antagonist, did not affect histamine contraction, implying that histamine-induced contraction of guinea pig gallbladders is mediated only by H(1) receptors. Verapamil (1 micromol/l) completely inhibited the phorbol 12,13-dibutyrate-induced contraction of the strips from both ethanol-fed and control guinea pigs. The histamine-induced contraction was partly inhibited in the absence of Ca(2+) in the medium. In the gallbladder strips from both ethanol-fed and control guinea pigs, ethanol at 25 mmol/ in vitro did not affect the histamine-induced contraction in the absence of extracellular Ca(2+). Tolerance to the inhibitory action of ethanol developed selectively on contractile responses to histamine and phorbol 12,13-dibutyrate. Chronic ethanol administration produces tolerance to in vitro gallbladder contractility mediated by the Ca(2+) entry through L-type Ca(2+) channels linked with protein kinase C activation.     

Pharmacological studies of 4-ethoxy-2-methyl-5-morpholino-3(2H)-pyridazinone (M73101). (3). General pharmacological actions (author's transl)]

General pharmacological actions of M73101, a new non-steroidal analgesic anti-inflammatory drug were investigated in mice, rats, guinea pigs, rabbits, cats and dogs. Intravenous administration of M73101 produced a slight transient fall in blood pressure, an increase in heart rate and a respiratory stimulation, but no remarkable change in the electrocardiogram. The contraction induced by epinephrine in the isolated ear vessels of rabbits relaxed by M73101. In the isolated trachea of guinea pigs, M73101 relaxed the contraction induced by histamine. Furthermore, M73101 inhibited the bronchoconstriction by histamine but not by bradykinin in guinea pigs. These properties of M73101 on the tracheal smooth muscle were similar to those seen with aminopyrine but different from those seen with aspirin which inhibited only the contraction by bradykinin in vivo, suggesting that M73101 is a compound with properties similar to basic non-steroidal anti-inflammatory drugs. M73101 inhibited the intestinal propulsion in mice and also the gastrointestinal movement in rats and dogs. Moreover, M73101 showed a spasmolytic activity on the isolated ileum of guinea pigs, but such was not due to any specific antagonistic action on the chemical mediators. On the other hand, M73101 had no effect on the isolated uterus and vas deferens of rats. M73101, unlike aminopyrine and phenylbutazone, slightly increased urine volume and electrolytes excretion in rats, indicating that this compound probably does not produced edema. M73101 showed no significant pharmacological activities on the blood sugar level, blood coagulation, platelet aggregation, methemoglobin formation and local irritation.     

Immunopharmacological studies on TBX, a new antiallergic drug (3). Inhibitory effects on histamine release from lung fragments and bronchoconstriction in guinea pigs

The effects of 9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one potassium salt (TBX), a new antiallergic drug, on histamine release from lung fragments, experimental asthma and isolated tracheal muscle were investigated in guinea pigs. TBX (10(-7) to 10(-4) g/ml) dose-dependently inhibited antigen-induced histamine release from lung fragments of guinea pigs passively sensitized with homologous IgE serum. Antigen inhalation-induced experimental asthma in passively sensitized animals was inhibited in a dose-dependent fashion by i.v. (1 to 5 mg/kg) and p.o. (10 to 100 mg/kg) administrations of TBX. In vivo bronchoconstriction by platelet-activating factor (PAF, i.v.) was also inhibited by TBX (0.3 to 10 mg/kg, i.v.). However, high concentrations of TBX (more than 3 x 10(-4) g/ml) were needed to inhibit PAF-induced platelet aggregation in vitro. With regard to the effect on isolated tracheal muscle, TBX itself at concentrations higher than 10(-5) g/ml induced dose-dependent reduction in the resting tonus, which was not affected by pretreatment with propranolol. Neither the leukotriene D4-induced contraction nor the prostaglandin F2 alpha-induced one was specifically antagonized by TBX. The results obtained indicate that TBX is an antiasthmatic agent effective in inhibiting both IgE- and PAF-induced bronchoconstriction, possibly by interfering with mediator release.     

盐酸戊乙奎醚对胃解痉作用的药效学研究

研究盐酸戊乙奎醚(PQN)肌肉注射及灌胃给药对麻醉及清醒家兔在体胃及豚鼠离体胃条的抑制收缩作用。结果表明，PQN能抑制由乙酰胆碱(Ach)和氯贝胆碱引起的胃内压上升，拮抗Ach对离体胃条的收缩作用，并能抑制离体胃条的自主收缩。     

Activity of the oxidation products of oleum terebinthinae "Landes" on guinea pig airway smooth muscle in vivo and in vitro

The oxidation products of Oleum Terebinthinae "Landes" (Ozothin; in the following briefly called Ox. O. T. L.) have been described in many studies as being of benefit in the treatment of disturbed tracheobronchial function in obstructive airways diseases. Previous literature has dealt mainly with the influence of Ox. O. T. L. on the visco-elastic properties of mucus. However, the purpose of the present work was to study the bronchospasmolytic component. Using a standard methodology for the measurement of bronchospasmolytic effects, it could be demonstrated that Ox.O.T.L., given orally or as an aerosol, protected conscious guinea pigs against histamine-induced bronchoconstriction. The potency was lower than that of isoprenaline but was significant and reproducible. These results in vivo are paralleled by effects observed on guinea pig lung strips and tracheal spiral preparations. Ox.O.T.L. relaxed, in a dose-dependent fashion, guinea pig lung strip preparations contracted with histamine. Potency and efficacy was, however, less than that of isoprenaline. Similarly, in guinea pig tracheal spiral preparations, Ox.O.T.L. was less potent than isoprenaline in counteracting carbachol-elevated tone. However, efficacy equalled that of isoprenaline. Ox.O.T.L. was approximately 3 times more potent in the isolated tracheal spiral preparation than in lung strips. The activity of non-oxidised turpentine oil and terpin hydrate against histamine-induced bronchoconstriction in conscious animals and in the isolated organ preparations was substantially lower than that of the oxidation products of O.T.L.     

Effect of oxitropium bromide (Ba253) on isolated respiratory smooth muscle and release of chemical mediators from passively sensitized lung fragments

The effect of oxitropium bromide (Ba253), a quaternary scopolamine derivative, on the resting tonus and agonist-induced contraction of isolated guinea pig airway smooth muscle and on the anaphylactic release of histamine and immunoreactive leukotrienes (i-LTs) from lung fragments were investigated and compared with those of Sch1000, atropine and isoproterenol. Ba253 dose-dependently inhibited the acetylcholine (ACh)-induced contraction of the isolated trachea and lung parenchyma. The degree of inhibitory potency was similar to that of Sch1000 and 10 times higher than that of atropine. Ba253 minimally influenced the resting tonus or contractions induced by other agonists including histamine, serotonin and LTD4. Sch1000 and atropine had similar or slightly stronger inhibitory effects on the tonus and contractions than Ba253. On the other hand, low concentrations of isoproterenol solely relaxed the resting tonus and inhibited the the agonist-induced contractions of both preparations. Neither Ba253 nor Sch1000 inhibited the anaphylactic release of histamine and LTs from both guinea pig and human lung fragments, but both mediator releases from either species were slightly inhibited with dose-dependency by atropine and potently inhibited by isoproterenol. From these results, it is suggested that Ba253 is a relatively specific antagonist to cholinergic receptors and might be possibly effective as an inhalant for asthma.     

Evidence for a pulmonary B3 bradykinin receptor

We have examined pulmonary effects of bradykinin (Bk) in vivo and in vitro in guinea pigs and their potential inhibition by antagonists of Bk B1 and B2 receptors. Bk was a potent bronchoconstrictor in vivo and caused contractions of isolated, epithelium-denuded trachealis. D-Arg[Hyp3,D-Phe7]-Bk (NPC567) and D-arg[Hyp3,Thi5,8,D-Phe7]-Bk (NPC349), B2 receptor antagonists, were weak inhibitors of Bk-induced bronchoconstriction in vivo and were virtually inactive as antagonists of Bk-induced airway smooth muscle contraction. Several other B2 antagonists as well as B1 antagonist, des-Arg9-[Leu8]-Bk, did not inhibit Bk-induced tracheal contraction. The B1 receptor agonist des-Arg9-Bk was without effect on tracheal tone. Tracheal responses to Bk were unaffected by antagonists of muscarinic, histamine, serotonin, and catecholamine receptors. The inability of the antagonists to inhibit Bk is unlikely to be due to their degradation, because NPC567 was only weakly active in the presence of inhibitors of kininase I (EC 3.4.11.2), kininase II (EC 3.4.15.1), and neutral endopeptidase (EC 3.4.24.11). These studies were corroborated by ligand binding experiments in guinea pig and ovine airways. In [3H]Bk binding, the Bk antagonists had no effect in guinea pig trachea, slightly displaced [3H]Bk in ovine trachea, and inhibited approximately 60% of total specific binding in lung. des-Arg9-[Leu8]-Bk and several other agents, including atropine, neurokinin A, substance P, and vasoactive intestinal peptide, had no effect on lung Bk binding. Bk and its analogs were not degraded during the binding assay. These data suggest that pulmonary tissue, particularly in the large airways, contains a novel Bk binding site, a B3 receptor, which may be involved in Bk-induced bronchoconstriction.