Beta-adrenoceptor desensitization in a model of experimental asthma in guinea-pigs.

We investigated the possible occurrence of the desensitization of pulmonary beta-receptors in a model of experimental asthma such as the ovalbumin sensitized guinea-pig. Although some differences were observed between normal and asthmatic guinea-pigs, the desensitization procedure (isoproterenol (ISO) 10(-6) M x 20 min x 2) markedly impaired the relaxing capacity of ISO, epinephrine (EPI) and procaterol. With the beta 2 agonist procaterol, the sensitized tissues seemed to be more sensitive compared to normal. In parallel, the desensitization procedure produced a greater decrease in the relaxing capacity of procaterol in the sensitized tracheas. On the other hand, the two unselective beta-agonists (ISO and EPI) did not seem to discriminate between the two experimental conditions used. These data suggest that the immunological disturbance due to the active sensitization may induce a modification in beta-adrenoceptor reactivity. The results obtained with EPI after anaphylactic challenge are in agreement with this. In fact, the relaxing capacity of EPI was markedly reduced by antigen challenge.

The PAF-acether receptor antagonist BN-52021 inhibits mediator release during guinea-pig active lung anaphylaxis.

An anaphylactic reaction was induced with the specific antigen (1 mg Ovalbumin) in perfused lungs from actively sensitized guinea-pigs in order to evaluate the ability of the ginkgolide BN-52021 (0.4, 4, 40 micrograms/ml) to modulate the mediator release. The ginkgolide reduces in a dose dependent manner the release of histamine (22%, 45% and 75% of inhibition), TXB2 (77% of inhibition at the maximal dose used) and of SRS-A to a lower extent (only 33% at the higher dose). BN-52021 was still powerful in reducing histamine release induced by immunological reaction in indomethacin treated animals. In conclusion, the present "in-vitro" results confirm the beneficial activity of this ginkgolide, already demonstrated by the same Authors in "in-vivo" experiment, in anaphylactic reactions, and further substantiate the wider spectrum of action of the ginkgolide beside its specific PAF receptor antagonistic activity.

Croton oil pleurisy induces pulmonary hyperreactivity.

Inflammatory process of the airways has been claimed to be relevant to the development of bronchial hyperreactivity in different experimental models. We investigated the consequences of pleural inflammation induced in the guinea-pigs by croton oil injection into the pleural space. Croton oil injection was followed by the development of an inflammatory reaction localized to the pleura as shown by recovery of inflammatory exudate from the pleural cavity of treated animals. An increased number of white cells was observed in the pleural fluid of treated animals as compared to control. Moreover, the croton oil induced inflammation was characterized by development of pulmonary hyperreactivity which involved both airway and vascular smooth muscles. We also studied this phenomenon in an animal model of asthma, such as the actively sensitized guinea-pigs. Polymorphonuclear leukocyte and particularly eosinophil recruitment was increased in this experimental condition and a different trend in the development of the hyperreactive phenomenon was observed. Our data support the relationship between inflammatory process within the pleural space and increased reactivity of pulmonary tissues. The possible involvement of different classes of white cells in this phenomenon has also been discussed.

Pharmacology of natural compounds. I. Smooth muscle relaxant activity induced by a Ginkgo biloba L. extract on guinea-pig trachea.

A standardized Ginkgo biloba L. extract containing flavonol glycosides induces a concentration-dependent relaxation of guinea-pig trachea in vitro and antagonizes in vivo bronchoconstriction induced by various agonists. The action of the extract appears to be mediated partially by an interaction with the eicosanoid system particularly through specific stimulation of the PGE2 biosynthesis and partially by beta-adrenoceptor activation. The relaxation of guinea-pig trachea induced by the extract is in fact antagonized by indomethacin (2 x 10(-8)M), ETYA (3.4 x 10(-8)M) and sotalol (4 x 10(-6)M). The concentration-response curves obtained with tracheal preparation from reserpinized guinea-pig and those performed in the presence of a glutathione depletor (CDNB 1 x 10(-5)M) are modified in a similar manner confirming that the extract can act on both the systems: adrenergic as well as prostaglandinergic.

New pharmacological data on the bronchospasmolytic activity of bamifylline.

Resistance to lung inflation and blood pressure were monitored together with biological and radioimmunological determination of circulating thromboxane A2 (TxA2) in anaesthetized guinea-pig. Bamifylline, a 2-benzyl-[4,5-d]-imidazopyrimidine derivative, and theophylline were compared for their antagonistic activity against the pulmonary effect of histamine (0.05 mumol/kg i.v.), leukotriene C4 (LTC4, 0.016 mumol/kg i.v.), platelet-activating factor (PAF, 0.0002 mumol/kg i.v.) and acetylcholine (0.1 mumol/kg i.v.). Bamifylline, as well as theophylline, showed a dose-dependent antagonistic activity against both bronchoconstriction and TxA2 generation induced by the above agonists. However, except for histamine where the two compounds were equiactive, bamifylline was 2 times more potent than theophylline. The maximal inhibitory activity was found against bronchoconstriction induced by PAF (ED50 = 6.5 mumol/kg i.v.) followed by histamine (ED50 = 9.5 mumol/kg i.v.), acetylcholine (ED50 = 24.3 mumol/kg i.v.) and LTC4 (ED50 = 31.6 mumol/kg i.v.). Bamifylline (3, 10, 30, 100 mumol/kg i.v.) and theophylline (3, 10, 30, 100 mumol/kg i.v.) protected guinea-pig from antigen-induced bronchoconstriction and TxA2 generation in ovalbumin actively sensitized animals. Also in this series of experiments bamifylline was more potent than theophylline, the ED50 being 9.3 mumol/kg i.v. and 22.9 mumol/kg i.v., respectively. These pharmacological data represent new support for the protecting effect of bamifylline against respiratory damage induced by well known anaphylaxis mediators.

Angiotensin II: a releaser of PGI2 from fetal and newborn rabbit lungs.

Angiotensin II (AII) induces generation of prostacyclin (PGI2) in rabbit lung in vitro at different ages, i.e., fetus, newborn and adult. Particularly, neonatal rabbit lungs display a pattern of sensitivity to AII in producing PGI2, measured as 6-oxo-PGF1 alpha, which seems to be higher than that observed in fetal lungs. The PGI2 release appears to be specific for AII stimulation since the vasoconstriction induced by noradrenaline and ergotamine was not associated with generation of this lipidic material. The inability of PGI2 to relax the extralobar pulmonary artery in the newborn suggests that the lung microcirculation is the most likely site where the vasodilating and antiaggregatory functions of PGI2 may have a physiological role.

Prostacyclin (PGI2) generation in lungs of fetal and newborn rabbit.

Perfused lungs from fetal (26-28 days of gestation) and newborn rabbits preferentially transform arachidonic acid into a substance which mimics PGI2 activity on different isolated tissues in cascase. These data support the hypothesis that antiplatelet and vasodilating vasodilating activity of PGI2 generated in the lungs may contribute to the characteristics of the fetal circulation.

The role of histamine H1- and H2-receptors in the generation of thromboxane A2 in perfused guinea-pig lungs.

1. When isolated perfused lungs from normal and ovalbumin sensitized guinea-pigs were challenged with histamine and 2-methylhistamine (agonists for H1-receptor), a release of thromboxane A2-like substance was observed. The effect of histamine on production of thromboxane A2 (TXA2) in sensitized lungs, was more pronounced than in normal lungs (P less than 0.01). 2. Specific activation of histamine H2-receptors in normal lungs with large doses (100 micrograms) of dimaprit and 4-methylhistamine, does not produce thromboxane-like or prostaglandin-like substances. 3. Perfusion of the lungs with pyrilamine (10 micrograms/ml) inhibited the release of arachidonate metabolites induced by histamine H1-receptor stimulation, whereas cimetidine (5 micrograms/ml) was ineffective. 4. It is concluded that only the stimulation of histamine H1-receptors appears to be responsible for generation of thromboxane A2 and other prostaglandin-like substances in normal guinea-pig lungs. In sensitized lungs, an increased ability of histamine to release TXA2 could be due to a possible interconversion of H2 into H1-receptors.

Prostacyclin (PGI2) in pregnant human uterus.

Prostacyclin lowers the tonus and reduces the spontaneous motility of isolated pregnant human myometrium. This effect seems to be related to coclic-AMP accumulation, since PGI2 increases the formation of this cyclic nucleotide in incubated minces of pregnant and non-pregnant uterus. The ability of this tissue to generate a labile substance which inhibits platelets aggregation, has been demonstrated and discussed.

Pharmacological activity of PGI2 and its metabolite 6-oxo-PGF1alpha on human uterus and fallopian tubes.

The actions of prostacyclin (PGI2) and its stable metabolite 6-OXO-PGF1alpha were investigated in strips of normal human uterus and in fallopian tubes. Both compounds were also compared with natural prostaglandins (PGE2, PGF2alpha and PGD2). PGI2 showed biphasic response both in uterus and fallopian tubes qualitatively and quantitatively similar to that induced by PGE2 and PGD2; prostacyclin was also able to inhibit the spasmus induced by PGF2alpha but not that induced by BaCl2 and vasopressin. 6-0XO-PGF1alpha on the other hand induced only small contractions on both tissues investigated. The authors discusse the possible implication of these findings in the physiology of the reproductive system.

PIP: To obtain more information on the importance of prostacyclin (PGI2), and of its stable metabolite 6-oxo-PGF1, in the maintenance of uterine and placental circulation, their pharmacological activity was studied on strips of nonpregnant human uterus and human fallopian tubes, and compared with the action of natural prostaglandins PGE2, PGF2 and PGD2. Prostacyclin induced a biphasic response on strips of uterus and of fallopian tubes; in 6 different experiments an initial contraction followed by relaxation associated with loss of spontaneous motility was constantly observed in a dose dependent manner; PGE2 and PGD2 also inhibited the spasmus induced by PGF2, but not that induced by BaCI2 and vasopressin. The contractions caused by 6-oxo-PGF1 on both uterine and fallopian tube strips were considerably less potent. These experiments clearly demonstrate that PGI2 interferes with spontaneous motility of tonus of the normal uterus. It must be underlined that the effect of PGI2 and of 6-oxo-PGF1 is species dependent, since in rat uterus, unlike in the human uterus, both compounds induce contractions.