dinoprost and Bronchial-Spasm

The Intrinsic Sympathetic Activity (ISA) of the beta-1-adrenoceptor blocker celiprolol was tested in a series of pharmacological and clinical investigations. Celiprolol shows much more pronounced positive chronotropic effects in spontaneously beating atria of cats than in those of guinea-pigs and rats. Positive inotropic effects of celiprolol are much pronounced in the left kitten atrium, but scarcely demonstrable in the kitten papillary muscle. Celiprolol has no influence on the adenylyl cyclase activity of the dog heart. In reserpinized rats and reserpinized, adrenalectomized, vagotomized cats celiprolol increases the heart rate to the same extent as the beta-blocker pindolol. In ganglion-blocked dogs celiprolol distinctly increases heart rate and left ventricular contraction force. Celiprolol relaxes isolated human arterial and venous strips and induces a transient increase of the femoral arterial blood flow in anaesthetized dogs. Celiprolol relaxes isolated bovine tracheal muscle preparations and reduces the airway resistance in anaesthetized cats infused with serotonin. The intrinsic chronotropic effects of celiprolol in cat atria in vitro and in reserpinized rats in vivo and the relaxing effects of celiprolol in isolated bovine tracheal muscles are antagonized by propranolol, and therefore these actions may be explained by the ISA of celiprolol. However the vascular relaxing effects of celiprolol in vitro and in vivo and the bronchodilating effects in the serotonin-infused cat are not blocked by propranolol. In order to obtain a more precise characterization of these surprising effects, further pharmacological investigations were done. In the isolated femoral artery of the dog the concentration-response curve of calcium chloride is not influenced by celiprolol while it is antagonized by verapamil. A serotonin antagonistic effect cannot be demonstrated for celiprolol either in receptor binding studies or on the blood pressure of anaesthetized dogs. Celiprolol inhibits the methacholine bronchospasm in rats and the prostaglandin F2 alpha-induced bronchoconstriction in cats. The histamine-induced bronchoconstriction in dogs is scarcely affected by celiprolol while it is enhanced by propranolol. In radioligand studies celiprolol shows a tenfold higher affinity for alpha-2 in comparison to alpha-1 receptors. Celiprolol enhances the inhibitory effect of clonidine in the electrically stimulated vas deferens of the rat in vitro.(ABSTRACT TRUNCATED AT 400 WOR

Topics: Adrenergic beta-Antagonists; Animals; Asthma; Blood Coagulation; Bronchi; Bronchial Spasm; Calcium Channel Blockers; Celiprolol; Dinoprost; Heart; Hemodynamics; Histamine; Humans; Myocardial Infarction; Propanolamines; Prostaglandins F; Receptors, Adrenergic, alpha; Respiration; Serotonin Antagonists; Sympathomimetics

We studied the effects of salbutamol, ipratropium bromide and cromolyn sodium on PGF2 alpha-induced bronchospasm in ten patients with asthma. Initially, the bronchial reactivity to IC-PGF2 alpha and the DP20-PGF2 alpha were determined. Recalculations were made two days later and again 1 h after administration of various drugs given on different days. Salbutamol and ipratropium bromide induced significant bronchodilation and of similar magnitude 1 h after administration. On the day salbutamol was given, surface area under the dose-response curve to PGF2 alpha was significantly higher and the final drop of FEV1 significantly lower than those observed on days when placebo, ipratropium bromide and cromolyn sodium were given. No differences among these values were found for placebo, ipratropium bromide and cromolyn sodium. Thus, beta 2 stimulants attenuate significantly PGF2 alpha-induced bronchospasm, while ipratropium bromide and cromolyn sodium do not have protective effect.

Topics: Adolescent; Adult; Albuterol; Asthma; Atropine Derivatives; Bronchial Provocation Tests; Bronchial Spasm; Cromolyn Sodium; Dinoprost; Dose-Response Relationship, Drug; Female; Humans; Ipratropium; Male

We have demonstrated that PGF2 alpha potentiates airway contraction in vitro and suggested that this response may be mediated by TxA2. We have localized the site of action of PGF2 alpha to a point distal to the parasympathetic ganglion and shown that it is a specific effect since PGD2 produces no similar potentiation. The mechanism of the potentiation may be by a direct alteration in smooth muscle sensitivity induced by TxA2 (Fig. 4). In our previous studies we have been able to induce hyperresponsiveness in vivo (Berend et al., 1986) but no increased responsiveness in vitro (Armour et al., 1987b). In vivo airway hyperresponsiveness may depend on the presence of a mediator like TxA2 which has a short half-life, is produced by continual stimulation of inflammatory cells and which is "washed out" in vitro once the source of stimulation is removed. The fact that we can demonstrate an increase in sensitivity in vitro using PGF2 alpha or a TxA2 analogue, combined with the fact that both mediators are released from a variety of inflammatory cells suggests that one or both of these agents may mediate part of the increased responsiveness observed in asthma.

Topics: Animals; Asthma; Bronchi; Bronchial Spasm; Carbachol; Dinoprost; Histamine; Muscle, Smooth; Prostaglandins F; Rabbits; Thromboxane A2; Trachea

A case of inadvertent intravascular injection of PGF2alpha during induction of labor by intraamniotic injection for fetal demise, involving alternating extreme hypotension and hypertension, is described. The woman was a 29-year old in late 2nd trimester with oligohydramnios, but no other related history. She was given epidural anesthesia, 7.5 mg midazolam and 5 mg morphine S04 for anxiety. Because of oligohydramnios, 300 ml Ringers lactate was instilled to dilute the PG. A test dose of 1 mg PGF2alpha was tolerated well. 80 g urea and 20 mg PGF2alpha were injected over 10 minutes. A few minutes later contractions began, followed by complaints of burning on face and chest and dyspnea. Oxygen was given by mask. Systolic pressure fell to 70 mm by cuff; peripheral pulses could not be palpated, but the patient remained alert and oriented. She was given 35 mg ephedrine and increased iv fluids. She remained dyspneic, her extremities became mottled, and she complained of chest pressure, severe headache and severe breast tenderness. Blood pressure rose to 220/135 mm Hg; pulse to 95, and respiratory rate to 44. Pulse oximetry, detectable at the earlobe only, was 94% saturation. After 50 mg labetalol, blood pressure fell to 134/77, but symptoms remained. For 2 hours blood pressure swung between 76/50 and 225/125, until delivery of the fetus. An arterial line could not be started because of extreme vasoconstriction. Central venous pressure was 13 cm H20. After artificial rupture of the membranes and removal of remaining PG, blood pressure stabilized. Delivery was accomplished without incident. The symptoms and labile blood pressure were considered to be due to intravascular injection of PGF2alpha, caused by repeated bolus injection at each uterine contraction. In case of PG induction for fetal demise, it is recommended that anesthesiologists be prepared to treat intravascular collapse, hypertension and bronchoconstriction.

Topics: Abortion, Induced; Absorption; Adult; Anesthesia, Epidural; Bronchial Spasm; Dinoprost; Ephedrine; Female; Humans; Hypertension; Hypotension; Infusions, Intravenous; Pregnancy

In this paper we report an inhibitory effect of (-)-baclofen on many models of bronchial hyperreactivity both in vivo and in vitro. (-)-Baclofen protects guinea-pigs from the anaphylactic bronchospasm induced in sensitized animals by an ovalbumin aerosol and from that induced by aerosols of histamine and PGF2 alpha. Moreover (-)-baclofen reduces the TXA2 and TXB2 output induced by ovalbumin from isolated sensitized guinea-pig lungs. On the other hand (-)-baclofen does not show antihistaminic, anticholinergic or antiprostaglandinic action on isolated tracheal preparations. It is concluded that baclofen can provide protection from bronchial hyperreactivity possibly through a modulation of autonomic nervous system activity.

Topics: Acetylcholine; Anaphylaxis; Animals; Baclofen; Bronchial Spasm; Dinoprost; Guinea Pigs; Histamine Antagonists; Lung; Male; Prostaglandins F; Thromboxane A2; Thromboxane B2

We studied the effects of repeated exposures of antigen on airway reactivity to mediators of anaphylaxis and immediate response to the antigen. Seven antigen-sensitive sheep were exposed to aerosols of Ascaris suum antigen 5 times biweekly; a control group of seven sheep underwent the same exposure regimen with saline vehicle. Sheep were assigned to experimental (Ascaris) or control groups so the distribution of animals with regard to bronchial reactivity to mediators was about the same. Airway reactivity was assessed by determining the effects of aerosolized histamine (10-1,000 micrograms), prostaglandin F2 alpha (PGF2 alpha, 10-300 micrograms), and a stable analogue of thromboxane A2 (U-46619, 1-100 micrograms) on lung resistance (RL) and dynamic lung compliance (Cdyn). Before treatment, experimental and control groups showed similar changes in RL and Cdyn, with analogue greater than histamine greater than PGF2 alpha. At the highest dose of each agonist, mean increases in RL were 50, 123, and 29%, respectively, and mean decreases in Cdyn were 21, 45, and 12%. During the first 15-min exposures to antigen aerosol, mean RL had increased by 125% and Cdyn decreased by 38% of base-line values; hyperinflation following the exposures reduced the changes to 56 and 31%, respectively. Changes in RL and Cdyn during the final antigen exposures and following postexposure hyperinflation were reduced significantly (P less than 0.05) compared with the initial exposures. Baseline RL and Cdyn before and after the exposures to antigen or saline were not significantly different. Airway reactivity to histamine, PGF2 alpha, or analogue was not significantly altered in these atropinized animals over the range of doses studied.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aerosols; Airway Resistance; Animals; Antigens; Ascaris; Bronchial Provocation Tests; Bronchial Spasm; Dinoprost; Dose-Response Relationship, Drug; Histamine; Lung; Mast Cells; Neutrophils; Prostaglandins F; Sheep; Skin Tests

We have studied the effect of repeated in vivo antigen exposure on in vitro airway responsiveness in sensitized sheep. Fourteen sheep underwent five biweekly exposures to aerosolized Ascaris suum antigen or saline. Following this exposure regimen, the animals were killed and tracheal smooth muscle and lung parenchymal strips were prepared for in vitro studies of isometric contraction in response to histamine, methacholine, prostaglandin F2 alpha, and a thromboxane A2 analogue. No alteration in tracheal smooth muscle responsiveness was observed between saline- and antigen-exposed tissue. In contrast, by use of lung parenchymal strips as an index of peripheral airway responsiveness, significant increases in responsiveness to histamine and a thromboxane A2 analogue (10(-6) and 10(-5) M) were observed in antigen-exposed tissue compared with saline controls. These results demonstrate that repeated antigen exposure in vivo selectively increase the responsiveness of peripheral lung smooth muscle to certain chemical mediators of anaphylaxis.

Topics: Animals; Antigens; Ascaris; Bronchial Spasm; Dinoprost; Histamine; Lung; Methacholine Chloride; Methacholine Compounds; Muscle Contraction; Muscle, Smooth; Prostaglandins F; Respiratory System; Sheep; Thromboxane A2; Trachea

Prostaglandin F2 alpha (PGF2 alpha) is generated by human lung tissue in response to a number of stimuli and is widely viewed as a bronchoconstrictor mediator. We have shown that aerosolized PGF2 alpha in concentrations between 1 and 100 micrograms/ml caused dose-related bronchoconstriction, but that continued stimulation at higher concentrations resulted in a partial return of pulmonary function toward control, suggesting that airways were refractory to further stimulation. To explore the mechanism and specificity of airway refractoriness induced by PGF2 alpha, we examined bronchomotor responses evoked by repeated PGF2 alpha stimulation, repeated histamine stimulation, and PGF2 alpha stimulation followed by histamine. Studies were carried out on 3 separate days in 7 subjects with allergic asthma. For each subject the aerosol concentration of each agonist remained constant throughout the study. Responses were measured as the percent change in FEV1 versus time, and comparisons were made between the first and second agonist challenge of each study day. We found that prior stimulation with PGF2 alpha resulted in diminished airway responsiveness, not only to PGF2 alpha but to histamine as well. In contrast, similar refractoriness could not be induced by repeated histamine stimulation, indicating that the PGF2 alpha-induced decrease in responsiveness was not a nonspecific effect of bronchoconstriction per se. Further, the finding that PGF2 alpha caused a decrease in the response to histamine suggests that diminished airway responsiveness was not due to down-regulation of specific PGF2 alpha receptors. Our findings suggest that in addition to its bronchoconstrictor properties, PGF2 alpha may play a role in the modulation of acute airway responses.

Topics: Adolescent; Adult; Aerosols; Asthma; Bronchi; Bronchial Provocation Tests; Bronchial Spasm; Dinoprost; Dose-Response Relationship, Drug; Forced Expiratory Volume; Histamine; Humans; Male; Prostaglandins F

Topics: Adult; Asthma; Bronchial Provocation Tests; Bronchial Spasm; Dinoprost; Female; Humans; Male; Prostaglandins E; Prostaglandins F; Radioimmunoassay

The effect of nifedipine, a calcium slow channel blocking drug, was investigated by varying routes of administration in a canine model of pharmacologically induced bronchoconstriction. Control bronchopulmonary responses, i.e., increases in pulmonary resistance (RL) and decreases in dynamic lung compliance were accomplished by aerosols of prostaglandin F2 alpha and histamine in normal pentobarbital-anesthetized beagles. When infused i.v. within the range 200 to 400 micrograms/kg, nifedipine afforded significant protection vs. RL changes due to prostaglandin F2 alpha (84--89% inhibition). Aerosol pretreatment by nifedipine (0.1 and 1.0%) also produced significant inhibition in RL changes caused by prostaglandin F2 alpha. A single i.v. injection (200 micrograms/kg) of nifedipine provided significant protection against RL changes due to a histamine challenge for 240 min. The onset of protection occurred within 15 min and maximum protection occurred during the 60 to 90-min period after the single injection of nifedipine. A single aerosol pretreatment of nifedipine (0.1%) significantly blocked RL changes against successive histamine aerosol challenges at 15-, 30- and 60-min time periods. Infused nifedipine failed to have any relaxant effect on the resting base line of either RL or dynamic lung compliance, whereas aerosolized nifedipine did decrease resting airway tone intrinsically, although not significantly. In addition, cardiovascular side effects by the aerosol route were slight compared to those observed by the i.v. route of nifedipine. Therefore, delivery of a calcium channel antagonist by either the aerosol or i.v. route can inhibit pharmacologically induced bronchoconstriction.

Topics: Aerosols; Anesthesia; Animals; Bronchial Spasm; Calcium Channel Blockers; Dinoprost; Dogs; Female; Histamine; Injections, Intravenous; Male; Nifedipine; Prostaglandins F; Pyridines

Prostaglandins are mainly used in clinical medicine for midterm abortion and to terminate pregnancy. Systemic adverse reactions include nausea and vomiting, which occur in approximately half of the patients and, to a lesser extent, diarrhea. Although bronchospasm occurs infrequently, PGF2 should be avoided in asthmatics. Cardiorespiratory failure culminating in prolonged coma and death has been reported. Moreover, convulsions and EEG changes have been observed in a comparatively small number of cases.

Topics: Abortifacient Agents; Abortion, Induced; Bronchial Spasm; Diarrhea; Dinoprost; Dinoprostone; Female; Heart Arrest; Humans; Pregnancy; Prostaglandins; Prostaglandins E; Prostaglandins E, Synthetic; Prostaglandins F; Seizures; Vomiting

The introduction of dinoprost tromethamine (Prostin F2 Alpha) as an abortifacient in the second trimester of pregnancy represents the first clinical use of a prostaglandin. Various synthetic analogues of the naturally occurring derivatives are being employed investigationally in the treatment of peptic ulcer, hypertension, asthma, and hypercalcemia. In the United States, dinoprost tromethamine is primarily administered intra-amniotically. Despite the fact that a substantial number of patients experience allergic reactions, hypertension, bronchospasm, nausea, vomiting, cramps, and diarrhea, the efficacy and relative safety of dinoprost tromethamine establish it as superior to intra-amniotic instillation of hypertonic saline. Cervical laceration, laceration or rupture of the lower uterine segment, retention of the placenta, and hemorrhage in part reflect the intensity of uterine contraction induced by dinoprost. Experience in administration improves the therapeutic response and diminishes adverse reactions.

Topics: Abortifacient Agents; Bronchial Spasm; Diarrhea; Dinoprost; Dose-Response Relationship, Drug; Drug Evaluation; Drug Hypersensitivity; Female; Humans; Hypertension; Injections; Muscle Contraction; Myometrium; Nausea; Pregnancy; Pregnancy Trimester, Second; Prostaglandins F; Vomiting