Iloprost (ZK 36374) modulates the responses to beta-adrenoceptor agonists in guinea-pig airways and pulmonary vasculature

The effect of iloprost on airway smooth muscles and its influence on the actions of beta-agonists and histamine were studied in the isolated perfused lung and isolated tracheal strips from guinea-pigs. Bolus injection of iloprost into the pulmonary artery elicited a concentration-dependent decrease in pulmonary perfusion pressure and an increase in airway resistance. These effects are not mediated through cholinergic, serotoninergic and histaminergic receptors. A rapid tachyphylaxis affected the effect of iloprost in airway resistance but not in pulmonary perfusion pressure. Iloprost did not induce a response in the isolated tracheal strips and did not alter the effect of histamine in both tracheal strips and airway resistance. This compound, however, caused an inhibition in the airway resistance-reducing effect of adrenaline and isoprenaline in the isolated perfused lung and a potentiation in the perfusion pressure-increasing effect of adrenaline. Iloprost also inhibited the relaxing effect of adrenaline and isoprenaline in the isolated tracheal strips precontracted with histamine and potentiated the inhibitory effect of propranolol against adrenaline and isoprenaline. From these results it was concluded that: Iloprost, a stable analogue of prostacyclin, modulates the beta-adrenoceptor blocking effect of propranolol in both airway smooth muscles and pulmonary vasculature.     

The bronchodilator acitivity of an 11-deoxyprostaglandin (AY 23 578).

The bronchodilator activity of AY-23 578 was studied in vivo and in vitro techniques. In the conscious guinea pig, aerosols of AY-23 578, prostaglandin (PGE2) E2, and isoproterenol afforded significant protection against histamine-induced convulsions. In the anesthetized guinea pig, where changes in tracheal pressure were taken as an index of bronchoconstriction, AY-23 578, PGE2, and isoproterenol were equipotent in inhibiting the bronchoconstriction induced by histamine. AY-23 578, PGE2, and isoproterenol reduced or prevented neostigmine-, prostaglandin F2alpha- or carbachol-induced increases in pulmonary resistance, and decreases in dynamic compliance in the anesthetized cat. The activities of the former two compounds were qualitatively similar but less potent than isoproterenol. In both the guinea pig and the cat, the aerosol administration of effective bronchodilator doses of AY-23 578 did not exhibit any significant cardiovascular effects. Both AY-23 578 and PGE2 caused relaxation of the isolated guinea pig tracheal strip; PGE2 was about six times more potent than AY-23 578. It is concluded that AY-23 578 is an effective bronchodilator in both the guinea pig and cat.     

Inhibition of antigen and calcium ionophore A23187 induced contractions of guinea pig airways by isoprenaline and forskolin

Isoprenaline and forskolin both inhibit contractions induced by antigen or by the calcium ionophore A23187 of guinea pig tracheal spirals and parenchymal strips. Antigen-induced airway contraction is considerably more sensitive to the inhibitory effects of isoprenaline than is A23187-induced contraction. In contrast, forskolin is equiactive as an inhibitor of antigenic and ionophoric contractions. Forskolin is a more effective inhibitor of the prolonged phase of antigen-induced tracheal contraction than of the initial peak phase, which may suggest selectivity for the lipoxygenase pathway of arachidonic acid metabolism. Isoprenaline inhibits the mechanisms of the primary peak phase and of the prolonged phase equally. Although there were little, if any, differences between normal and sensitized tissues in the modulation of A23187-induced contractions of parenchyma, distinct differences were observed in trachea. Low concentrations (10(-8)-10(-7) M) of isoprenaline and forskolin enhanced A23187-induced contraction of sensitized, but not normal trachea. Higher concentrations were inhibitory. The results demonstrate that sensitization affects the modulation by isoprenaline and forskolin of A23187-induced contraction of guinea pig trachea.     

A novel anti-asthmatic quinone derivative, AA-2414 with a potent antagonistic activity against a variety of spasmogenic prostanoids

The anti-asthmatic activity of AA-2414 [(+/-)-7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptano ic acid] has been studied in vivo and in vitro. Experimental allergic asthma was inhibited by orally administered AA-2414 in a dose-dependent manner. AA-2414, 0.08-1.25 mg/kg (p.o.), inhibited the bronchconstriction in guinea pigs induced by a prostaglandin endoperoxide analogue (U-46619), leukotriene D4 (LTD4), and platelet activating factor (PAF) with a long duration of action. The compound did not inhibit histamine-induced bronchoconstriction. AA-2414 reduced the induction of pulmonary inflation caused by LTD4 aerosol inhalation. AA-2414 competitively inhibited the contractile response to U-46619 in guinea pig tracheal and parenchymal strips and dog saphenous vein strips with pA2 values of 7.69, 8.29 and 6.79, respectively. Furthermore, the contractile responses of guinea pig tracheal strip to PGD2, 9 alpha, 11 beta-PGF2 and PGF2 alpha were inhibited with pA2 values of 7.20, 7.79 and 5.71, respectively. These results suggest that AA-2414, a quinone derivative, is a novel, potent and orally active antagonist of a variety of spasmogenic prostanoids.     

Biological activity of leukotriene sulfones on respiratory tissues

The biological activity of synthetic leukotriene C4, D4 and E4 sulfone has been determined in respiratory smooth muscle in vitro and in vivo. The sulfones of LTC4, LTD4 and LTE4 were potent contractile agonists on indomethacin-treated guinea pig tracheal chains with respective pD2-values of 8.2, 8.0 and 7.9. Contractions were submaximal (75-85% of the cholinergic maximum), slow in onset, prolonged in duration, slowly reversed by washing (compared to acetylcholine or histamine) and were partially reversed by 2 muM FPL-55712. The sulfones of LTC4, LTD4 and LTE4 also contracted indomethacin-treated guinea pig parenchyma (respective pD2's of 7.9 8.2 and 7.8) and rat parenchyma (respective pD2's of 7.1, 7.2 and 7.2) but were inactive on rat trachea (0.01-2.0 muM). When administered intravenously to anaesthetized guinea pigs, the sulfones of LTD4, LTE4 and to a lesser degree LTC4 (respective ED50's - 0.5; 2.0 and 4.6 microgram/kg) elicited dose-dependent increases in inflation pressure which were antagonized by FPL-55712 and indomethacin. Leukotriene C4, D4 and E4 sulfones display a qualitatively similar profile of biological activity to that of their corresponding sulfides.     

A comparison of the bronchodilator activity of (±) 11-deoxy prostaglandin E1 with its 15-methyl analogue, (doxaprost)

The bronchodilator activity of (±) 11-deoxy prostaglandin E₁ was compared to the activity of its (±) 15-methyl analogue, (doxaprost). Both compounds inhibited histamine-induced bronchoconstriction in the anesthetized guinea pig where changes in tracheal pressure were measured. Doxaprost was 73 and 32 times more potent than (±) 11-deoxy PGE₁ by the aerosol and i.v. routes, respectively. Doxaprost also demonstrated a longer duration of effect. Both compounds decreased pulmonary resistance in the 5HT tonal cat. There was no difference in the potency of the two compounds. However, doxaprost had a longer duration of effect. Both compounds caused a fall in mean arterial blood pressure after i.v. administration in the guinea pig but not after aerosol administration in the guinea pig and cat. Both compounds caused relaxation of the isolated guinea pig tracheal strip when tone was induced with carbachol. There was no difference in the potency of the two compounds. The increased activity $\text{in vivo}$ but not $\text{in vitro}$ of the 15-methyl analogue doxaprost is consistent with a lack of enzyme inactivation.     

Endotracheal cuff pressure and tracheal mucosal blood flow: endoscopic study of effects of four large volume cuffs.

Large volume, low pressure endotracheal tube cuffs are claimed to have less deleterious effect on tracheal mucosa than high pressure, low volume cuffs. Low pressure cuffs, however, may easily be overinflated to yield pressures that will exceed capillary perfusion pressure. Various large volume cuffed endotracheal tubes were studied, including Portex Profile, Searle Sensiv, Mallinkrodt Hi-Lo, and Lanz. Tracheal mucosal blood flow in 40 patients undergoing surgery was assessed using an endoscopic photographic technique while varying the cuff inflation pressure. It was found that these cuffs when overpressurised impaired mucosal blood flow. This impairment of tracheal mucosal blood flow is an important factor in tracheal morbidity associated with intubation. Hence it is recommended that a cuff inflation pressure of 30 cm H2O (22 mm Hg) should not be exceeded.     

Relaxant effects of different fractions from Tymus vulgaris on guinea-pig tracheal chains

In previous studies, the relaxant effect of Tymus vulgaris has been demonstrated on guinea pig tracheal chains. Therefore, in the present study, the relaxant effects of n-hexane, dichloromethane, methanol and aqueous fractions of Tymus vulgaris on tracheal chains of guinea pigs were examined. The relaxant effects of four cumulative concentrations of each fraction (0.4, 0.8, 1.2 and 1.6 g%) in comparison to saline as negative control and four cumulative concentrations of theophylline (0.2, 0.4, 0.6 and 0.8 mM) were examined for their relaxant effects on precontracted tracheal chains of guinea pig by 60 mM KCl (group 1) and 10 ìì methacholine (group 2, n = 7 for each group). In group 1, all concentrations of the n-hexane fraction and theophylline and three last concentrations (0.8, 1.2 and 1.6 g%) of dichloromethane and two higher concentrations (1.2 and 1.6 g%) of methanol fractions showed significant relaxant effects compared to that of saline (p<0.05 to p<0.001). In group 2, all concentrations of theophylline, n-hexane and dichloromethane fractions and three concentrations (0.8, 1.2 and 1.6 g%) of methanol and two higher concentrations (1.2 and 1.6 g%) of aqueous fractions showed significant relaxant effects compared to that of saline (p<0.05 to p<0.001). In addition, with group 1, the relaxant effect of all concentrations of all fractions except the n-hexane fraction, were significantly less than those of theophylline (p<0.05 to p<0.001). The n-hexane fraction showed higher relaxant effect than theophylline. The relaxant effect of all concentrations of the n-hexane fraction and the three last concentrations (0.8, 1.2 and 1.6 g%) of dichloromethane and aqueous fractions were significantly greater in group 2 than in group 1 (p<0.05 to p<0.001). There were significant positive correlations between the relaxant effects and concentrations for theophylline and all fractions (except aqueous fraction in group 1) in both groups, but a negative correlation for the aqueous fraction in group 1 (p<0.05 to p<0.001). These results showed a potent relaxant effect for n-hexane and weaker relaxant effect for other fractions from Tymus vulgaris on tracheal chains of guinea pigs.     

Isolation, characterization, and pharmacological actions of peptide histidine valine 42, a novel prepro-vasoactive intestinal peptide-derived peptide

The primary structure and biological activity of a novel prepro-vasoactive intestinal peptide (prepro-VIP)-derived peptide has been determined from an adrenal pheochromocytoma. The peptide was purified sufficiently for characterization by fast atom bombardment mapping after cation-exchange and reverse-phase fast protein liquid chromatography. The sequence of this novel peptide corresponds exactly to prepro-VIP-81-122 and has been designated peptide histidine valine 42 (PHV-42). Synthetic PHV-42 reduced both the force and frequency of spontaneous contractions of isolated rat uterus and was at least 12 times more potent than peptide histidine methionine (prepro-VIP-81-107), and over a hundred times more potent than noradrenaline. PHV-42 was also more potent than peptide histidine methionine in relaxing smooth muscle preparations of rat stomach and guinea pig trachea, but was approximately 4-fold less potent in reducing blood pressure than VIP. PHV-42 thus forms a separate subsystem in the VIP family of peptides and may be the most biologically active product of prepro-VIP in certain tissues such as the uterus and trachea.     

Effects of pneumatic antishock garment inflation in normovolemic subjects

This study examines the effects of inflation of pneumatic antishock garments (PASG) in 10 normovolemic men (mean age 44 +/- 6 yr) undergoing diagnostic catheterization. Seven subjects had normal heart function and no evidence of coronary artery disease (CAD); three patients had CAD. High-fidelity multisensor catheters were employed to simultaneously record right and left heart pressures before PASG inflation and after inflation to 40, 70, and 100 mmHg. A thermal dilution catheter was used to obtain pulmonary capillary wedge pressure and cardiac output. Counterpressure increases greater than or equal to 40 mmHg were associated with significant changes in left and right heart pressures. Right and left ventricular end-diastolic pressures increased 100% (P less than 0.01); mean pulmonary arterial and aortic pressures increased 77 and 25%, respectively (P less than 0.01); systemic vascular resistance increased 22% (P less than 0.05) and pulmonary vascular resistance did not change in normal subjects at maximum PASG inflation. Heart rate, cardiac output, and aortic and pulmonary arterial pulse pressures did not change during inflation in either group. Right and left ventricular end-diastolic pressures and pulmonary capillary wedge pressure were greater (P less than 0.05) in the CAD group compared with the normal subjects during PASG inflation. The data suggest that the primary mechanism whereby PASG inflation induces changes in central hemodynamics in normovolemic subjects is through an acute increase in left ventricular afterload. PASG changes in afterload and pulmonary capillary wedge pressure imply that these devices should be used with caution in patients with compromised cardiac function.     

Atrial natriuretic peptide in hypoxia

A growing number of mammalian genes whose expression is inducible by hypoxia have been identified. Among them, atrial natriuretic peptide (ANP) synthesis and secretion is increased during hypoxic exposure and plays an important role in the normal adaptation to hypoxia and in the pathogenesis of cardiopulmonary diseases, including chronic hypoxia-induced pulmonary hypertension and vascular remodeling, and right ventricular hypertrophy and right heart failure. This review discusses the roles of ANP and its receptors in hypoxia-induced pulmonary hypertension. We and other investigators have demonstrated that ANP gene expression is enhanced by exposure to hypoxia and that the ANP so generated protects against the development of hypoxic pulmonary hypertension. Results also show that hypoxia directly stimulates ANP gene expression and ANP release in cardiac myocytes in vitro. Several cis-responsive elements of the ANP promoter are involved in the response to changes in oxygen tension. Further, the ANP clearance receptor NPR-C, but not the biological active NPR-A and NPR-B receptors, is downregulated in hypoxia adapted lung. Hypoxia-sensitive tyrosine kinase receptor-associated growth factors, including fibroblast growth factor (FGF) and platelet derived growth factor (PDGF)-BB, but not hypoxia per se, inhibit NPR-C gene expression in pulmonary arterial smooth muscle cells in vitro. The reductions in NPR-C in the hypoxic lung retard the clearance of ANP and allow more ANP to bind to biological active NPR-A and NPR-B in the pulmonary circulation, relaxing preconstricted pulmonary vessels, reducing pulmonary arterial pressure, and attenuating the development of hypoxia-induced pulmonary hypertension and vascular remodeling.     

Plasma atrial natriuretic peptide levels in children with cardiac diseases: correlation with cGMP levels and haemodynamic parameters

In children with various forms of cardiac diseases (aged 2 months to 16 years) significantly higher plasma atrial natriuretic peptide (ANP; range 36-680, median 247 pg/ml) and cyclic 3'5'-guanosine monophosphate (cGMP; range 0.2-46, median 8.2 pmol/ml) levels were found than in control children (p less than 0.0001). In control children (aged 4 months to 17 years) plasma ANP and cGMP levels were measured in the range of 2.4-98 pg/ml and of 0.2-2.8 pmol/ml, respectively. There was a linear correlation between the two parameters in children with cardiac diseases (r = 0.62, p less than 0.01). Children with elevated mean right atrial pressure (i.e., greater than 6 mm Hg) showed significantly higher plasma ANP levels than children with normal atrial pressure (p less than 0.01). However, there was only a weak linear correlation between mean right atrial pressure and plasma ANP levels (r = 0.48, p less than 0.01). Plasma ANP levels from right atrium, pulmonary artery, left atrium and left ventricle were significantly higher than those from vena cava (p less than 0.05). Analysis of ANP-like immunoreactive material by high performance liquid chromatography suggested that alpha-ANP is the major form of circulating ANP in blood of children with cardiac diseases.     

The pharmacology of L-670,596, a potent and selective thromboxane/prostaglandin endoperoxide receptor antagonist

L-670,596 ((-)6,8-difluoro-9-rho-methylsulfonyl benzyl-1,2,3,4- tetrahydrocarbazol-1-yl-acetic acid) has been shown to be a potent receptor antagonist as evidenced by the inhibition of the binding of 125I-labeled PTA-OH to human platelets (IC50, 5.5 x 10(-9) M), inhibition of U-44069 induced aggregation of human platelet rich plasma (IC50, 1.1 x 10(-7) M), and competitive inhibition of contractions of the guinea pig tracheal chain induced by U-44069 (pA2,9.0). The compound was also active in vivo as shown by inhibition of arachidonic acid and U-44069 induced bronchoconstriction in the guinea pig (ED50 values, 0.04 and 0.03 mg/kg i.v., respectively), U44069 induced renal vasoconstriction in the pig (ED50, 0.02 mg/kg i.v.), and inhibition of ex vivo aggregation of rhesus monkey platelets to U-44069 (active 1-5 mg/kg p.o.). The selectivity of the compound was indicated by the failure to inhibit, first, ADP-induced human or primate platelet aggregation and, second, bronchoconstriction in the guinea pig in vivo and contraction of the guinea pig tracheal chain in vitro to a variety of agonists. It is concluded that L-670,596 is a potent, selective, orally active thromboxane A2/prostaglandin endoperoxide receptor antagonist.     

The effects of some natural prostaglandins on isolated human circular bronchial muscle.

PGE1 relaxed isolated human circular bronchial muscle over a wide concentration range as did isoprenaline. Surprisingly isoprenaline was more potent than PGE1. PGF2alpha weakly contracted this muscle preparation whereas histamine was more potent. PGE2, however, produced paradoxical results, relaxing some tissues and contracting others, always in a concentration-related manner irrespective of tissue tone. In preparations that contracted to PGE2, tachyphylaxis induced to PGF2alpha also applied to PGE2, but did not affect PGE1 relaxations of histamine contractions. These findings suggest that pge2 can stimulate either PGF2alpha or PGE1 receptors of isolated human bronchial muscle.     

Influence of pulmonary inflations on discharge of pontile respiratory neurons

The purpose of this study was to characterize the influence of pulmonary inflations on the discharge patterns of rostral pontile respiratory neurons. Decerebrate and paralyzed cats were ventilated with a servo-respirator which produced patterns of pulmonary inflation, assessed by tracheal pressure, which paralleled alterations in integrated activity of the phrenic nerve. Neurons with respiratory-modulated neuronal activities were recorded in the pneumotaxic region of the nucleus parabrachialis medialis and Kolliker-Fuse nucleus, as well as in the trigeminal motor nucleus. Approximately equal numbers of neurons had phasic and tonic respiratory-modulated discharge patterns. The discharge patterns of most neurons were not qualitatively altered when pulmonary inflation was prevented. However, withholding inflation did cause the recruitment of some respiratory-modulated neuronal activities. Similar findings were obtained in normocapnia and hypercapnia. Results support the concept that the discharge of neurons in the pneumotaxic region may exert phasic, as well as tonic, influences on ventilatory activity.     

Release of atrial natriuretic polypeptide by graded right atrial distension in anesthetized dogs

In order to verify the contribution of right atrial pressure to atrial natriuretic polypeptides (ANP) release, we measured plasma levels of immunoreactive (ir)-ANP when graded rise of right atrial pressure was executed in anesthetized dogs. Increasing right atrial pressure (RAP) from 2.7 +/- 0.6 to 9.0 +/- 0.7 mmHg, plasma levels of ir-ANP in aorta tended to increase by 33% but not significantly (p greater than 0.05). However, when RAP was increased from 9.0 +/- 0.7 to 17.0 +/- 1.1 mmHg, ir-ANP levels in aorta were significantly (p less than 0.05) increased by 132% of control within 5 min from the start of RAP elevation. The RAP elevation produced a sustained increase in plasma levels of ir-ANP. There was a positive correlation between right atrial pressure and plasma levels of ir-ANP. The plasma levels of ir-ANP were similar between aorta and pulmonary artery. These results demonstrate that increasing atrial pressure is closely correlated with ANP release and ANP is not greatly metabolized by pulmonary circulation.     

Design,synthesis and in vitro evaluation of (R)-4-(2-(tert-butylamino)-1-hydroxyethyl)-2-(hydroxymethyl)phenyl hydrogen phenylboronate: A novel salbutamol derivative with high intrinsic efficacy on the β2 adrenoceptor

We tested a set of boron containing arylethanolamine derivatives on the human and guinea pig β₂ adrenoceptor (β₂AR) 3-D structures by docking methodology. The compound with the highest affinity based on docking analysis, (R)-4-(2-(tert-butylamino)-1-hydroxyethyl)-2-(hydroxymethyl)phenyl hydrogen phenylboronate (boronterol) was synthesized, characterized and tested in guinea pig tracheal rings at basal tone and with histamine-induced contractions. Boronterol was at least eightfold more potent than salbutamol as a smooth muscle relaxant drug (judged by the EC₅₀ values) and showed a similar maximal relaxant effect as isoproterenol. ICI118,551 showed competitive antagonism on the relaxing effect of boronterol. These results suggest the β₂AR agonist action of boronterol.     

Comparison of Cardiorespiratory Effects of Isoprenaline and Salbutamol in Patients with Bronchial Asthma

The effects of isoprenaline and salbutamol administered orally, by inhalation, or by intravenous infusion were compared in 13 asthmatic patients. Bronchodilator activity was assessed by serial measurement of specific airways conductance (SGaw). Log-dose response curves were obtained for both drugs and showed them to be equipotent as bronchodilators. Cardiovascular effects were variable, but in general, isopenaline caused greater rise in pulse rate and a greater change in blood pressure than the same dose of salbutamol.Cardiorespiratory measurements during continuous intravenous infusion of increasing doses of both drugs suggested a greater effect of isoprenaline than the same dose of salbutamol on metabolic rate, pulmonary ventilation, pulmonary gas exchange, cardiac output, and heart rate. The effect of salbutamol on the heart rate was about 10 times less than that of isoprenaline but lasted longer.     

Bornchoconstriction induced by N-formyl-methionyl-leucyl-phenylalanine in t he guinea pig; involvement of arachidonic acid metabolites

The chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (F-met-leu-phe) was shown to be a potent myotropic agent on the guinea-pig parenchymal strip (IC₅₀), 2 × 10⁻⁷ M). The response was unaffected by the histamine (H₁) antagonist, mepyramine, but in the presence of the cyclooxygenease inhibitor, indomethacin, the dose response curve was shifted to the left (IC₅, 4 × qo⁻⁸ M) and the maximal response reduced. Injection of F-met-leu-phe into perfused guinea pig lungs resulted in the release of leukotriene-like activity which was detected by superfusion over guinea-pig ileum preparations in the presence and absence of FPL-55712. Intravenous injection of F-met-leu-phe to spontaneously breathing anaesthetized guinea pigs resulted in transient increases in pulmonary resistance and blood pressure and decreases in dynamic compliance and heart rate. The pulmonary parameters were significantly inhibited by BW 755C, indomethacin, FPL-55712 and a contractile prostanoid antagonist, L-640,305. These results demonstrate that F-met-leu-phe is potent bronchoconstrictor in the guinea pig and that the peptide may induce these changes through the generation of products of the cyclooxygenase and lipoxygenase pathways of arachidonic acid metabolism.     

Phosphoramidon potentiates the bronchoconstriction induced by inhaled bombesin in guinea pigs

The effect of the neutral endopeptidase inhibitor, phosphoramidon, on the bronchoconstriction induced by aerosolized bombesin in the guinea pig was investigated. Administered by aerosol for 1 min, bombesin (0.01 or 0.1 mg/ml) induced a dose-dependent increase in pulmonary inflation pressure. Pretreatment of the guinea-pigs with phosphoramidon (0.1 mM), administered by aerosol for 15 min, 15 min prior to challenge, markedly potentiated the increase in pulmonary inflation pressure induced by bombesin (0.01 mg/ml) and substance P (0.1 mg/ml). This result suggests a local hydrolysis of bombesin by airway neutral endopeptidase reducing the activity of this peptide on smooth muscle.