Biomedical subjects

E Naline

Publications and source records attributed to E Naline.

At least 73 records · Page 4Linked to original sources

PubMed1992

Effect of epithelium removal and of enkephalin inhibition on the bronchoconstrictor response to three endothelins of the human isolated bronchus.

The three endothelins ET-1, ET-2 and ET-3 induced a potent contractile response in the human isolated bronchus with an intact epithelium, which proceeded on two different stages. The first stage was observed at low concentrations (high potency) (10(-12) to 10(-9) M) but corresponded to a low intrinsic activity (Emax maximal effect induced by ACh 10(-3) M), the second stage appeared at higher concentrations and corresponded to higher intrinsic activity. The rank order of potency for the two stages of contractile activity was ET-1 greater than ET-2 = ET-3. Removal of the epithelium significantly enhanced the two stages of the contractile responses to the three endothelins and abolished the differences in potency efficacy that were observed between ET-1, ET-2 and ET-3 when the epithelium was present. Phosphoramidon (10(-5) M), an enkephalinase inhibitor, was as potent as epithelium removal in enhancing the contractile responses to these agonists at low concentrations (first stage of contraction, 10(-16) to 10(-9) M). However, with high concentrations of endothelins (greater than 10(-9) M, second stage of contraction), phosphoramidon was less potent than epithelium removal in enhancing the contractile responses. In epithelium-denuded strips, preincubation with phosphoramidon did not further increase the maximal contractions induced by/or the potencies of ET-1, ET-2 or ET-3. After epithelium removal, responses to low doses of endothelins were attenuated by nicardipine (10(-6) M) whereas responses to high doses of the endothelins were not affected, as was also observed when the epithelium was present. (ABSTRACT TRUNCATED AT 250 WORDS)

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1992

A potent and selective non-peptide antagonist of the neurokinin A (NK2) receptor.

SR 48968 is a potent and selective non-peptide antagonist of the neurokinin A (NK2) receptor. SR 48968 selectively inhibited neurokinin A binding to its receptor and was a competitive antagonist of neurokinin A-mediated contraction of different isolated smooth muscle preparations from various species including human. In vivo, the compound inhibited the bronchoconstriction induced by neurokinin A in guinea pigs. SR 48968 can be used to study the physiological or pathological role of neurokinin A and may be useful in the treatment of neurokinin A-dependent pathology.

Animals↗

PubMed1992

Contractile effect of alpha,beta-methylene ATP on the guinea-pig isolated trachea.

The effects of alpha,beta-methylene adenosine 5'-triphosphate (alpha,beta-methylene ATP), 2-chloroadenosine and R-PIA (N6-(L-2-phenylisopropyl)-adenosine) and their interaction with dipyridamole, indomethacin, 8-phenyl-theophylline, diazepam and other agonists of central or peripheral benzodiazepine receptors were studied on the guinea-pig isolated trachea. alpha,beta-methylene ATP exerted contractile effects on the guinea-pig isolated trachea; - log EC50 and E(max) values were 8.86 +/- 0.19 and 31.3 +/- 2.3 (n = 31) (% vs acetylcholine 10(-3) M) respectively. In comparison with other purinergic receptor agonists, the rank order of potency was: alpha,beta-methylene ATP greater than 2-chloroadenosine greater than R-PIA. alpha,beta-methylene ATP and 2-chloroadenosine had significantly (P less than 0.05) greater efficacy (E(max)) than R-PIA. Indomethacin (3 x 10(-6) M) and 8-phenyltheophylline (10(-7) to 10(-5) M) significantly reduced the contractile effect of 2-chloroadenosine and R-PIA but did not affect alpha,beta-methylene ATP-induced contraction. Conversely, dipyridamole significantly reduced (10(-7) M) or suppressed (10(-6) M) the contractile effects of alpha,beta-methylene ATP whereas it only partially reduced (10(-6) M) the contractile effects of high concentrations of 2-chloroadenosine or R-PIA. Diazepam potentiated the efficacy of alpha,beta-methylene ATP. The E(max) (% vs acetylcholine 10(-3) M) values were 26.1 +/- 2.0 (n = 10) in control conditions and 45.9 +/- 4.6 (n = 5; P less than 0.05) in the presence of diazepam 10(-5) M. Diazepam did not modify the contractile effects of 2-chloroadenosine or R-PIA. Ro5-4864 (10(-7) to 10(-5) M), an agonist of peripheral benzodiazepine receptors, potentiated the contractile effects of alpha,beta-methylene ATP to the same extent as diazepam. Clonazepam, an agonist of central benzodiazepine receptors, did not modify these effects. Antagonists of central (flumazenil) or peripheral (RP 52028) benzodiazepine receptors had no influence on the interaction between diazepam or Ro-4864 and alpha,beta-methylene ATP. In conclusion, alpha,beta-methylene ATP exerts on guinea-pig isolated trachea a contractile effect which is not modified by indomethacin and 8-phenyltheophylline, but is reduced by dipyridamole. It is suggested that this effect might involve P2 chi receptor stimulation.

2-Chloroadenosine↗

PubMed1992

Formoterol and salbutamol inhibit bradykinin- and histamine-induced airway microvascular leakage in guinea-pig.

1. The effects of the beta 2-adrenoceptor agonists, salbutamol and formoterol, on the increase of microvascular permeability induced by histamine or bradykinin in guinea-pig airways have been studied in vivo. Extravasation of intravenously injected Evans blue dye was used as an index of permeability. The effects of salbutamol and formoterol on the increase in pulmonary airway resistance induced by histamine or bradykinin have also been studied. 2. The increase in pulmonary airway resistance induced by histamine or bradykinin was totally inhibited by salbutamol and formoterol. The ED50 of the two mediators were 0.59 +/- 0.21 (n = 5) and 0.20 +/- 0.14 (n = 5) micrograms kg-1 respectively for salbutamol, and 0.13 +/- 0.12 (n = 6) and 0.02 +/- 0.01 (n = 6) micrograms kg-1 respectively for formoterol. 3. Salbutamol (10 and 30 micrograms kg-1) and formoterol (1 and 10 micrograms kg-1) inhibited the increase of microvascular permeability induced by histamine (30 micrograms kg-1) in the guinea-pig airways. The inhibitory effect was predominant in the trachea and the main bronchi, with a maximum inhibition of 20 to 50%. The two drugs had little or no inhibitory effect on the other structures studied, viz. nasal mucosa, larynx, proximal and distal intrapulmonary airways. 4. Salbutamol and formoterol (1 and 10 micrograms kg-1) abolished the increase in microvascular permeability induced by bradykinin (0.3 micrograms kg-1). This inhibitory effect of two beta-adrenoceptor stimulants was predominant in the trachea and the nasal mucosa where it was observed with 1 microgram kg-1 of the beta-adrenoceptor agonists.In the main bronchi, and in the proximal and distal intrapulmonary airways, the effects of bradykinin were abolished by 10 pg kg- of formoterol and salbutamol.5. The effects of bradykinin, but not those of histamine, were significantly reduced (nasal mucosa, main bronchi and distal intrapulmonary airways) or abolished (trachea, proximal intrapulmonary airways) by morphine 10mgkg-1, i.v. These results suggest that an indirect effect, through non-adrenergic noncholinergic (NANC) nerves is involved in the action of bradykinin on the microvascular permeability.6. In conclusion, intravenously injected beta-adrenoceptor stimulants can inhibit, partially or totally, the increase of airways microvascular permeability induced by intravenous histamine or bradykinin. However, these effects require doses that are higher than those that inhibit the increase in pulmonary airway resistance induced by these mediators. As suggested by the results obtained with morphine, the higher efficacy of beta2-adrenoceptor agonists versus bradykinin may occur through activation of presynaptic receptors of the non-adrenergic non-cholinergic (NANC) nerves preventing release of inflammatory neuropeptides such as substance P and neurokinin A.

Adrenergic beta-Agonists↗

PubMed1992

Contractile activity of big endothelin-1 on the human isolated bronchus.

1. We have studied the contractile activity of the 39 amino acid precursor of endothelin-1 (ET-1), big endothelin-1 (big ET-1), on human isolated bronchi. The contribution of the metalloproteases, neutral endopeptidase (NEP) and angiotensin converting enzyme (ACE), in the presence or absence of the epithelium lining, by use of specific inhibitors, was also evaluated on the effects of big ET-1. 2. Big ET-1 elicited a potent contraction of human isolated bronchus. The -log EC50 value for big ET-1 was 7.53 +/- 0.08 (n = 11) and Emax 78.5 +/- 3.8% (% of ACh 3mM). 3. Incubation of human isolated bronchi with the NEP inhibitor phosphoramidon (10(-5) M) induced a rightward shift of the concentration-response curve induced by big ET-1 (10(-9) M to 3 x 10(-7) M). Similar results were observed when human bronchi were incubated with thiorphan (10(-5) M), but the shift to the right was significantly less (P less than 0.01) than that observed in the case of phosphoramidon (-0.35 +/- 0.05 vs -0.67 +/- 0.07 log unit). 4. The two inhibitors of angiotensin I converting enzyme (ACE), captopril or enalapril diacid, did not affect the concentration-response curve for contraction induced by big ET-1. 5. When the epithelium was removed, a leftward shift of the concentration-response curve of big ET-1 (10(-9) M to 3 x 10(-7) M) was observed. Incubation of human isolated bronchi with phosphoramidon or thiorphan (10-5M) or with enalapril diacid or captopril did not modify the leftward shift of the concentration-response curve for big ET-1 after epithelium removal.6. These results suggest that big ET-1 elicits potent contractile activity in the human isolated bronchus and that its effect is the consequence of the conversion to ET-1 by a phosphoramidon-sensitive metalloprotease which, although different from NEP and ACE, appears to be similar to the endothelinconverting enzyme (ECE) described in other studies in animals.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1992

Effects on the isolated human bronchus of SR 48968, a potent and selective nonpeptide antagonist of the neurokinin A (NK2) receptors.

Tachykinins produce concentration-dependent contraction of the human isolated bronchus by stimulation of receptors that belong to the NK2 type. The aim of this study was to investigate the inhibitory effects of a new, potent, and selective nonpeptide antagonist of the neurokinin A (NKA) (NK2) receptors, SR 48968 [(S)-N-methyl-N-[4-acetylamino-4-phenylpiperidino-2-(3,4-dichlorophenyl) butyl]benzamide] on human isolated airways. Our experiments were performed on human isolated bronchi obtained from patients with lung cancer. Phosphoramidon, 10(-5) M, was added to the bath to inhibit neurokinin metabolism. SR 48968 induced a parallel shift to the right of the concentration-response (C/R) curves to [Nle10]-NKA(4-10), a specific NK2 receptor agonist. The antagonism was of the competitive type, with a pA2 of 9.40 +/- 0.19 (slope = 0.95 +/- 0.08, n = 13). The (R)-enantiomer of SR 48968 was 100-fold less potent and a noncompetitive antagonist (slope = 0.56 +/- 0.11, n = 8); pA2 and slope of the racemate were 8.86 +/- 0.21 and 1.09 +/- 0.21 (n = 7), respectively. Under similar conditions, racemic CP-96,345, a nonpeptide NK1 antagonist, did not modify the C/R curves to [Nle10]-NKA(4-10) until 10(-7) M. SR 48968 did not modify C/R curves to acetylcholine, histamine, KCI, or PGF2 alpha on the human isolated bronchus. Finally, SR 48968 shifted to the right C/R curves to substance P on isolated human bronchi, whereas racemic CP-96,345 was without effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗

PubMed1991

High-performance liquid chromatographic method for the determination of the three main oxidative and 3-carboxylic antipyrine metabolites in human urine.

The oxidative metabolism of xenobiotics is usually explored using the antipyrine test, which consists of determining the production clearances and urinary percentages of three major antipyrine metabolites 4-hydroxyantipyrine, norantipyrine and 3-hydroxymethylantipyrine. The total forms of these compounds are generally determined by high-performance liquid chromatography (HPLC). However, the 3-carboxylic acid metabolite (3-carboxyantipyrine), which is the ultimate oxidation form in the 3-hydroxylation pathway, should also be taken into account, but so far its determination by HPLC has not been reported. A simple and accurate HPLC method has now been developed to determine the three major metabolites plus 3-carboxyantipyrine. In this method, all compounds are extracted in an aprotic non-polar solvent, at pH 3.5 for the major metabolites and unchanged antipyrine, then at pH 0.9 for 3-carboxyantipyrine. Total forms are evaluated after enzymatic hydrolysis. Throughout the procedure, attention is paid to the relative instability of norantipyrine and 4-hydroxyantipyrine. Recovery, accuracy and precision are discussed. The method has been applied to the determination of relative amounts (percentage of the dose administered) excreted in the urine of ten adult subjects 48 h after ingestion of antipyrine (600 mg). The proportion of 3-carboxyantipyrine excreted was 4.5 +/- 0.2%, which is in agreement with published values obtained by gas chromatography. The excretion rates of the major metabolites also were similar to those reported in the literature, thereby confirming that the reported method is valid. 3-Carboxyantipyrine is totally excreted as the free form and norantipyrine almost completely as glucuroconjugate.

Antipyrine↗

PubMed1991

The effect of cetirizine on the human isolated bronchus: interaction with salbutamol.

The effects of cetirizine (C), a new generation, nonsedative, H1-antihistamine drug, were studied on human isolated bronchi. C is a potent antagonist of the bronchial muscle contraction induced by histamine, irrespective of whether C is administered by cumulative addition or prophylactically. In the former case, this effect of C was significant at a concentration of 3 X 10(-8) mol/L and was maximal at a concentration of 10(-5) mol/L. The -log of concentration of C causing 50% of the maximal effect induced was 7.30 +/- 0.05 (n = 6), and the effect produced was not significantly modified by bronchial epithelium removal. When C was administered prophylactically, the concentration-response curves to histamine were displaced to the right, but the reduction of maximum histamine response suggests a noncompetitive type of antagonism. C is devoid of notable anticholinergic effects. At concentrations of 10(-8) to 10(-7) mol/L, C proved capable of enhancing the relaxant effect produced by salbutamol (10(-7) to 3 X 10(-7) mol/L) on human isolated bronchi that had been contracted by either histamine or acetylcholine (ACh). The synergy appeared to be additive or potentiating, depending on salbutamol (SAL) concentrations. Under similar conditions, mepyramine does not potentiate the effects of SAL against histamine. Finally, at concentrations of 10(-8) to 10(-6) mol/L, C reduced the functional antagonism observed between SAL and ACh, as can be observed by the increase, in the presence of C, of the maximal relaxant effect of SAL on contractions produced by 10(-3) mol/L of ACh. We may, therefore, conclude that C appears to be a specific antihistamine on human isolated bronchi and that it appears to potentiate the bronchodilator effect of SAL on this preparation.

Acetylcholine↗

PubMed1991

Effect of atrial natriuretic peptide and on atriopeptins on the human isolated bronchus. Comparison with the reactivity of the guinea-pig isolated trachea.

ANF, ANF7-28 and atriopeptins (AP1, AP2 and AP3) (10(-11) to 3 x 10(-7) M) induce a relaxant response on the guinea-pig isolated trachea, which is partially potentiated by the enkephalinase inhibitor thiorphan 10(-5) M but is unmodified by epithelium removal. Conversely, these drugs were found to be without any significant relaxant effect on the isolated human bronchus. Several hypotheses, such as the activation of ANF receptors not located on airway smooth muscle or an indirect effect of ANF in vivo are suggested to explain the discrepancy between these in vitro results and those of clinical trials in asthmatic subjects.

Amino Acid Sequence↗

PubMed1991

Penetration of minocycline into lung tissues.

The penetration of minocycline into different lung tissues and bronchial mucus was studied in 17 patients undergoing pulmonary surgery for cancer. The patients received oral minocycline 100 mg at night for 3 days preceding surgery. Minocycline concentrations were measured in plasma samples collected before the operation and in tissues and mucus taken from in and around the part of the lung that was surgically removed. Mean tissue or mucus concentration to plasma concentration ratios were 3.78 +/- 1.10 for lung parenchyma, 4.04 +/- 1.31 for bronchial walls, 3.37 +/- 1.00 for pulmonary arterial walls, 1.99 +/- 1.80 for intraluminal mucus collected from bronchi located in healthy tissue proximal to the tumour, 5.16 +/- 3.26 for intraluminal mucus collected in a bronchus distal to the tumour, and 3.06 +/- 1.99 for catheter-collected mucus from the trachea and principal bronchi. These results indicate that minocycline is found in high concentration in all types of lung tissue and mucus in man.

Adult↗

PubMed1991

Influence of diazepam, alpidem, zolpidem and zopiclone, on the response to adenosine of the guinea pig isolated trachea.

It has been reported that dipyridamole and some benzodiazepines potentiate the responses to adenosine in peripheral organs and in particular in the guinea pig isolated atria or trachea by inhibition of adenosine uptake and/or metabolism. In this study, we have examined the sensitization of guinea pig isolated trachea to relaxant responses to adenosine produced by dipyridamole, diazepam and 3 compounds chemically unrelated to benzodiazepines but which display selective agonistic activity towards the central (zolpidem and zopiclone) or peripheral (alpidem) type benzodiazpine receptors. In preparations under spontaneous tone and in the absence of adenosine, dipyridamole (10(-5) M) and diazepam (10(-5)-10(-4) M), alpidem (3 x 10(-6) M-10(-5) M) and zopiclone (10(-6)-10(-4) M) induced a relaxation of the airway smooth muscle. In addition, dazepam (10(-4) M) attenuated the phasic response to histamine (10(-5) M). Dipyridamole (10(-5) M) and diazepam (10(-4) M) respectively produced a 56.2 and 32.4-fold potentiation of adenosine relaxant effects. Alpidem (10(-6)-10(-5) M), zolpidem (10(-6)-10(-4) M) and zopiclone (10(-6)-10(-4) M) were without any significant effect on the adenosine concentration-response curves. Moreover, alpidem, zolpidem, and zopiclone did not modify the 2-chloroadenosine dose-response curves nor the diazepam induced sensitization of adenosine-induced relaxation. In conclusion, adenosine sensitization of the guinea pig isolated trachea caused by diazepam might involve a peripheral benzodiazpine receptor subtype coupled to a nucleoside transporter system which is different from those recognized by compounds derived from the imidazopyridine series.

2-Chloroadenosine↗

PubMed1990

Calcium dependence of the contraction produced by endothelin (ET-1) in isolated guinea-pig trachea.

Endothelin (ET-1, 1 pM to 0.1 microM) produced a concentration-dependent contraction of isolated guinea-pig trachea. BAY K 8644 (1 microM) did not significantly alter the concentration-response curve for ET-1. Incubation with nicardipine (10 microM) partly inhibited responses to low concentrations (10 pM to 1 nM) of ET-1 while verapamil (10 microM) and diltiazem (10 microM) were ineffective. La3+ (10 microM) and Cd2+ (10 microM) preferentially depressed the responses evoked by high concentrations (30 nM-0.1 microM) of ET-1 without affecting the responses evoked by low concentrations of the peptide. Incubation in Ca2(+)-free (with EDTA, 1 mM) medium resulted in suppression of the responses elicited by low concentrations of ET-1 and partial inhibition of the responses elicited by high concentrations of the peptide. It is concluded that responses to ET-1 are dependent on extracellular Ca2+. The promotion of Ca2+ entry by ET-1 is not confined to a particular class of Ca2+ channel. An intracellular source of Ca2+ is also mobilized by high concentrations (greater than 10(-9) M) of ET-1.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1990

Receptors for neurokinins in human bronchus and urinary bladder are of the NK-2 type.

Human tissues such as the isolated bronchus and urinary bladder respond to neurokinins with concentration-dependent contractions, which appear to be due to the activation of receptors. We characterized these receptors in the present study using agonists (the naturally occurring neurokinins and some selective agonists) as well as newly identified antagonists. The order of potency of the agonists in the two preparations was as follows: neurokinin A (NKA) greater than substance P (SP) greater than neurokinin B (NKB) (bronchus) and NKA greater than NKB greater than SP (bladder), which suggests the presence of NK-2 receptors. This was confirmed by data obtained with two antagonists, one of which was shown to be competitive and selective for NK-2 type receptors. It thus appears that receptors of the NK-2 type are present in humans along the tracheo-bronchial tree and in the urinary system.

Bronchi↗

PubMed1990

Comparative beta-adrenoceptor blocking effects of propranolol, bisoprolol, atenolol, acebutolol and diacetolol on the human isolated bronchus.

Five beta-adrenoceptor blockers, propranolol, acebutolol, diacebutolol, atenolol and bisoprolol, were tested for their antagonistic effect against isoprenaline on human isolated bronchi. The results showed (1) that only propranolol exerted a competitive antagonistic effect against isoprenaline (pA2 = 9.40 +/- 0.22, n = 7) whereas the other drugs did not, and (2) that, in the presence of beta-adrenoceptor blockers in the plasma concentrations reported after a single usual therapeutic dose, the doses of isoprenaline giving the same bronchodilator effect must be multiplied by 32.6, 5.51, 4.63, 2.82 and 1.95 respectively with propranolol, diacetolol, acebutolol, atenolol, and bisoprolol. It was concluded that (1) atenolol and bisoprolol were the least potent drugs at bronchial level in therapeutic plasma concentrations and (2) that tests performed on the human isolated bronchus might be a useful screening procedure for new drugs with potential activity on the airways.

Adrenergic beta-Antagonists↗

PubMed1990

Contractile activity of three endothelins (ET-1, ET-2 and ET-3) on the human isolated bronchus.

1. The effects of three endothelins: (i) the classical or human/porcine endothelin (ET-1); (ii) [Trp6, Leu7] endothelin (ET-2) and (iii) [Thr2, Phe4, Thr5, Tyr6, Lys7, Tyr14] endothelin or rat endothelin (ET-3) were tested on the human isolated bronchus. 2. ET-1 produced a concentration-dependent contraction of the human isolated bronchus that proceeded in two different steps. The first step was observed at very low concentrations (pD2 = 11.01 +/- 0.17, n = 10) but corresponded to a low intrinsic activity (Emax = 15.6 +/- 1.8% of Emax = 26.1 +/- 2.9% of ACh 3 x 10(-3) M, n = 5, P less than 0.05), reduced by nicardipine 10(-6) M (Emax = 6.0 +/- 2.6% of ACh 3 x 10(-3) M, n = 5, P less than 0.05) and strongly inhibited in calcium-free medium. The second step of the action of ET-1 corresponded to a lesser potency (pD2 = 7.90 +/- 0.17, n = 9) but a higher intrinsic activity (Emax = 82.5 +/- 4.7% of ACh 3 x 10(-3) M). This effect was not significantly modified by nicardipine 10(-6) M or by Bay K 8644 10(-7) M. Neither of the two effects was modified by indomethacin 3 x 10(-6) M. 3. The effects of ET-2 and ET-3 were qualitatively similar to those of ET-1 but quantitatively different; for these two steps of contracting activity and for potency and efficacy the ranking was: ET-1 greater than ET-2 = ET-3. 4. Thus, ET-1 appears to be the most potent of these three substances in its effect on the human isolated bronchus. Its activity seems to involve the action of voltage-dependent calcium channels at low concentrations (10-12 to 10-9M), whereas other mechanisms are involved at higher concentrations (10-8 to 3 x 10-7M).

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1990

Effects of cularine and other isoquinoline alkaloids on guinea-pig trachea and human bronchus.

The relaxant effects of the isoquinoline alkaloids, cularine, antioquine, obaberine and 6, 7-dimethoxy-1, 2, 3, 4-tetrahydroisoquinoline, with structures related to that of papaverine, have been studied on the guinea-pig isolated trachea and human bronchus against contractions induced by acetylcholine (ACh), histamine, neurokinin A (NKA) and KCl. These effects were compared with those of papaverine and theophylline. Among the alkaloids tested, the most potent was cularine, the relaxant activity of which, in terms of pD2, was between those of papaverine and theophylline. The results showed that for the guinea-pig isolated trachea and the human bronchus, the cularine concentrations required to inhibit K(+)-induced contractions were close to those necessary to counteract ACh-, histamine- and NKA-induced contractions. The relaxant activity of cularine was not modified when it was tested on tracheal preparations under resting tone or after epithelium removal. In addition, cularine was able to inhibit Ca2(+)-induced contractions in a Ca2(+)-free, K(+)-enriched solution at the same concentrations as those which inhibited the action of the different contractile agents in normal Krebs solution. All these data show that cularine displays non-specific antispasmogenic activity on guinea-pig and human airways. The lower relaxant activity (pD2) of cularine compared with papaverine suggests the importance of free rotation of the isoquinoline-benzyl ring linkage as well as of the degree of hydrogenation of the heterocyclic ring in the spasmolytic effects of isoquinoline compounds.

Adenosine↗

PubMed1990

Structure-activity study of neurokinins: antagonists for the neurokinin-2 receptor.

A series of 21 peptides were synthesized and tested in a variety of isolated organs in order to determine their potential as neurokinin-2 (NK-2) antagonists. The peptides have been tested in the three monoreceptor systems, the dog carotid artery (NK-1), the rabbit pulmonary artery (NK-2) and the rat portal vein (NK-3) as well as on other preparations containing NK-2 receptors, such as the rat vas deferens, the hamster urinary bladder, the guinea-pig trachea and the human urinary bladder. Some of the compounds have also been tested on the human isolated bronchus. Three compounds, of which two are linear peptides, Ac.Leu-Asp-Gln-Trp-Phe-Gly.NH2, Thr-Asp-Tyr-D-Trp-Val-D-Trp-D-Trp-Arg.NH2 and a cyclic one, cyclo[Gln-Trp-Phe-Gly-Leu-Met] have been shown to reduce or eliminate the effects of neurokinin A (NKA) in practically all the preparations containing NK-2 receptors. The first compound was found to be selective for the NK-2 receptor and showed only agonistic or no activity on the other receptor systems, while the second compound showed some antagonistic effects not only on the NK-2 but also on the other systems. The cyclic compound was found to be fairly selective for the NK-2 receptor. The first compound (Ac.Leu-Asp-Gln-Trp-Phe-Gly.NH2) was characterized with respect to its specificity for neurokinins (NK): it was found to be inactive on receptors for acetylcholine, noradrenaline, angiotensin and des Arg9-bradykinin in the rabbit pulmonary artery. Moreover, the compound exerted a competitive type of antagonism on the rabbit pulmonary artery and on the hamster urinary bladder. Although of moderate affinity, the NK-2 receptor antagonists described in this paper provide important tools for pharmacological studies on NK.

Amino Acid Sequence↗

PubMed1989

Lack of effect of terfenadine on theophylline pharmacokinetics and metabolism in normal subjects.

The pharmacokinetics of oral theophylline (250 mg) and the production of its metabolites (3-methylxanthine, 1-methyluric acid, 1,3-dimethyluric acid) were studied before and after the administration of oral terfenadine (120 mg twice daily for 16 days) in 10 healthy volunteers. Comparison of volumes of distribution, elimination half-lives, areas under the plasma concentration-time curves, plasma clearance of theophylline and elimination of theophylline metabolites indicated that terfenadine had no significant effect on theophylline pharmacokinetics and metabolism.

Adult↗