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Biomedical subjects

M L Candenas

Publications and source records attributed to M L Candenas.

32 records · Page 2Linked to original sources
PubMed1992

Inhibitory and contractile effects of okadaic acid on rat uterine muscle.

The effects of okadaic acid and its interactions with various agents known to increase, by different mechanisms, the intracellular levels of cyclic AMP and/or cyclic GMP were investigated in isolated strips of rat myometrium. Okadaic acid showed inhibitory effects at concentrations between 10(-7) M and 3 x 10(-6) M. At higher concentrations, a biphasic, contractile and then relaxant response was observed. The results obtained suggest that, in rat uterine smooth muscle, the inhibitory effects of okadaic acid are not entirely mediated by the activation of cyclic AMP- and/or cyclic GMP-dependent pathways. The data also point to the existence of a clear interaction between okadaic acid and methylxanthines, although further studies are needed to clarify the mechanisms involved in this interaction.

Animals↗
PubMed1992

Influence of benzodiazepines on the response of the guinea-pig isolated trachea to the contractile action of adenosine.

The effects of diazepam and other agonists of central or peripheral benzodiazepine receptors were studied on the contractile action of adenosine, 2-chloroadenosine and R-PIA (N6-(L-2-phenylisopropyl)-adenosine) on the guinea-pig isolated trachea. These effects were compared to those of dipyridamole. Diazepam 10(-7) to 10(-5) M potentiated the efficacy of adenosine; the maximal contractile effect of adenosine (% vs. acetylcholine 10(-3) M) was 20.4 +/- 4.2 (n = 21) in control conditions and 45.5 +/- 3.7 (n = 6; P less than 0.001) in the presence of diazepam 10(-5) M. Ro5-4864 (10(-7) to 10(-5) M) or alpidem (10(-7) to 10(-5) M), both agonists of peripheral benzodiazepine receptors, potentiated the contractile effects of adenosine to the same extent as diazepam. Clonazepam and zopiclone, both agonists 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 Ro5-4864 and adenosine. Conversely, dipyridamole significantly reduced (10(-7) M) or suppressed (10(-6) M) the contractile effects of adenosine. The contractile effects of 2-chloroadenosine and R-PIA were weakly affected in presence of high concentrations of diazepam and dipyridamole. Epithelium removal potentiated the contractile effect of adenosine on the guinea-pig isolated trachea and increased the potentiating effect of diazepam. It is concluded that benzodiazepines and related compounds can potentiate the contractile effect of adenosine on the guinea-pig isolated trachea through the activation of a peripheral receptor for the benzodiazepines and the resulting inhibition of adenosine uptake.

2-Chloroadenosine↗
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

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↗
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

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

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↗
PubMed1989

A study of beta-adrenoceptors in rat lung parenchymal strip.

The aim of the present study was to characterize the beta-adrenoceptor population in rat lung strip. For this purpose, Schild plots were obtained for the beta-adrenoceptor antagonists atenolol (beta 1-selective), butoxamine (beta 2-selective) and propranolol (non-selective), using three different agonists:isoprenaline (non-selective), salbutamol (beta 2-selective) and noradrenaline (beta 1-selective). The slopes of these Schild plots were close to the theoretical value of unity, and pA2 values determined with isoprenaline, salbutamol and noradrenaline as agonists were: for propranolol, 7.86 +/- 0.22, 7.72 +/- 0.15 and 7.89 +/- 0.23; for atenolol, 5.19 +/- 0.05, 5.33 +/- 0.07 and 5.47 +/- 0.22 and for butoxamine, 6.31 +/- 0.11, 6.34 +/- 0.03 and 5.99 +/- 0.23, respectively. These data suggest that pharmacological responses of rat isolated lung strip to beta-adrenoceptor agents are mediated by a homogeneous population of beta 2-adrenoceptors, although the presence of a minor population of beta 1-adrenoceptors undetected by the agonists used cannot be excluded.

Albuterol↗
PubMed1988

[Influence of endogenous catecholamines on responses of rat lung to beta-adrenergic agonists].

Relaxation responses to the beta-adrenoceptor agonists: isoprenaline (non selective), salbutamol (beta 2-selective) and noradrenaline (plus phentolamine 10(-5) M) (beta 1-selective) have been obtained on rat lung parenchymal strips in the absence and presence of pargyline and tropolone (monoamino-oxidase and catechol-O-methyltransferase inhibitors), cocaine (neuronal uptake blocking agent), corticosterone (extraneuronal uptake inhibitor) as well as in reserpinized rat. Responses to these beta-adrenergic agonists were not potentiated in the presence of any of these inhibitors. This indicates that endogenous catecholamines, enzymatic or uptake processes, do not modulate beta-adrenoceptor mediated responses of rat lung strip and demonstrates that there is no correlation between neuronal uptake/beta 1-adrenoceptors and extraneuronal uptake/beta 2-adrenoceptor mediated responses, as had previously been suggested.

Adrenergic alpha-Agonists↗
PubMedDate not supplied

Antioquine: a new bisbenzylisoquinoleine alkaloid with calcium antagonist activity.

The objective of this work was to examine the smooth muscle relaxing properties of antioquine, compared to papaverine, in isolated rat uterus. The results obtained show that both antioquine and papaverine are capable of relaxing sustained contractions induced by Ca2+ in K-depolarizing solution as well as the spontaneous activity of rat uterus. Antioquine (0.1 mM, 0.5 mM and 1 mM) also induces a displacement to the right of the dose-response curves to Ca2+, and the antagonism was not competitive. Papaverine produced a decrease in the frequency and amplitude of contractile responses induced by oxytocin, and these inhibitory effects were observed regardless of whether papaverine was added before or after the induced contractions. On the other hand, antioquine only modified the frequency of contractile responses to oxytocin or desynchronized cumulative dose-response curves to oxytocin when the uterus was preincubated with this alkaloid before addition of the agonist. These experiments suggest that the relaxant effects produced by antioquine may be due to the blockade of calcium movements across the cell membrane, mainly through voltage-operated channels, whereas papaverine affects Ca2+-entry both through VOCs and through ROCs.

Alkaloids↗
PubMedDate not supplied

Incubated or superfused rat lung parenchymal strip: a valid preparation for direct measurement of beta-responses.

Responses to the beta-adrenoceptor agonists isoprenaline (Iso) (non selective), salbutamol (Sal) (beta 2-selective) and noradrenaline (NA) (beta 1-selective) were studied on incubated and superfused rat lung strip. In both conditions, Iso and Sal elicited dose-related relaxations of lung strip and these responses were unaffected by the presence of phentolamine (Phen) 10(-5) M. Contractile responses to NA were obtained when it was used alone whereas in the presence of Phen 10(-5) M, NA elicited relaxant responses. The relative potencies of Iso : Sal : NA (plus Phen) were 100 : 20 : 0.69. This demonstrates that beta 2-adrenoceptor is the predominant beta-subtype involved in responses. Propranolol (10(-4) M) completely abolished the relaxant responses to Iso. However, after the addition of Iso tissue responded normally to drugs acting by other mechanisms. Thus, relaxations were obtained with caffeine and contractions with acetylcholine (AcH) or NA. This shows that responses to Iso are mediated only by beta-adrenoceptors. Propranolol and the selective beta-blocking agents butoxamine (beta 2) and atenolol (beta 1) competitively antagonized the effects of Iso. The Schild plots obtained had slopes which did not differ significantly from -1 and mean pA2 values were: 7.82 for propranolol; 6.32 for butoxamine and 5.22 for atenolol. These experiments were carried out in the absence of catecholamine uptake inhibitors, since in a preliminary set of experiments no significant changes of lung strip responses to Iso were observed in the presence of cocaine (10(-5) M) or corticosterone (10(-5) M). In conclusion, it appears that incubated rat lung strip possesses intrinsic tone and, although it cannot be considered a representative preparation of peripheral airways, it provides a valid model for investigating the direct-effects of drugs which act at beta-adrenoceptors.

Albuterol↗