Sympathomimetic vasoconstrictors as nasal decongestants.
Explore the source record for details and available documents.
Humans↗
Biomedical subjects
S R O'Donnell
Publications and source records attributed to S R O'Donnell.
Evidence that nitric oxide from the endothelium attenuates inherent tone in isolated pulmonary arteries from rats with hypoxic pulmonary hypertension.
1. The inherent contractile tone, and its modulation by the endothelium, have been studied in isolated pulmonary artery preparations taken from rats in which pulmonary hypertension was induced by exposure to a hypoxic environment (10% O2) for 14 days. Control rats were housed in room air. 2. All preparations in which the endothelium was left intact relaxed in response to acetylcholine (43 +/- 4% and 54 +/- 9%, reversal of the noradrenaline-induced contraction in control and hypoxic rats, respectively) indicating that the endothelium was functional in both groups of rats. 3. Exposure of the preparations to Ca(2+)-free physiological salt solution containing 2 mM EGTA for 30-40 min had no effect on preparations from control rats but caused relaxation in preparations from hypoxic rats. The relaxation (taken as a measure of the inherent tone in the preparations) was larger in preparations without endothelium (14.5 +/- 1.9 mN mm-2; n = 5) than in preparations with endothelium (9.1 +/- 1.2 mN mm-2; n = 5). 4. In preparations from hypoxic rats the magnitudes of the contractions to 80 mM K+ and to noradrenaline (0.1 microM) were less than in preparations from control rats. This may have been because the preparations from hypoxic rats were already partially contracted due to the inherent tone. 5.The nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME, 0.1-1 100 microM)had negligible effect on preparations from control rats or on endothelium-denuded preparations from hypoxic rats, but produced concentration-dependent contractions (maximum contraction 7.4 +/- 0.7 mN mm-2 (n = 4) with 100 micro M) in endothelium-intact preparations from hypoxic rats. This effect of L-NAME was prevented by L-arginine (1 mM) but not by D-arginine (1 mM).6. Contractions to L-NAME were also seen in endothelium-intact arteries from control rats if the preparations were first partially contracted by exposure to K+, endothelin, U46619 (thromboxane mimetic)or noradrenaline.7 It is concluded that isolated pulmonary artery rings from hypoxic rats, but not those from control rats, have substantial inherent tone. This inherent tone is normally attenuated by the generation of an endothelium-derived factor that is probably NO. A stimulus for the release of NO from the endothelium may be the contraction of the underlying smooth muscle, whether the contraction is inherent in the tissue, as in preparations from hypoxic rats, or is induced by a vasoconstrictor spasmogen.
Acetylcholine↗
Pinacidil-induced relaxation in pulmonary arteries isolated from pulmonary hypertensive and normotensive rats and pre-contracted with different spasmogens.
Vasorelaxant responses to the potassium channel opening drug, pinacidil, were obtained on preparations of pulmonary artery and aorta taken from rats with pulmonary hypertension (induced by chronic hypoxia or monocrotaline) and pre-contracted either submaximally with endothelin-1 (ET-1), PGF2 alpha, U46619 (thromboxane-mimetic) or noradrenaline (NA), or with 80 mM K+. In pulmonary artery, but not aorta, from pulmonary hypertensive rats the maximum relaxant response to pinacidil was increased, when compared with data in control rats, irrespective of the spasmogen used to precontract the tissues. The increase in maximum was associated with relaxation to below the tissue resting baseline and probably reflected the presence of inherent contractile tone in arteries from pulmonary hypertensive rats. In addition the potency (-log EC50) of pinacidil was increased in pulmonary arteries from pulmonary hypertensive rats but this was seen only in preparations contracted with ET-1 (30-fold increase) or NA (seven-fold increase) and not in those contracted with PGF2 alpha, U46619 or K+. As a result, in ET-1 contracted preparations from pulmonary hypertensive rats pinacidil was 29-fold more potent on pulmonary artery than on aorta. To explain the increase in potency it is speculated that during the development of pulmonary hypertension the mechanism whereby ET-1 and NA contract pulmonary arteries may change from one in which Ca2+ influx plays only a minor role to one in which Ca2+ influx predominates, although no direct evidence to support this speculation has yet been obtained.
Animals↗
Beta 2-agonist bronchodilators--advances versus controversies.
Explore the source record for details and available documents.
Adrenergic beta-Agonists↗
Dopamine and adrenaline, but not isoprenaline, are substrates for uptake and metabolism in isolated perfused lungs of rats.
The uptake and subsequent metabolism by catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO) of dopamine, adrenaline, isoprenaline and noradrenaline in isolated perfused lungs of rats has been examined. In lung preparations in which COMT and MAO were inhibited, the uptake of 3H-labelled dopamine, (-)-adrenaline and (-)-noradrenaline, but not (+/-)-isoprenaline, was reduced by cocaine (10 or 100 mumol/l). The rank order of the Km values of the amines that were substrates for uptake in the lungs were: dopamine (0.246 mumol/l) less than noradrenaline (0.967 mumol/l) less than adrenaline (3.32 mumol/l). These results are consistent with transport of catecholamines in rat lungs by Uptake1. In lung preparations with COMT and MAO intact, dopamine and noradrenaline were removed from the circulation (50% and 32%, respectively) and mainly metabolized. There was very little (3.0%) removal of isoprenaline by the lungs and adrenaline was not included in this part of the study. In lung preparations in which only MAO was inhibited, the rank order of COMT activity for O-methylation of the amines was dopamine much much greater than noradrenaline greater than or equal to adrenaline (kCOMT values: 4.98 min-1, 0.357 min-1 and 0.234 min-1, respectively). If dopamine or adrenaline are perfused through the pulmonary circulation in isolated lungs of the rat, they are taken up and then metabolized by COMT and MAO, as also occurs for noradrenaline. Isoprenaline is not a substrate for uptake in the lungs.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Vascular uptake of catecholamines in perfused lungs of the rat occurs by the same process as Uptake1 in noradrenergic neurones.
The aim of the study was to determine whether the uptake process for catecholamines in rat lungs is Uptake1, Uptake2 or a distinct process with some properties of both Uptake1 and Uptake2. The initial rate of uptake of noradrenaline was measured in isolated lungs of rats perfused with 2 nmol/l 3H-(-)-noradrenaline for 2 min with monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) inhibited, in the absence or presence of drugs that are substrates or inhibitors of Uptake1 or Uptake2 or of alterations in the ionic composition of the Krebs solution. The rank order of the IC50 values for inhibition of uptake of noradrenaline in the lungs by drugs that are substrates or inhibitors of Uptake1 or Uptake2 is compatible with the conclusion that uptake of catecholamines in rat lungs occurs by Uptake1, and not by a process with the properties of Uptake2. Additional evidence was provided by the marked inhibition of uptake in the lungs when the Na+ concentration in the Krebs solution was decreased from 143 to 25 mmol/l and by the lack of inhibition when the K+ concentration was increased from 5.9 mmol/l to either 10.9 or 20.9 mmol/l. Further experiments were included in the study to obtain data additional to histological evidence (Hughes et al. 1969; Nicholas et al. 1974) regarding the site of Uptake1 in rat lungs. Pretreatment of rats with either 6-hydroxydopamine (to destroy noradrenergic neurones) or reserpine (to inhibit synaptic vesicle uptake) had no effect on the deamination or accumulation of noradrenaline in lungs perfused with 3H-noradrenaline (COMT inhibited).(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Reduced relaxant potency of nitroprusside on pulmonary artery preparations taken from rats during the development of hypoxic pulmonary hypertension.
1. Relaxant responses to nitroprusside were examined on U46619-contracted pulmonary artery ring preparations from rats exposed to hypoxia, in chambers containing 10% oxygen, for 1, 3, or 14 days, or for 14 days followed by 12 days in room air. Control rats were housed in room air. 2. After 3 days of hypoxia (but not 1 day), rats had elevated pulmonary artery pressure, right ventricular hypertrophy and polycythemia. After 14 days of hypoxia there was, in addition, hypertrophy of the pulmonary artery. In rats returned to room air for 12 days after 14 days of hypoxia, there was still some right ventricular and vascular hypertrophy but no increase in pulmonary artery pressure or polycythemia. 3. The potency (neg log EC50) of nitroprusside on pulmonary arteries taken from rats after 3 or 14 days of hypoxia was significantly less than on preparations from control rats (3 and 11 fold, respectively). This was not seen after 1 day of hypoxia or after 14 days of hypoxia followed by 12 days in room air. Removal of the endothelium from the preparations had no effect on the potency of nitroprusside in control or hypoxic rats (14 days). 4. In preparations from hypoxic, but not control, rats (14 days), the maximum response to nitroprusside was > 100% (177% reversal of the U46619 contraction) in the absence, but not in the presence, of the endothelium, indicating that pulmonary arteries from hypoxic rats had inherent tone which could be counteracted by a relaxing factor from the endothelium. 5. Exposure of rats to hypoxia (14 days) did not affect the potency of nitroprusside on aorta or trachea.6. It is concluded that exposure of rats to hypoxia results in reversible desensitization of the vascular smooth muscle of pulmonary artery to nitroprusside. The time course of this desensitization suggests that it is probably associated with the elevated pulmonary artery pressure or maintained hypoxaemia rather than with the vascular hypertrophy.7. It is postulated that the increase in pulmonary artery pressure and/or the maintained hypoxaemia may cause chronic release of nitric oxide from the pulmonary vascular endothelium or smooth muscle resulting in desensitization of soluble guanylate cyclase to the action of nitroprusside.
Animals↗
Responses to vasodilator drugs on pulmonary artery preparations from pulmonary hypertensive rats.
1. Relaxant responses to six vasodilator drugs, with different mechanisms of action, were examined on noradrenaline (0.1 microM)-contracted ring preparations of pulmonary artery and aorta taken from rats with pulmonary hypertension induced by monocrotaline or chronic hypoxia. 2. On pulmonary artery preparations from monocrotaline-treated rats, compared with controls, (a) the maximum relaxation to pinacidil and cromakalim was significantly increased, but their potency (negative log EC50) was unchanged, (b) the potencies of nitroprusside and sodium nitrite were significantly reduced (10 fold and 3 fold respectively), but there was no change in the maxima, (c) for nicorandil there was an increase in maximum relaxation and a decrease in potency (3 fold), and (d) for atriopeptin II there was no change in potency or maximum. 3. The increase in maximum relaxation for pinacidil and the decrease in potency for nitroprusside were also demonstrated in pulmonary artery preparations from rats with chronic hypoxic pulmonary hypertension. The other four drugs were not examined in preparations from hypoxic rats. 4. In both models of pulmonary hypertension, no change in maximum response or potency was seen on aortic preparations for any of the vasodilator drugs. 5. In control preparations, none of the drugs was more potent on pulmonary artery than on aorta (i.e. they were not pulmonary-selective). In preparations from pulmonary hypertensive rats, pinacidil was selective for pulmonary artery, in contrast to nitroprusside which was selective for aorta.6. It is concluded that the development of pulmonary hypertension in rats is accompanied by changes in the responsiveness of the pulmonary arteries to some vasodilator drugs; whether or not these changes occur depends on the mechanism of action of the vasodilator drug, but they are independent of the method of inducing pulmonary hypertension.7. It is postulated that the reduction in potency seen for nitroprusside, sodium nitrite and nicorandil may be due to desensitization of soluble guanylate cyclase in pulmonary vascular smooth muscle in pulmonary hypertension.
Animals↗
Attenuation of bradykinin-induced mucosal inflammation by topical budesonide in rat trachea.
The extravasation of plasma proteins and formation of interendothelial gaps in submucosal microvessels by mucosally-applied bradykinin (BK), were studied in the rat trachea. The effects of topical and systemic (s.c.) glucocorticoid budesonide (BUD) were investigated in the presence or absence of inhibitors of BK-degradtive enzymes (captopril and thiorphan 10 microM to inhibit angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP), respectively). Inhibition of these enzymes markedly increased the inflammatory responses to BK. Topical BUD (3 microM, 10 min contact, 90 min before BK) significantly decreased the volume of plasma in the tracheal lumen, both in the absence and presence of the enzyme inhibitors. Thus, the main anti-transudation mechanism of topical BUD is not related to modulation of BK-breakdown. However, this may be the mechanism for systemic BUD. Neither topical nor systemic BUD prevented interendothelial gap formation.
Administration, Topical↗
Isolated perfused lungs of guinea-pig, in contrast with rat, lack an uptake process for noradrenaline.
The uptake and metabolism of noradrenaline were compared in isolated perfused lungs of guinea-pigs and rats. Lungs were perfused with 3H-(-)-noradrenaline either a) at a concentration of 10 nM for 20 min in experiments to measure the metabolism of the amine or b) at a concentration of 2 nM for 2 min, in the presence or absence of 10 microM cocaine and with MAO and COMT inhibited, in experiments to measure the uptake of noradrenaline. The total formation of metabolites during the 20 min perfusion period was 36.2 +/- 2.3 pmol g-1 (n = 6) in guinea-pig lungs, and 526 +/- 26 pmol g-1 (n = 6) in rat lungs (14.5-fold greater). In guinea-pig lungs, the rate of uptake of noradrenaline was 0.392 +/- 0.044 pmol g-1 min-1 (n = 3) and was unaffected by cocaine, whereas in rat lungs it was 5.63 +/- 0.03 pmol g-1 min-1 (n = 5) and was inhibited (88%) by cocaine. It is concluded from these results that the lungs of the guinea-pig lack the specific uptake process that, in rat lungs, allows removal of noradrenaline from the pulmonary circulation.
Animals↗
Increased relaxation by felodipine on pulmonary artery from rats with monocrotaline-induced pulmonary hypertension does not reflect functional impairment of the endothelium.
The effects of the calcium entry blocking drug, felodipine, were examined against the spasmogens, noradrenaline, 5-hydroxytryptamine (5-HT) and endothelin on pulmonary artery preparations taken from rats treated with saline or monocrotaline (endothelium present) and from untreated rats (endothelium removed). In saline-treated rats, the potencies (negative log EC50) of noradrenaline, 5-HT and endothelin were 7.97, 5.25 and 8.39 respectively, and felodipine (10 nM) reduced the maximum responses to noradrenaline (28% reduction) and 5-HT (47% reduction), without reducing their potency. In monocrotaline-treated rats, the potencies of noradrenaline, 5-HT and endothelin were 8.43, 6.42 and 8.44, and felodipine significantly reduced the potencies of noradrenaline (0.60 log units) and 5-HT (0.48 log units) in addition to reducing their maximum responses (60% and 69% reductions, respectively). Felodipine had no effect on endothelin in either group of rats. Removal of the endothelium caused a small increase in the potency of 5-HT, but had no influence on the other spasmogens or on the effects of felodipine. It is concluded that monocrotaline treatment of rats leads to increases in a) the potencies of noradrenaline and 5-HT on pulmonary artery, and b) the effectiveness of felodipine against these two spasmogens. Neither of these increases can be attributed to monocrotaline-induced endothelial cell damage.
Animals↗
Tissue selectivity and spasmogen selectivity of relaxant drugs in airway and pulmonary vascular smooth muscle contracted by PGF2 alpha or endothelin.
1. The spasmolytic effects of smooth muscle relaxant drugs with different mechanisms of action have been examined on isolated preparations of guinea-pig trachea and rat pulmonary artery. The preparations were contracted with concentrations of prostaglandin F2 alpha (PGF2 alpha) or endothelin selected to give approximately 80% of the agonist maximum response on each tissue. These concentrations also caused similar levels of tone (% of tissue maximum contraction) on each tissue. 2. With endothelin as the spasmogen, the potassium channel opening drug, pinacidil, was more potent on trachea (-log IC50 5.49) than on pulmonary artery (4.39), i.e. was airway-vascular selective, whereas with PGF2 alpha as the spasmogen it was more potent on pulmonary artery (6.01) than on trachea (5.27), i.e. was vascular-airway selective. 3. With endothelin as the spasmogen, fenoterol was also airway-vascular selective (8.35 on trachea; little effect on pulmonary artery), nitroprusside was vascular-airway selective (7.50 on pulmonary artery; 5.99 on trachea) and forskolin was non-selective (6.69 on trachea; 6.70 on pulmonary artery). Thus, the airway-vascular selectivity of the relaxant drugs varied with the drug. 4. On pulmonary artery, pinacidil, nitroprusside and forskolin were all more potent against PGF2 alpha than against endothelin, i.e. 42, 4 and 7 fold respectively. On trachea, these drugs were equipotent against PGF2 alpha and endothelin. 5. The results suggest that, in pulmonary artery, but not in trachea, the relative contribution of protein kinase C activation and calcium influx to the maintenance of tonic contractions to endothelin and PGF2 alpha may be different. If protein kinase C activation should be the predominant mechanism for endothelin in pulmonary artery, then it may be more difficult to reverse this with relaxant drugs that lower intracellular calcium. 6. The study indicates that the airway-vascular selectivity of relaxant drugs can be spasmogen-dependent as well as dependent on the mechanism of action of the relaxant drug. Thus, relaxant drugs, whether of interest for their airway or vascular effects, should be tested against a full range of spasmogens of likely pathophysiological importance.
Animals↗
Endothelin-induced contractions of rat pulmonary artery are not affected by drugs acting on potassium channels.
The effects of the potassium channel opening drug, pinacidil, and the potassium channel closing drug, tetraethylammonium (TEA), on concentration-response (contraction) curves to spasmogens on rat pulmonary artery were examined. Pinacidil (3 microM) decreased, and TEA (2 mM) increased contractions to 5-hydroxytryptamine (5-HT) more than it did to noradrenaline but contractions to endothelin-1 were only minimally affected. It is concluded that the mechanism whereby endothelin-1 contracts rat pulmonary artery differs from that of noradrenaline or 5-HT in that it does not involve membrane depolarization or calcium entry through voltage operated calcium channels.
Animals↗
An in situ preparation of rat trachea for studying the effects of mucosally applied anti-asthma drugs on mediator-induced plasma exudation.
An animal model is described for testing the effects of anti-asthma drugs on mediator-induced airway inflammation. An in situ segment of trachea is slowly perfused with normal saline in spontaneously breathing, anaesthetised rats. Both the anti-asthma drug and the inflammatory mediator can be applied directly to the airway mucosal surface at the same and/or different times. The amount of plasma in samples of perfusate is monitored. Application of a mediator, such as bradykinin, results in an increase in the amount of plasma in the tracheal lumen (and hence in the perfusate). Plasma in the perfusate can be estimated without injecting a labelled tracer for plasma exudation by using a protein native fluorescence (PNF) method as described by Miller-Larsson & Brattsand (3).
Administration, Topical↗
Endothelin and 5-hydroxytryptamine on rat pulmonary artery in pulmonary hypertension.
Contractile responses to endothelin, 5-hydroxytryptamine (5-HT), noradrenaline and potassium were obtained on isolated preparations of pulmonary artery from rats made pulmonary hypertensive by an injection of monocrotaline (105 mg/kg s.c.) 4 weeks previously. When compared with data obtained in control rats, the potencies (negative log EC50 values) for 5-HT, noradrenaline and potassium were increased (30, 3- and 3-fold, respectively), and the maximum contractions (mN/mm2) to endothelin, noradrenaline and potassium were reduced (65, 40 and 45% reduction). These changes were not seen 2 weeks after injection of monocrotaline, before pulmonary hypertension developed, or in preparations of aorta. It is concluded that monocrotaline-induced pulmonary hypertension affects pulmonary vascular responsiveness to spasmogens differentially. The comparative importance of endothelin and 5-HT as pulmonary vasoconstrictors may change in monocrotaline-induced pulmonary hypertension, there being an increase in responsiveness to 5-HT and a decrease in responsiveness to endothelin.
Acetylcholine↗
Pinacidil antagonism of endothelin-induced contractions of smooth muscle in the lungs: differences between tracheal and pulmonary artery preparations.
Contractions to endothelin and their reversal by pinacidil have been examined in isolated preparations of guinea pig and rat trachea and rat pulmonary artery. Indomethacin attenuated endothelin (less than or equal to 10 nM) on guinea pig trachea, but not on the rat tissues. This indicates that part of the effect of endothelin on guinea pig trachea is indirect and mediated by cyclooxygenase products. Endothelin (direct effects) was more potent on pulmonary artery than on guinea pig or rat trachea (negative log EC50 values: 8.42, 7.71 and 7.76, respectively) and was also a more effective spasmogen on pulmonary artery (maximum was the tissue maximum, i.e., greater than or equal to 80 mM K+) than on trachea (maximum was 60-70% of the tissue maximum to 10 microM carbachol). Pinacidil was less effective preventing (anti-spasmogenic) than reversing (spasmolytic) contractions to endothelin on either tissue type. This is compatible with different mechanisms for the initiation and maintenance of smooth muscle contraction in these tissues. As a spasmolytic against endothelin (0.03 microM), pinacidil was less potent on rat pulmonary artery than on guinea pig or rat trachea (negative log IC50 values: 4.45, 5.65 and 5.49, respectively). This may reflect 1) the greater tone induced by endothelin on pulmonary artery, 2) a smaller receptor reserve for endothelin in trachea and/or 3) a different mechanism whereby endothelin contracts pulmonary vascular smooth muscle compared with tracheal smooth muscle.
Animals↗
Early and late tracheobronchial plasma exudation by platelet-activating factor administered to the airway mucosal surface in guinea pigs: effects of WEB 2086 and enprofylline.
The effects of the platelet-activating factor (PAF) antagonist, WEB 2086, and the xanthine, enprofylline, on PAF-induced plasma exudation in tracheobronchial airways has been studied in guinea pigs. Superfusion of PAF (4 nmol) onto the tracheal mucosal surface caused a significant exudation of the i.v. plasma tracers [131I]albumin and fluorescein isothiocyanate-dextran (fluorescein-labeled dextran MW 156 kDa) during the first 15 min after PAF (early response) and also 5 hr later (late response). The early, but not the late, response could be identified histologically by a particulate tracer (carbon given i.v.) which was trapped in submucosal leaky vessels. WEB 2086 [3 mg (6.6 mumol)/kg] caused significant attenuation of both the early plasma exudative response (with loss of carbon-labeled vessels) and the late plasma exudative response to PAF. The late response was equally well attenuated by enprofylline [4.85 mg (25 mumol)/kg] given before PAF. It is concluded that PAF-induced late (as well as early) plasma exudative responses in guinea pig tracheobronchial airways are the result of specific receptor activation by topical PAF and that the antiasthma xanthine enprofylline can inhibit this PAF-induced late response. Our data suggest that particulate tracers, such as carbon, cannot detect microvessels involved in the ongoing late phase exudative response to PAF.
Animals↗
Analysis of the O-methylated metabolites of isoprenaline, adrenaline and noradrenaline in physiological salt solutions by high-performance liquid chromatography with electrochemical detection.
This study provides the first report of a sensitive, simple and rapid high-performance liquid chromatographic (HPLC) assay for the simultaneous analysis of isoprenaline and its metabolite, 3-O-methylisoprenaline, in samples of physiological salt solutions. The assay does not require time-consuming sample clean-up or extraction procedures and uses a Nova-Pak C18 column, an isocratic mobile phase and an amperometric detector. In addition, small modifications to the composition of the mobile phase have also provided sensitive assays for noradrenaline and adrenaline and their O-methylated or O-methylated deaminated metabolites (normetanephrine, metanephrine, 3-methoxy-4-hydroxyphenylethylene glycol and 3-methoxy-4-hydroxymandelic acid). These HPLC assays are sufficiently sensitive and rapid to replace the use of [3H]amines and column chromatographic separation of the metabolites for most in vitro studies on the uptake and subsequent metabolism of catecholamines by monoamine oxidase and/or catechol-O-methyltransferase in tissues.
Animals↗