Biomedical subjects

L O Cardell

Publications and source records attributed to L O Cardell.

46 records · Page 3Linked to original sources

PubMed1996

Contractile endothelin-B (ETB) receptors in human small bronchi.

Endothelins (ETs) are a family of novel regulatory peptides and various lines of evidence suggest an important role for ETs in regulating pulmonary function. Two receptors for endothelin, ETA and ETB, have been found in the human lung, and according to recent studies a non-ETA receptor seems to mediate the contraction of large sized human bronchi. Several studies have emphasized the importance of small bronchi in the pathogenesis of airway disease. In the present paper, improved methodology was used which enables in vitro studies of small human bronchi down to a diameter of 0.5-1.0 mm. Using the new methodology we have tried to further characterize this receptor. Small bronchi from the distal parts of the bronchial tree were obtained from pulmonary tissue removed from 15 patients with lung cancer. They were dissected and cut into ring segments, in which isometric tension was recorded. ET-1, ET-2 and ET-3 elicited strong concentration-dependent contractions of the human small bronchus. Basically, the three peptides were equipotent with about the same maximal response. Upon reapplication, they all showed the same tachyphylaxis pattern, reaching half the initial contraction. Comparative analysis of IRL 1620, a selective ETB receptor agonist, revealed that the effect of the ETB agonist was, in all respects, similar to the responses induced by the ETs. PD 145065, a combined ETA/ETB receptor antagonist competitively inhibited the contractions induced by IRL 1620, whereas FR139317, a selective ETA receptor antagonist, was without effect. In conclusion, the present study shows that accurate measurements can be made in vitro on small human bronchi and all present data are in favour of an ETB receptor mediating endothelin-induced contraction of human bronchi smaller than 1.0 mm.

Acetylcholine↗

PubMed1994

Endothelins: a role in cerebrovascular disease?

Vasoactive factors produced and released by the endothelium exert a powerful influence on vascular tone in the cerebral circulation. Impaired endothelium-dependent responses, such as decreased production of endothelium-derived relaxing factors, and/or release of endothelium-derived contractile factors may give rise to different pathophysiological conditions. Among the endothelium-derived contractile factors the endothelins have recently received particular attention. Endothelin-1 is the major isoform in the endothelin family, which also includes endothelin-2 and endothelin-3. Endothelin-1 is synthesized within the endothelium of cerebral vessels, whereas both endothelin-1 and endothelin-3 in addition have been identified in neurons and glia. Recent electrophysiological work has suggested a neuromodulatory role for these peptides, but at present the general interest is mainly focused on their vasoactive role. Physiological stimuli such as hypoxia, anoxia, and hemodynamic shear stress will stimulate the endothelial endothelin production. In the brain, at least two types of specific subreceptors have been cloned; ETA receptors, exclusively associated with blood vessels and ETB receptors also found on glial, epithelial, and ependymal cells. The endothelins seem so far to be the most potent vasoconstrictors yet identified. The circulating plasma levels of immunoreactive endothelin are low. Since more than 80% of the total amount released from endothelial cells seems to be secreted towards the underlying smooth muscle, endothelins have been ascribed a local vasoregulatory role. Endothelins are believed to be involved in several of our most common cerebrovascular diseases and the present review comments on their possible pathophysiological role in subarachnoid haemorrhage, cerebral ischemia, and migraine.

Amino Acid Sequence↗

PubMed1994

Characterization of the histamine receptors in the guinea-pig lung: evidence for relaxant histamine H3 receptors in the trachea.

1. The histamine receptors were characterized on isolated circular segments of trachea and pulmonary arteries from the guinea-pig. The motor responses to histamine H1-, H2- and H3-receptor agonists and antagonists were tested and the responses obtained were analysed in relation to the respiratory epithelium and the vascular endothelium. 2. Histamine induced a biphasic response in trachea and in pulmonary arteries. In low concentrations, histamine acted as a potent relaxant agent of precontracted segments and in moderate concentrations it constricted both precontracted and resting segments. When arterial segments from different parts of the pulmonary vascular tree were compared, only small interregional differences in the vasomotor response were seen. 3. Mepyramine caused a parallel shift to the right of the histamine-induced concentration-response curves for both the trachea and the pulmonary artery, indicating a contractile H1-receptor. Cimetidine did not affect the histamine-induced contraction of the trachea, but a shift to the left was evident for low concentrations of histamine in the pulmonary artery. This is consistent with a dilator H2-receptor in the pulmonary artery. The pA2-value for mepyramine in the pulmonary artery, 8.75, was not affected by the presence of cimetidine. Thioperamide, a selective H3 antagonist, shifted the concentration-response for the trachea to the left. Schild analysis for histamine and mepyramine yielded a line with a slope of 0.61, whereas the same analysis in the presence of thioperamide yielded a line with a slope of 1.05 and an approximated pA2-value of 9.57. These results indicate the presence of a relaxant H3 receptor in the trachea. In precontracted tracheal segments, application of mepyramine and cimetidine did not affect the low dose histamine relaxation. Thioperamide caused a parallel shift of the histamine concentration-response curve to the right, supporting the suggestion of a dilator H3-receptor in the trachea. The pA2-value for thioperamide, in the presence of mepyramine, was 7.79. In precontracted pulmonary arteries the histamine-induced dilatation was small. In the presence of mepyramine a rather strong histamine-induced dilatation became evident and this concentration-response curve could be shifted to the right by cimetidine, with a pA2-value of 6.49. This is compatible with a dilator H2-receptor. 4. The H1-receptor agonists, thiazolylethylamine, 2-methylhistamine and pyridylethylamine and the rather unselective H2-agonist, 4-methylhistamine, induced contraction of resting tracheal and pulmonary arterial segments. In precontracted segments of trachea, all H1 and H2 agonists studied induced a dilator response. The two rather unselective histamine receptor agonists 2-methylhistamine and 4-methylhistamine were about 100 times more potent than other H1 and H2 agonists tested. In the pulmonary artery, the H2 agonists, impromidine, dimaprit and 4-methylhistamine induced a concentration-dependent relaxation. The relaxation of the pulmonary artery, elicited by the H1 agonists,thiazolylethylamine and pyridylethylamine, was smaller, but more potent than the response induced by the H2 agonists. This may reflect the presence of a separate dilator H1-receptor.5. R-alpha-methylhistamine induced a three phased response in precontracted tracheal segments. In low concentrations, a concentration-dependent dilator response appeared. At moderate concentrations, a stage with a plateau or a small contraction was seen, followed at high concentrations by a new concentration-dependent relaxation. The first dilator phase was similar to that obtained for histamine in the same preparation.6. Removal of the epithelium or endothelium enhanced the contractile histamine response in both the trachea and the pulmonary artery as well as the dilator response in the trachea. These results support the hypothesis that the endothelial layer may serve as a barrier against the penetration of certain mediators. In the precontracted pulmonary artery, the small initial dilatation was abolished whereas the second dilatation seen in the presence of mepyramine was slightly reduced. This may reflect the influence of two separate histamine receptors, one of which is associated with the release of an endothelium dependent dilator factor or factors.7. In the guinea-pig trachea, histamine-induced contraction is mediated through H1-receptors where as dilatation probably involves an H3-receptor on the smooth muscle. The guinea-pig pulmonary artery appears to be endowed with a contractile H1 receptor on the smooth muscle cells and a dilator H1 receptor located on the endothelium. A dilator H2 receptor on the smooth muscle cells seems, at least in vitro, to be the most potent mediator of histamine-mediated pulmonary arterial dilatation.

Animals↗

PubMed1994

Low plasma concentrations of VIP and elevated levels of other neuropeptides during exacerbations of asthma.

Neuropeptides in the lung occur in neurons, neuroendocrine and inflammatory cells. Their widespread distribution and physiological effects suggest that they may play important roles in asthma. We investigated whether, during an exacerbation of asthma, patients displayed changes in plasma levels of the neuropeptides vasoactive intestinal peptide (VIP), calcitonin gene-related peptide (CGRP), substance P (SP), and neuropeptide Y (NPY). Venous blood from 25 adult patients attending the emergency ward with an exacerbation of asthma was sampled before and after treatment. Plasma levels of VIP-, SP-, CGRP- and NPY-like immunoreactivity (-LI) were determined by immunoassay, and the results obtained were compared with findings in 21 healthy controls. The mean plasma levels of VIP-LI were lower in patients (3.4 +/- 0.4 pmol.l-1) than in controls (10.4 +/- 0.7 pmol.l-1), whereas the levels of CGRP-LI (43.7 +/- 3.4 pmol.l-1), SP-LI (4.6 +/- 0.4 pmol.l-1) and NPY-LI levels (159 +/- 6 pmol.l-1) were higher in patients than in controls (21.1 +/- 3.4; 2.2 +/- 0.2 and 105 +/- 8 pmol.l-1, respectively). A relationship was seen between the reversibility of obstruction, expressed as improvement of peak expiratory flow upon treatment, and the neuropeptide levels, such that lower VIP-LI levels and higher CGRP-LI levels correlated with less reversibility. Plasma levels of neuropeptides, VIP-LI and CGRP-LI in particular, may therefore be employed as predictors of responsiveness to bronchodilatory therapy.

Acute Disease↗

PubMed1993

Helospectin/helodermin-like peptides in guinea pig lung: distribution and dilatory effects.

The lower airways of guinea pigs were analysed for helospectin and helodermin using immunocytochemistry. A moderate supply of helospectin/helodermin-like immunoreactive nerve fibers and few nerve fibers displaying helodermin immunoreactivity was seen in the smooth muscle, around seromucous glands and small blood vessels in the trachea and around bronchi and pulmonary blood vessels. Helospectin I-, helospectin II- and helodermin-induced suppression of smooth muscle responses were analysed using isolated circular segments of trachea and pulmonary arteries of guinea pigs. In both airways and arteries the peptides caused a concentration-dependent relaxation of precontracted segments. The maximal relaxant activity observed was more pronounced in the airways than in the arteries. The effects of the helospectins and helodermin were compared to those of vasoactive intestinal peptide (VIP), peptide histidine isoleucine (PHI), pituitary adenylate cyclase activating peptide (PACAP) and acetylcholine (ACh). All peptides, with the exception of PACAP, caused a total or nearly total relaxation of the precontracted tracheal segments. In the trachea PACAP was significantly more potent than the other five peptides whereas only small potency differences were seen in the pulmonary artery. The relaxant responses to helospectin I, helospectin II and helodermin in the trachea and the intrapulmonary arteries were unaffected by pretreatment with atropine, prazosin, yohimbine, propranolol, mepyramine and cimetidine. Conceivably, nerve fibers containing helospectin and helodermin may play a role in the regulation of airway resistance and in the regulation of local pulmonary blood flow.

Acetylcholine↗

PubMed1993

A novel ETA-receptor antagonist, FR 139317, inhibits endothelin-induced contractions of guinea-pig pulmonary arteries, but not trachea.

1. The effects of a proposed endothelin-receptor antagonist, FR 139317, on the contraction induced by endothelin-1, endothelin-2 and endothelin-3, were analysed on isolated circular segments of pulmonary arteries and rings of trachea from the guinea-pig. 2. The pharmacological profiles of endothelin-1 and endothelin-2 were almost identical in the guinea-pig pulmonary artery, whereas endothelin-3 demonstrated a weaker and less potent contractile effect. The contractions induced by endothelin-1 and endotheliln-2 were competitively antagonized by FR 139317. Schild plot analysis revealed a straight line with a slope that did not differ from unity. The pA2 value was 6.65. In contrast, the endothelin-3 induced contractile response was unaffected by FR 139317. 3. In tracheal segments endothelin-1, endothelin-2 and endothelin-3 evoked contractions of similar magnitude and sensitivity. FR 139317 had no effect on the endothelin-induced contractions in tracheal segments. 4. In ring segments of pulmonary artery and trachea, potassium, noradrenaline and histamine caused concentration-dependent contractile effects. These contractions were not modified by FR 139317 in the concentration range 10(-7) to 3 x 10(-6)M. 5. FR 139317 seems to be a selective ETA-receptor antagonist which competitively antagonizes the endothelin-1- and endothelin-2-induced contractions of guinea-pig isolated pulmonary arteries. Thus, the guinea-pig pulmonary artery appears to be endowed with one receptor type (ETA) which is antagonized by FR 139317 and with another endothelin-receptor subtype which responds to endothelin-3, but is not antagonized by FR 139317. In the trachea, all three peptides act on a homogeneous population of receptors which is unaffected by FR 139317. This suggests an ETA-receptor in the guinea-pig pulmonary artery and another receptor, probably of ETB-type, in the guinea-pig trachea.

Animals↗

PubMed1992

Evidence for multiple endothelin receptors in the guinea-pig pulmonary artery and trachea.

1. The responses of the three peptides, endothelin 1 (ET-1), endothelin 2 (ET-2) and endothelin 3 (ET-3) were analysed on isolated circular segments of pulmonary arteries and trachea from the guinea-pig. 2. In the pulmonary artery, the vasomotor responses to the endothelins, expressed as the maximum contraction (Emax%), had the order ET-1 greater than ET-2 greater than ET-3 while the order of potency (pD2) was ET-1 = ET-2 greater than ET-3. ET-1 and ET-2 caused cross-desensitization, but did not affect the responses to ET-3. ET-3 did not cause cross-desensitization to ET-1 or ET-2 although it induced homologous desensitization. Finally, the effects of ET-1 and ET-2 were additive to those of ET-3. The additive effect of ET-3 to those of ET-1 or ET-2 was more difficult to demonstrate, given the profound contraction produced by ET-1 and to a lesser extent by ET-2. 3. In the trachea, the rank order of potency, additivity and desensitization were different from the pulmonary artery. Basically, all three peptides were equipotent but less potent than ET-1 in the artery. There was no evidence for additivity and only a slight tendency to tachyphylaxis was seen. 4. The guinea-pig pulmonary artery appears to be endowed with one receptor type which is sensitive to ET-1/ET-2 and with another receptor type which responds preferentially to ET-3. In the trachea, neither of these receptors appears to be present since all three peptides apparently act on a homogeneous population of receptors with characteristics different from those of the two arterial receptors. This suggests a third non-isopeptide selective type of endothelin receptor.

Animals↗

PubMed1991

Pituitary adenylate cyclase activating peptide (PACAP) in guinea-pig lung: distribution and dilatory effects.

The lower airways of guinea-pigs were analyzed for pituitary adenylate cyclase activating peptide (PACAP) using immunocytochemistry. In the trachea a moderate supply of PACAP-immunoreactive nerve fibers occurred around smooth muscle bundles, glands and small blood vessels. In the lung, PACAP-immunoreactive nerve fibers were distributed around small glands and bronchi. A rich supply of PACAP immunoreactive nerve fibers was found around blood vessels in the lungs. PACAP-suppressed smooth muscle responses were analysed using isolated circular segments of trachea, pulmonary arteries and aorta of guinea-pigs. In both airways and arteries PACAP caused a concentration-dependent relaxation of precontracted segments. The maximal relaxation effects were more pronounced in the airways than in the arteries while the order of potency was aorta greater than pulmonary artery greater than trachea. The effect of PACAP was compared to those of acetylcholine (ACh) and vasoactive intestinal peptide (VIP). In the pulmonary artery the vasomotor responses expressed as maximal dilatation had the order: ACh greater than VIP = PACAP while the order of potency was PACAP = VIP greater than ACh. In the trachea, PACAP was slightly more potent than VIP. The relaxatory responses to PACAP in the trachea and the intrapulmonary arteries were unaffected by pretreatment with atropine, prazosin, yohimbine, propranolol, mepyramine, cimetidine and Spantide. Removal of the endothelium abolished PACAP-induced vascular relaxation. Conceivably, PACAP-containing nerve fibers play a role in the regulation of airway resistance and local blood flow.

Analysis of Variance↗

PubMed1990

Analysis of endothelin-1-induced contractions of guinea-pig trachea, pulmonary veins and different types of pulmonary arteries.

Endothelin-I (ET-I), a peptide produced by the vascular endothelium, has been found to produce strong and persistent contractions of various blood vessels. In the present study, the effects of ET-I were studied on isolated pulmonary arteries from four different levels (main pulmonary artery, large lobar arteries, small lobar arteries and intrasegmental arteries) of the guinea-pig. In addition, the effects of ET-I on pulmonary arteries were compared with those of pulmonary veins and trachea. ET-I elicited a strong concentration-dependent contraction of pulmonary arteries, veins and trachea. The effects of ET-I were more pronounced in pulmonary arteries than in corresponding veins. Significant regional variations within the pulmonary arterial system were disclosed. The tracheal segments showed the same sensitivity and the same degree of relative maximal contraction as the pulmonary veins. Although the cellular mechanisms behind the action of ET still are not clear, our results favour a direct action of ET-I on the vascular smooth muscle during vasoconstriction. Furthermore, the ET-I-induced contraction in guinea-pig lung seems to be independent of extracellular calcium.

Animals↗

PubMedDate not supplied

Characterisation of endothelin induced relaxation in guinea-pig airways: evidence for dilatory ETA- and ETB-receptors.

Receptors involved in endothelin induced relaxation were characterized on isolated circular segments of guinea-pig trachea. The motor responses to endothelin-1 (ET-1), ET-2 and ET-3 as well as the effects of the ETB-receptor agonist, BQ 3020, and the ETA-receptor antagonist, FR 139317, were tested. The responses obtained were analysed in relation to the nitric oxide (NO) synthase inhibition by NG-monomethyl L-arginine (L-NMMA). In submaximally precontracted tracheal segments ET-1 and ET-2 induced concentration-dependent dilatations. ET-3 induced a biphasic response in precontracted segments, at low concentrations a small contraction followed by a dilatation at higher concentrations. FR 139317 blocked the low concentration induced dilatation by ET-1/ET-2, unmasking a contractile response. The dilatation induced by higher ET-1/ET-2 concentrations was unaffected by FR 139317 which also did not affect the dilatory response of ET-3. These results indicate the presence of two dilatory receptors. One of these was of ETA type, since it was antagonized by FR 139317 while the other receptor probably was of the ETB type, since all three endothelins in the moderate concentration range caused a uniform dilatation which was unaffected by FR 139317. Furthermore, BQ 3020 induced potent relaxation of the precontracted segments. In resting tracheal segments all three endothelins caused an identical contraction, suggesting a contractile ETB-receptor. However, BQ 3020 along with another ETB-agonist, IRL 1620, failed to induce contraction which indicates the possibility of two different subtypes of the ETB-receptor, one involved in dilatation and the other in contraction. Experiments with the nitric oxide synthetase inhibitor L-NMMA on precontracted segments showed a similar change as when FR 139317 was used. This suggests that the dilatory ETA-receptor depends on nitric oxide (NO) for mediating the dilation. On the other hand, the dilatory ETB-receptor response was unaffected by L-NMMA which suggests a mechanism unrelated to NO.

Animals↗