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At least 541 records · Page 30Linked to original sources
PubMed2004

Influence of agonist intrinsic activity on the desensitisation of beta2-adrenoceptor-mediated responses in mast cells.

1. The aim of the present study was to determine whether the intrinsic activity of an agonist influences the extent of desensitisation of beta(2)-adrenoceptor-mediated responses in human lung mast cells. 2. The effects of a wide range of beta-adrenoceptor agonists (10(-10)-10(-5) m) on the IgE-mediated release of histamine from mast cells were determined. The intrinsic activity of agonists was established by comparing the maximal inhibitory response (E(max)) of an agonist relative to the maximal response obtained with the full agonist, isoprenaline. The intrinsic activity order for the inhibition of histamine release was isoprenaline (1.0)>formoterol (0.94)>fenoterol (0.89)>terbutaline (0.84)>salbutamol (0.69)>clenbuterol (0.65)>salmeterol (0.30)>dobutamine (0.20). 3. There was a significant (P<0.05) positive correlation (r=0.81) between the extent to which beta-adrenoceptor agonists inhibited histamine release and the degree to which the agonists caused elevations in cAMP in mast cells. 4. Further studies investigated the effects of long-term (24 h) incubation of mast cells with beta-adrenoceptor agonists on the subsequent ability of isoprenaline to inhibit histamine release. At concentrations of agonists selected to occupy a large percentage (88%) of beta(2)-adrenoceptors, there was a significant (P<0.05) correlation (r=0.73) between the relative intrinsic activity of agonists as inhibitors of histamine release and the extent of functional desensitisation induced by the agonists. At lower receptor occupancies, however, there was no correlation between the relative intrinsic activity of agonists and the extent of agonist-induced desensitisation. 5. These data indicate that, under experimental conditions where high receptor occupancies prevail, agonist intrinsic activity influences the extent of desensitisation of beta(2)-adrenoceptor-mediated responses in mast cells.

Adrenergic beta-2 Receptor Agonists↗
PubMed2000

The effect of sorbinil, an aldose reductase inhibitor, on aortic function in control and streptozotocin-induced diabetic rats.

1. The present study investigates the effect of treatment of 14-day streptozotocin-diabetic rats with the aldose reductase inhibitor, sorbinil, on changes ex vivo in aortic vasoconstriction and vasodilation. 2. Maximum contractile responses and aortic sensitivity to phenylephrine were significantly enhanced in aortae from 14-day diabetic rats, in accordance with our previous data. 3. Endothelium-dependent relaxations to carbachol were, in contrast, depressed, although endothelium-independent relaxations to forskolin and sodium nitroprusside were unaltered. 4. Sorbinil treatment of diabetic animals failed to prevent any of these diabetes-induced alterations in aortic function, and indeed exacerbated some of these alterations. In addition, sorbinil treatment caused altered aortic responses in control animals, which sometimes mirrored those found in diabetic animals. 5. It can be concluded that sorbinil may have actions in addition to, and independent of, polyol pathway inhibition. Thus, sorbinil may not be an effective tool for the investigation of aldose reductase inhibition within the vascular system of the rat.

Aldehyde Reductase↗
PubMed2000

M3 muscarinic receptors but not M2 mediate contraction of the porcine detrusor muscle in vitro.

1. The objective of the study was to determine the role of muscarinic receptor subtypes in mediating contraction of the porcine detrusor smooth muscle in vitro. 2. Strips of pig detrusor muscle were set up in physiological salt solution and the tensions developed by the tissues were recorded. Responses to carbachol were obtained in the absence and presence of a range of muscarinic antagonists (4-DAMP, methoctramine, darifenacin, oxybutynin, tolterodine and pirenzepine). Antagonist affinity values (pKB values) were calculated and compared with those quoted in the literature for these antagonists at each of the muscarinic receptor subtypes. 3. The M3-selective antagonists, 4-DAMP and darifenacin had high affinities (pKB values of 9.4 and 8.6, respectively). Oxybutynin, tolterodine and pirenzepine had affinities of 8.2, 8.1 and 6.8, respectively, whilst the M2-selective agent methoctramine had a relatively low affinity (pKB = 6.1). The rank order of affinities was, therefore, 4-DAMP > darifenacin > oxybutynin > tolterodine > pirenzepine > methoctramine for the pig detrusor. Correlation of the antagonist affinities obtained on the bladder with those published for these antagonists at the five muscarinic receptor subtypes identified the M3(m3)-receptor as the muscarinic subtype mediating detrusor contractile responses in vitro. 4. These data suggest that a small population of M3-muscarinic receptors must mediate direct contractile responses of the pig detrusor muscle to muscarinic receptor stimulation in vitro.

Animals↗
PubMed2001

The effect of streptozotocin-induced diabetes on cardiac beta-adrenoceptor subtypes in the rat.

1. The present study investigates the effect of short-term experimental diabetes of 14-days duration on the beta-adrenoceptor subtypes of the rat heart. 2 .beta-adrenoceptor-mediated functional responses to submaximal doses of isoprenaline were enhanced in Langendorff-perfused hearts from diabetic rats, manifested as greater changes in tension, heart rate and rates of tension development (+dT/dt) and decline (-dT/dt). 3. Radioligand binding data demonstrated that total cardiac beta-adrenoceptor density and affinity for [3H]-dihydroalprenolol was unchanged by diabetes, although a decrease in beta1-adrenoceptor density and increase in beta2-adrenoceptor density was observed. 4. In conclusion, hearts from 14-day streptozotocin-induced diabetic rats demonstrate a number of alterations within the beta-adrenoceptor system. However, the enhanced beta-adrenoceptor-mediated responses to isoprenaline were not caused by an overall increase in density of beta-adrenoceptors, but were accompanied by changes in the ratio of the beta-adrenoceptor subtypes.

Adrenergic beta-Agonists↗
PubMed2001

Arrhythmogenesis in isolated rat hearts with enhanced alpha-adrenoceptor-mediated responsiveness.

1. It has been postulated that stimulation of myocardial alpha-adrenoceptors is one of the primary mediators of the dysrhythmias which occur during periods of myocardial ischaemia and reperfusion. This study examines arrhythmogenesis during coronary artery occlusion and reperfusion in isolated perfused rat hearts from control animals and from rats with enhanced myocardial alpha-adrenoceptor responsiveness. 2. Rats were administered propylthiouracil (PTU) in their drinking water for 8 weeks. This treatment resulted in an enhanced responsiveness of isolated left atria to the alpha-adrenoceptor agonist phenylephrine compared with atria from control animals. 3. In Langendorff-perfused isolated hearts, the spontaneous rate of contraction was significantly lower in the PTU-pretreated group than in either age-matched or weight-matched controls. Occlusion of the left anterior descending artery (LAD) for 25 min resulted in ventricular tachycardia (VT) of similar incidence and duration in all groups and ventricular fibrillation (VF) in both control groups but not the PTU-pretreated group. 4. Following the 25-min ischaemic period the myocardium was reperfused for 10 min. The incidence and duration of VT and VF during this period was similar in all groups except that the duration of VF in the PTU-pretreated group was significantly lower than in controls. 5. In perfused hearts paced at 4 Hz, the incidence and duration of dysrhythmias during ischaemia and reperfusion was again similar in all groups, only the duration of VF being affected (reduced) by PTU-pretreatment. 6. In conclusion, this study does not lend support to the hypothesis that myocardial alpha-adrenoceptors have a primary role in arrhythmogenesis, but the data would support a role for these receptors in myocardial protection.

Adrenergic alpha-Agonists↗
PubMedDate not supplied

The minor population of M3-receptors mediate contraction of human detrusor muscle in vitro.

1 The objective was to determine the role of muscarinic receptor subtypes in mediating contraction of the human detrusor smooth muscle in vitro. 2 Contractile responses of human detrusor muscle strips to carbachol were obtained in the absence and presence of a range of muscarinic antagonists (pirenzepine, methoctramine, 4-diphenylacetoxy-N-methyl piperidine methiodide (4-DAMP), tropicamide, oxybutynin and tolterodine). Affinity estimates (pKB values) were calculated for the antagonists and correlated with values at the cloned muscarinic receptor subtypes quoted in the literature. 3 Pirenzepine, methoctramine and tropicamide drugs that have high affinities at M1, M2 and M4-receptors, respectively, all had low affinities on the human detrusor (pKB values of 6.8, 6.9 and 6.5, respectively), whilst the M3-selective antagonist 4-DAMP had a high affinity (9.5). Schild plots for all four antagonists had slopes of unity indicating an action at a single receptor. Oxybutynin and tolterodine also acted as competitive antagonists with affinity estimates of 7.6 and 8.1, respectively. 4 When the antagonist affinities obtained on the bladder were plotted against the values published for these antagonists at the cloned muscarinic receptor subtypes, the best correlations were obtained for the m3- and m5-muscarinic receptor subtypes. 5 These data suggest that direct contractile responses of the human detrusor muscle to muscarinic receptor stimulation in vitro are mediated solely via the M3-muscarinic receptor subtype with no contribution from the major M2-receptor population.

Aged↗
PubMed1997

Relaxant effects of potassium-channel openers on normal and hyper-reflexic detrusor muscle.

OBJECTIVE: To compare the effects of the potassium-channel openers, levcromakalim and YM934, in isolated human detrusor muscle from normal and hyper-reflexic bladders. MATERIALS AND METHODS: Strips of human detrusor muscle from normal and hyper-reflexic bladder were pre-contracted with carbachol and the potassium-channel openers (0.1-0.3 mumol/L) were added cumulatively to the organ baths. Other strips were field-stimulated at frequencies producing 25% and 75% of the maximum response to field stimulation. Contractions could be abolished by atropine (10 mumol/L) and tetrodotoxin (1 mumol/L). RESULTS: The hyper-reflexic bladder was significantly more sensitive to carbachol than the normal bladder but the maximum response was significantly lower in the hyper-reflexic tissue. There was no significant difference between the potency of the potassium-channel openers in normal and hyper-reflexic detrusor muscle. Hyper-reflexic bladder was significantly more sensitive to electrical field stimulation than was normal bladder: maximum responses to field stimulation were not significantly different. Concentration-response curves for the potassium-channel openers were displaced to the left in hyper-reflexic bladder at both 25% and 75% maximum frequencies: however, only with levcromakalim at 75% of the maximum frequency was the shift significant. CONCLUSION: The greater sensitivity of hyper-reflexic bladder to carbachol and field stimulation supports existing evidence for post-junctional supersensitivity in detrusor instability. The results of this study also suggest that there are no appreciable changes in KATP channel function in the unstable bladder.

Benzopyrans↗
PubMed1999

In vitro investigation of the bladder-vascular selectivity of levcromakalim and YM934 in human tissues.

OBJECTIVE: To examine the potencies of the potassium-channel openers (KCOs) levcromakalim and YM934 as relaxing agents on human detrusor and human mesenteric artery smooth muscle, and to determine their bladder-vascular selectivity in vitro. MATERIALS AND METHODS: Strips of human detrusor muscle and mesenteric artery (with the endothelium removed) were set up in physiological salt solution and the tension developed by the tissues recorded. Tissues were precontracted with a concentration of carbachol (detrusor) or phenylephrine (artery) which caused 80% of maximal contraction, and relaxation responses to levcromakalim and YM934 were then obtained. RESULTS: Both KCOs caused relaxation of the bladder detrusor muscle and the mesenteric artery. Maximal responses, when plotted as a percentage of the precontraction, were greater for both KCOs in the bladder muscle than the artery, but the differences were small and not statistically significant. The sensitivity (drug potency) of the detrusor muscle to the KCOs was more than twice that of the artery but this selectivity was only statistically significant for YM934. CONCLUSIONS: Only minor bladder-vascular selectivity for levcromakalim and YM934 could be detected in vitro. This suggests that neither drug would be tolerated clinically, although the results suggest that further development of bladder-selective KCO agents appears feasible.

Benzoxazines↗
PubMed2000

Lack of neuropeptide Y receptor detection in human bladder and prostate.

OBJECTIVE: To investigate the presence of functional neuropeptide Y (NPY) receptors in human bladder and prostate (both richly endowed with NPY-containing nerve fibers) using peptide YY (PYY) as the agonist. Materials and methods Binding studies were conducted using [125I]PYY as the radioligand. Organ-bath studies were performed on isolated tissue strips for direct (postjunctional) contractile effects and for (prejunctional) inhibition of field stimulation effects. Any possible degradation of PYY was determined using high-performance liquid chromatography (HPLC). RESULTS: In the radioligand binding studies no quantifiable specific [125I]PYY binding was detected in human bladder or prostate, while specific high-affinity binding was readily seen in rat cerebral cortex. In organ-bath experiments, PYY (up to 1 micromol/L) caused no contraction of human prostate or bladder, whereas noradrenaline and carbachol, respectively, were effective; the potency or efficacy of noradrenaline and carbachol were not altered by PYY. Field stimulation-induced contraction was not affected by PYY in either human bladder or prostate, but was readily inhibited in rat vas deferens. HPLC detected no relevant PYY degradation by human bladder or prostate homogenates. CONCLUSION: Human bladder and prostate express only very few if any functional NPY receptors.

Animals↗
PubMed2000

5-Hydroxytryptamine-induced potentiation of cholinergic responses to electrical field stimulation in pig detrusor muscle.

OBJECTIVE: To determine whether detrusor muscle from the pig can be used as a model to study presynaptic 5-hydroxytryptamine (HT)4-receptor-mediated effects on the electrical field stimulated (EFS) cholinergic responses previously identified in the human bladder. Materials and methods Strips of detrusor muscle were mounted in physiological Krebs' solution under 1 g tension and field stimulated (25 Hz, 0.01 ms duration, 60 V for 5 s) at 100-s intervals and allowed to equilibrate. Concentration-response curves to 5-HT (1 nmol/L to 300 micromol/L) were constructed in the presence and absence of the 5-HT4-selective antagonists RS-100235 and GR-113808 (both at 0.3, 1 and 3 nmol/L). All experiments were conducted in the presence of methiothepin and ondansetron (both 1 micromol/L) to block 5-HT1, -HT2 and -HT3 receptors. RESULTS: 5-HT potentiated the cholinergic responses to EFS in pig bladder strips in a concentration-dependent manner, with a maximum mean (SEM) potentiation of 48.3 (7.7)% of the resting tension (n = 25). Both RS-100235 and GR-113808 antagonized the effect of 5-HT with high affinity, yielding apparent pKB values which were consistent with the responses being mediated via the 5-HT4 receptor subtype. CONCLUSION: These data indicate that 5-HT can potentiate EFS responses in isolated pig bladder strips and that the 5-HT4 receptor subtype mediates this response. Therefore, the pig may be used as an effective model to study presynaptic 5-HT4 receptors previously reported in the human bladder.

Action Potentials↗
PubMed2003

Investigation of neurokinin-2 and -3 receptors in the human and pig bladder.

OBJECTIVE: To investigate the role of neurokinin (NK)-2 and -3 receptors in mediating the contraction of detrusor muscle strips from human and pig, to determine whether the pig is a good model for the study of tachykinin receptors in the human bladder, as the biological actions of tachykinins, e.g. substance P and NKA are mediated via three distinct receptor subtypes, NK-1, -2 and -3. MATERIALS AND METHODS: Strips of detrusor muscle were obtained from the bladder dome and neck of female pigs and from patients undergoing cystectomy. Cumulative concentration-response curves to NKA were obtained in the absence and presence of either the NK-2 receptor-selective antagonist SR48968 or the NK-3 receptor-selective antagonist SB223412. RESULTS: NKA produced concentration-dependent contractions in the human and pig detrusor muscle; the curves were shifted to the right by SR48968, with high affinity (pKB 8.9, 8.3 and 8.0 in the human, pig dome and pig neck, respectively), whereas SB223412 had a minimal effect (pKB 5.8, 5.8 and 6.3, respectively). CONCLUSION: These data confirm that the NK-2 receptor subtype mediates NKA-induced contraction of the human and pig detrusor muscle. The NK-3 receptor appears to have no role in detrusor contraction of either species. The results also provide evidence that the NK-2 receptor in human and pig are the same, and the latter may be an appropriate species to study tachykinin-induced contractions in human bladder.

Animals↗
PubMed2002

Muscarinic receptors of the urinary bladder: detrusor, urothelial and prejunctional.

1. The parasympathetic nervous system is responsible for maintaining normal bladder function, contracting the bladder smooth muscle (detrusor) and relaxing the bladder outlet during micturition. 2. Contraction of the bladder involves direct contraction via M3 receptors and an indirect 're-contraction' via M2-receptors whereby a reduction in adenylate cyclase activity reverses the relaxation induced by beta-adrenoceptor stimulation. 3. Muscarinic receptors are also located on the epithelial lining of the bladder (urothelium) where they induce the release of a diffusible factor responsible for inhibiting contraction of the underlying detrusor smooth muscle. The factor remains unidentified but is not nitric oxide, a cyclooxygenase product or adenosine triphosphate. 4. Finally, muscarinic receptors are also located prejunctionally in the bladder on cholinergic and adrenergic nerve terminals, where M1-receptors facilitate transmitter release and M2 or M4-receptors inhibit transmitter release. 5. In pathological states, changes may occur in these receptor systems resulting in bladder dysfunction. Muscarinic receptor antagonists are the main therapeutic agents available for treatment of the overactive bladder, but whether their therapeutic effect involves actions at all three locations (detrusor, prejunctional, urothelial) has yet to be established.

Animals↗
PubMedDate not supplied

The role of alpha1D-adrenoceptors in prostatic contraction examined using protection studies.

1 The aim of the study was to investigate the role of the alpha1D-adrenoceptor in alpha1-adrenoceptor-induced contraction of human prostate by means of protection experiments. 2 Responses of human prostate strips to noradrenaline were recorded, along with responses of rat aorta and vas deferens, tissues possessing predominantly alpha1D- and alpha1A-adrenoceptors respectively, for comparison. alpha1-adrenoceptors were then inactivated by incubation with the irreversible antagonist phenoxybenzamine. In some tissues alpha1A- or alpha1D-adrenoceptors were 'protected' from inactivation by incubation in the presence of the selective alpha1A- or 1D-adrenoceptor antagonists 5-methylurapidil and BMY 7378 before recording further responses to noradrenaline. 3 Phenoxybenzamine reduced the maximum noradrenaline-induced response and the potency of noradrenaline in all tissues. In rat vas deferens and human prostate, 5-methylurapidil protected alpha1A-adrenoceptors in a concentration-dependent manner. In rat aorta, 10 nM BMY 7378 almost fully protected alpha1D-adrenoceptors. However, concentrations of BMY 7378 up to 30-fold higher failed to protect receptors in the human prostate. 4 These results suggest that in human prostate functional alpha1D-adrenoceptors do not contribute to noradrenaline-induced contractile responses.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed2005

[On the acceptability of xenografts].

Transplantation represents a major advance in modern medicine with a major impact on the interactions between individuals and society. The numbers of patients undergoing organ transplantation increased steadily over the years and around 250,000 individuals are living nowadays in Europe with a transplanted organ. On the other hand, the numbers of cadaveric (brain-dead) donors used for organ transplantation remains stable, at around 5,000 each year, and the numbers of transplantation from living donors only slowly increase in Europe. Therefore, a gap is growing between the numbers of patients in need of a transplant and the numbers of organs available for transplantation. About 45,000 patients are currently on renal transplant waiting lists in Europe and, depending on the countries considered, 15 to 30 % of candidates for liver or heart transplantation die before a life-saving transplant becomes available to them. There is therefore an urgent need to implement innovative research and to take full advantage of recent biotechnological advances to explore new avenues in xenotransplantation, and to simultaneously address the ethical, societal and public health issues related to organ replacement. Much progresses have been accomplished in the understanding of xenograft rejection processes that include hyperacute, acute vascular and cellular rejection mechanisms. Strategies to promote xenograft survival that are currently under evaluation include genetic engineering of donor pigs, adapted immunosuppressive treatments and tolerance induction. Also, the psychological acceptance has been evaluated.

Animals↗
PubMed2006

Pathogenesis of bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD), initially described 40 years ago, is a dynamic clinical entity that continues to affect tens of thousands of premature infants each year. BPD was first characterized as a fibrotic pulmonary endpoint following severe Respiratory Distress Syndrome (RDS). It was the result of pulmonary healing after RDS, high oxygen exposure, positive pressure ventilation, and poor bronchial drainage secondary to endotracheal intubation in premature infants. With improved treatment for RDS, including surfactant replacement, oxygen saturation monitoring, improved modes of mechanical ventilation, antibiotic therapies, nutritional support, and infants surviving at younger gestations, the clinical picture of BPD has changed. In the following pages, we will summarize the multifaceted pathophysiologic factors leading to the pulmonary changes in "new" BPD, which is primarily characterized by disordered or delayed development. The contribution of hyperoxia and hypoxia, mechanical forces, vascular maldevelopment, inflammation, fluid management, patent ductus arteriosus (PDA), nutrition, and genetics will be discussed.

Bronchopulmonary Dysplasia↗
PubMed2001

Evaluation of disinfectant efficacy against hepatitis C virus using a RT-PCR-based method.

The methods traditionally used to evaluate the antiviral activity of antiseptics and disinfectants are based on cell cultures. However, such methods are not applicable to non-cultivable viruses such as hepatitis C (HCV). Therefore, in this case, virucidal activity is normally tested using surrogate viruses able to grow in cell culture. This paper describes a RT-PCR method for testing antiseptic/disinfectant activity against HCV, as a model for non-cultivable viruses. A chlorine-based agent used for skin and tissues, and a 2% glutaraldehyde solution used for endoscope disinfection, were the test materials. The results are discussed in the light of the use of these agents. The method is simple, fast and inexpensive, and could be used for tests on other viruses with minor modification.

Disinfectants↗
PubMed2001

A biomechanical analysis of intrascaphoid compression using the 3.00 mm Synthes cannulated screw and threaded washer: an in vitro cadaveric study.

This study evaluated the compressive capabilities of the 3.0 mm Synthes cannulated screw and threaded washer. A transverse osteotomy was performed at the waist of eight cadaveric scaphoids and a custom-designed load cell was inserted before internal fixion with a 3.0 mm cannulated screw and threaded washer. The mean intrascaphoid compression achieved was 108 (SD, 60) N. This compressive force is comparable to that produced by standard cortical screws.

Aged↗