Functional studies suggest the presence of prejunctional muscarinic autoreceptors on cholinergic nerves in human airways. However, these studies are an indirect method of evaluating changes in neurally evoked acetylcholine (ACh) release. We have investigated the presence of muscarinic autoreceptors in human and guinea pig trachea by comparing the effects of the muscarinic receptor antagonists pirenzepine (M1), methoctramine (M2), 4-DAMP (M3), and rispenzepine (M1/M3) on cholinergic neural contractile responses evoked by electrical field stimulation (EFS) and [3H]ACh release. The M1, M1/M3, or M3 antagonists inhibited the EFS-evoked cholinergic contractile response in a concentration-dependent manner (4-DAMP > rispenzepine > pirenzepine), whereas methoctramine facilitated this response at low concentrations ( < 3 microM). In ACh release studies, the M3 antagonist had no significant effect, whereas pirenzepine, methoctramine, and rispenzepine significantly increased ACh release in guinea pig trachea. In contrast, ACh release was significantly inhibited by the muscarinic agonist oxotremorine M. Methoctramine and the nonselective antagonist ipratropium bromide, but not the M1, M1/M3, or M3 antagonists, significantly increased ACh release in human trachea. These data suggest the presence of an autoinhibitory receptor on cholinergic nerve terminals in human and guinea pig trachea. In addition, the action of ipratropium bromide at the autoinhibitory receptor may limit its use in the treatment of obstructive airways disease.
Publisher Summary This chapter outlines a new approach to structural stainless steel design, which is based on exploiting the full deformation capacity of cross-sections, by adopting a continuous method of cross-section classification and member design coupled with more accurate material modeling. It presents recently generated laboratory test results, and shows how they are used in combination with existing test data to validate the proposed method. Average design advantages of around 20–25% are achieved. Significant improvements in performance may be achieved by basing the structural design of stainless steel members on the actual material behavior (rather than assuming an analogy with carbon steel). New test data on local buckling and plate element behavior is generated. Additional member tests on beams and pin-ended long columns are conducted. Using a new proposed design approach, average improvements of around 20%, that still produce safe side predictions of test data, are achieved. It is envisaged that the proposed design method will be incorporated into future revisions of Eurocode 3, bringing greater efficiency to structural stainless steel design and promoting more widespread use of the material.
Dr Rutherford asks: When you first heard that Andreas Grüentzig had successfully performed a transluminal coronary dilation in September 1977, what were your thoughts?Did it seem a sustainable therapy at the time?Dr Serruys replies: In 1975 at a meeting in Frankfurt, a key opinion leader at that time, Professor Paul Lichtlen, Chief of Cardiology at Hannover, was describing during a keynote lecture a significant coronary lesion with a thin fibrous cap and a large atheromatous core; today, we call this a vulnerable plaque.He mentioned somewhat sarcastically that Dr Andreas Grüentzig had developed a procedure he believed could dilate that type of lesion.There was of course a lot of skepticism whether the procedure could be performed without major distal embolization.I went to see Andreas Grüentzig and to look at his poster.He had tied a ligature with catgut around the coronary artery of a dog, and he was using his balloon to open this artificial narrowing.Honestly, I could not foresee the future of this therapeutic approach.At that time, the Department of Cardiology in Zürich (where Grüentzig worked) was headed by 2 cardiologists, Hans Peter Krayenbühl and Wilhelm Rutishauser.Krayenbühl was not in favor of attempting the procedure, but Rutishauser was more enthusiastic about it.The famous Chief of Cardiovascular Surgery, Dr Åke Senning, told the Board of the hospital that he would help Andreas and be present in the cardiac catheterization laboratory to back up a potential catastrophe.The story is that when Andreas deflated the balloon and the gradient disappeared, Senning left the laboratory, without even looking at the angiogram, convinced the result was good.In 1978, Grüentzig reported successful dilation of an 85% left anterior descending coronary stenosis by PTCA in a 38-year-old man with severe angina and theThe Birth, and Evolution,
We studied the Nobori coronary stent coated with a bioabsorbable polymer and the anti-proliferative agent Biolimus A9 which may reduce neointimal formation.Patients undergoing percutaneous coronary intervention for de novo lesions in up to two native coronary arteries, in 29 centres across Europe, Asia and Australia were randomly (2:1) assigned to receive the Biolimus A9 eluting stent Nobori (85 patients) or paclitaxel eluting stent Taxus(R) (35 patients). The two groups were well matched in baseline characteristics. The primary end point of non-inferiority for in-stent late loss of Nobori stent versus Taxus(R) stent, at 9 months, was reached with the values of 0.15+/-0.27 mm with Nobori stent and 0.32+/-0.33 mm with Taxus(R) stent (p=0.006). Neointimal volume obstruction was 2.2+/-6.0% and 8.9+/-9.2% for Nobori and Taxus(R) stent respectively (p=0.017). The rates of death, myocardial infarction and any target vessel revascularisation at 9 months were 0%, 4.7%, and 7.1% respectively for Nobori stent, and 0%, 8.6% and 14.3% respectively for Taxus(R) stent. Clinically-driven target lesion revascularisation rate was 0% for Nobori stent and 2.9% for Taxus(R) stent. Stent thrombosis rates at 9 months were 0% in both groups.In this trial the Nobori Biolimus A9 eluting stent proved to be safe and effective in reducing neointimal proliferation. The long term safety remains to be confirmed during the extended follow-up period of 5 years.
The effect of thiazide duretics on neurally and agonist-induced contractile responses of guinea pig airways in vitro were investigated. Tracheal or bronchial strips were suspended in organ baths and isometric tension recorded. Chlorothiazide (CTZ, 10−4 to 3 × 10−3 M), hydrochlorothiazide (HCTZ, 10−3 M), and dichlorphenamide (DCPM, 10−3 M) significantly potentiated contraction of tracheal strips induced by electrical field stimulation (EFS). They also increased acetylcholine (ACh)- but not carbachol-induced tracheal contraction. In the presence of atropine and propranolol, on the other hand, CTZ and DCPM but not HCTZ significantly inhibited EFS-induced contraction in bronchial strips. We determined whether carbonic anhydrase inhibition could mimic the effects of CTZ and DCPM. Acetazolamide (ATZ), an inhibitor of carbonic anhydrase, had no effect on either EFS- or ACh-induced contraction in tracheal strips but significantly inhibited nonadrenergic, noncholinergic (NANC) contractile responses induced by EFS in bronchial strips. CTZ, DCPM, and ATZ did not affect substance P-induced contractile responses in the bronchi. We conclude that CTZ, DCPM, and ATZ attenuate NANC neurally mediated bronchial contraction by preventing the release of contractile neuropeptides from sensory nerve endings. This effect may occur through inhibition of carbonic anhydrase activity. In addition, thiazide diuretics potentiate contractile responses to ACh in the trachea, probably through inhibition of acetylcholinesterase activity.
