I. E. Hughes

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 Ca2+‐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 μm) 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, 0.1–100 μm) 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 μm) 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 (thromboxanemimetic) 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.

A comparison in rabbit isolated hearts of the dysrhythmogenic potential of amitriptyline, maprotiline and mianserin in relation to their ability to block noradrenaline uptake.

1 In isolated hearts of rabbits, perfusion with (‐)‐noradrenaline (0.0059 to 5.9 μM) resulted in chronotropic and inotropic responses and a shortening of the interval between peak atrial and peak ventricular tensions (the A‐V contraction interval). No dysrhythmias developed but at higher concentrations (590 μM) 2 out of 7 hearts developed dysrhythmias (extrasystoles). 2 Perfusion with the antidepressants amitriptyline or maprotiline (4.8 μM) or mianserin (28.8 μM) reduced ventricular force, did not change heart rate and only amitriptyline reduced atrial force and lengthened the A‐V contraction interval. At 4.8 μM mianserin produced only a marginal shortening of the A‐V contraction interval. 3 At these concentrations no dysrhythmias developed but at higher concentrations (amitriptyline 8 μM. maprotiline 8 μM, mianserin 60 μM) all the agents produced dysrhythmias involving an interference with atrio‐ventricular synchronization. 4 In the presence of mianserin (4.8 μM) perfusion with noradrenaline (0.0059 to 5.9 μM) shortened the A‐V contraction interval and did not produce dysrhythmias. In the presence of amitriptyline or maprotiline (4.8 μM) or mianserin (28.8 μM) the A‐V contraction interval generally lengthened and most hearts developed dysrhythmias (usually involving interference with atrio‐ventricular synchronization). 5 [3H]‐(‐)‐Noradrenaline uptake in perfused rabbit hearts and in mouse isolated atria or vasa deferentia was inhibited by the antidepressants to a similar extent, amitriptyline being marginally most potent (molar potency taken as 1.0), maprotiline being less potent (1.5) and mianserin least potent (2.0). 6 It is concluded that of these three antidepressants, mianserin is least cardiotoxic in this preparation and that the ability of these antidepressants to predispose to noradrenaline‐induced dysrhythmias is not related to blockade of noradrenaline uptake.

Possible subdivisions among α‐adrenoceptors in various isolated tissues

The ratio (expressed in log10 units) of the equieffective concentrations of (+)‐ and (—)‐noradrenaline has been measured in a variety of isolated tissues in the presence of cocaine (1 times 10−5m), tropolone (3 times 10−5m) and (±)‐propranolol (5 times 10−7 to 5 times 10−5m). The values obtained fall into 3 distinct and statistically different groups. Firstly, a high group comprising (mean ± s.e.) mouse vas deferens (2·78 ± 0·04), rabbit duodenum (2·91 ± 0·07) and ileum (2·86 ± 0·05). Secondly a middle group comprising rabbit vas deferens (2·54 ± 0·04), bladder neck muscle (2·56 ± 0·07) and spleen (2·50 ± 0·02), guinea‐pig vas deferens (2·55 ± 0·10) and bladder neck muscle (2·48 ± 0·13) and rat deferens (2·40 ± 0·08) and thirdly, a low group comprising the bladder detrusor muscle from both the rabbit (2·08 ± 0·08) and the guinea‐pig (2·07 ± 0·04). Under the same conditions measurement of pA2 values for phentolamine and piperoxan against noradrenaline gave the following values in rat vas deferens (8·22 ± 0·07 and 6·72 ± 0·03 respectively) and mouse vas deferens (8·31 ± 0·05 and 6·53 ± 0·07 respectively). The results are discussed in relation to other findings concerning the nature of the α‐adrenoceptor in these tissues. In spite of the absence of any significant difference between the potency of the α‐adrenoceptor blocking agents in the two species it is suggested that α‐adrenoceptors may not belong to a single homogeneous population but may vary in their characteristics from tissue to tissue.

Computer-based learning: an aid to successful teaching of pharmacology?

Abstract. Various types of software have been developed for use in pharmacology courses. These include: simple drill (question and answer) software; electronic books; video material; tutorial type programs; simulations; and electronic learning environments for course organisation and delivery. These different types of software can be used in different ways to achieve very different learning objectives and gains in teaching efficiency. For example, software can be used: in tutorial and small group teaching; in lectures; to better prepare students for practical work; as a replacement for practicals; to provide options within a limited course structure; to supplement lectures and enable students to work at their own pace; to provide ongoing access to self-assessment throughout a course; to aid distance learning; as remedial teaching and to extend the student learning experience in areas which are too expensive or too time consuming or for which staff expertise does not exist.Evidence indicates that it is insufficient simply to make computer based learning material available to students. Like a laboratory class, it must be fully integrated into a module if real benefits are to be obtained. Students need to be taught how to learn from computer-based learning materials and how to integrate this learning tool in their learning strategy. Teachers need to be supported not only with information about the availability of software but, equally importantly, about how it can be integrated into modules.We are all delivering teaching and facilitating learning in a changing environment and subject to a variety of increasing pressures. It may well be that computer based learning materials may help to maintain a high quality of pharmacology teaching within this changing environment but we need more pedagogical research at the discipline level to establish how this can best be done.

Survey of methods of teaching and learning in undergraduate pharmacology within UK higher education

Many of the pharmacology teachers surveyed in a questionnaire on pharmacology teaching and learning are aware of nontraditional teaching and learning methods and believe they are both appropriate to the discipline and effective in producing learning gain in the students. The reasons that nontraditional teaching methods are not used extensively include a shortage of staff time together with a perception that nontraditional teaching methods are staff-time intensive, a lack of effective motivation and reward of staff by their institutions for implementing nontraditional teaching methods and a shortage of the appropriate facilities and resources required. The questionnaire and its results are discussed in this article.

Quantification of the characteristics of antagonists exhibiting both competitive antagonism and functional interaction.

1 Null equations have been derived which, when applied to log10 concentration‐tissue state curves for an agonist determined in the presence and absence of a competitive antagonist which also exhibits functional interaction, allow quantitation of the characteristics of the competitive and functional interactant effects. 2 Both the affinity constant of the antagonist for its receptors and numerical values characterizing the functional interaction can be obtained. 3 The null equations have been tested in a model system by using a mixture of papaverine hydrochloride (either 5 or 20 μM) and methyl atropine bromide (10 nM) to mimic a competitive antagonist which also shows functional interaction. 4 Agreement between values derived directly and indirectly from the model is good and validates the use of the null equations.

Pharmacological effects of meptazinol and its enantiomers on guinea-pig ileum and mouse vas deferens

Electrically induced twitch responses of mouse vas deferens and guinea-pig ileum were inhibited by morphine, normorphine and the peptide opioid agonist RX783006; naloxone blocked the effects of all three opioid agonists yielding Ke values which were not significantly different and which were within the range (1-4 nM) expected for mu-type receptors. At concentrations between 0.1 and 10 microM (+)-meptazinol inhibited the twitch response of the ileum while (-)-meptazinol produced potentiation. Naloxone (20 nM) completely blocked the effect of (+)-meptazinol and further increased the potentiation produced by (-)-meptazinol. In the mouse vas deferens preparation neither isomer affected the electrically induced twitch response at concentrations below 5 microM and higher concentrations (10-300 microM) produced potentiation. Naloxone (20 nM) did not modify this effect. It is concluded that both isomers are opioid agonists on the mu-receptors in guinea-pig ileum but not in mouse vas deferens and that a cholinergic component, which may contribute to the action of meptazinol in-vivo, is present to a smaller extent in the (+)-isomer.

Beyond the media: knowledge level interaction and guided integration for CBL systems

Abstract A pragmatic approach to designing computer based learning (CBL) environments that properly integrate with curricula, evolve as both the system requirements and curricula change and, perhaps more significantly, support additional and enhanced learning activities has been developed. The General-Purpose Integrated Learning Support (G-PILS) system is a tool-kit and “shell” that creates course/module specific learning support systems to manage the integration of courseware in a range of knowledge media (e.g. games, tutorial packages, simulations, electronic documents, interactive presentations) within tailored environments. The findings from a 2-year integrative evaluation of three such systems in pharmacology produced some intriguing results. One surprising and significant finding was that students valued on-line lecture notes delivered as word processor documents more than sophisticated tutorial courseware, because their contents could be modified and they could be used in multiple ways. The interpretation argued for here is that knowledge media should allow students to properly interact with the knowledge in the media (knowledge level interaction), thus enabling them to tailor knowledge representations to fit into their individual study habits. Further, as more knowledge media are used in curricula, it is argued that learners need instructional guidance about integrating them within their wider learning activities (guided integration).

KNOWLEDGE AND SKILLS NEEDS OF PHARMACOLOGY GRADUATES IN FIRST EMPLOYMENT :HOW DO PHARMACOLOGY COURSES MEASURE UP?

Department of Education in the UK, now the Department for Education and Employment, announced the provi- sion of funding to support the for- mation of Higher Education Disci- pline Networks. This innovation was designed to encourage the dis- semination of information and to promote good practice in specialist teaching. This outcome was to be achieved by involving employers and professional bodies, by changing teaching methods and by emphasiz- ing core and transferable skills with the view to improving the quality and the employability of graduates from UK higher education institutions. One of the initial 24 (now 35) networks funded was the Pharmacology Higher Education Network (http://cbl.leeds.ac.uk/ raven/pha/phHE.html) which has subsequently organized two work- shop& and here reports the results of a survey into the skills and knowl- edge needs of pharmacology gradu- ates in first employment. The survey also examined how some pharma- cology courses provided in the UK fulfilled the employment needs of these graduates.

But isn't this what you're paid for? The pros and cons of peer and self assessment

The rise in student numbers and other factors such as the limited availability of staff time have put pressures on the assessment process. The adoption of alternative approaches to assessment can h...