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Efficient photolabelling of muscarinic acetylcholine receptors was obtained using either two aryldiazonium salts or an azido derivative. These probes did not discriminate between muscarinic binding subtypes or affinity states and became irreversibly bound to the receptor sites, in an entirely atropine-protectable manner, upon ultraviolet irradiation. The extent of labelling was dependent both on probe concentration and on time of irradiation and reached up to 80% of the receptor population, under optimal alkylating conditions. In contrast to the azido derivative, both diazonium salts behave as potent irreversible labels of muscarinic receptors, provided energy-transfer photolabelling conditions were followed. Such an indirect activation of diazonium ligands, through an energy transfer from photoexcited tryptophan residues, has been previously found to increase the site-specificity and the rate of labelling of other acetylcholine binding proteins. Analogies in the photolabelling process of acetylcholinesterase or of nicotinic and muscarinic receptors by the two diazonium salts are discussed. Altogether, these findings suggest that these new probes may be promising tools to investigate the location and the topography of the agonist-antagonist binding domain on purified muscarinic receptors, through amino acid and/or sequence analyses of radioactive, photolabelled residues.

In 175 cases of chronic obstructive airway disease (most often chronic bronchitis) with severe ventilatory deficit in the majority of cases, the prognostic value of mean pulmonary arterial pressure (PAP) and other respiratory function parameters (FEV1, blood gases) was studied by calculation of survival rates using the actuarial method. The patients were cathetherised between 1968 and 1972 and the maximum period of follow-up is 10 years. The results demonstrated the definite prognostic value of PAP : 4 and 7 year survival rates were markedly different according to whether initial PAP was above or below 20 mmHg. However other haemodynamic (motor pressure through the pulmonary circulation) and non-haemodynamic (FEV1, PaCO2) parameters also would appear to be as useful as PAP in predicting survival in such patients. The prognosis is particularly bad in patients with severe pulmonary arterial hypertension (PAP greater than 30 mmHg). In this type of study, it is essential to bear in mind the influence of age. Survival rates differed significantly according to whether the subjects were over 60 years in age initially.

Localization of the ligand binding site on muscarinic acetylcholine receptors is one of the new fields of interest opened by the recent determination of their primary structures. Owing to their interesting photochemical properties, aryldiazonium salts may be considered as appropriate tools for "tagging" the agonist/antagonist binding domain and to get precise identification and positioning of covalently labelled residues along the primary sequence of these receptors. A series of aryldiazonium derivatives and some of their azido-analogs were synthesized and their reversible muscarinic binding component was assessed through competition experiments involving either the whole population of receptor sites [( 3H]QNB assay) or the super high affinity of their agonist binding sites [( 3H]OXO-M assay). Three compounds fulfilled the criteria for efficient photolabels, allowing substantial and irreversible occupation of the receptor sites to be obtained. Interestingly, the two diazonium derivatives which were selected have been previously described as potent photoprobes of the peripheral nicotinic receptor and of acetylcholinesterase, though displaying lower binding affinities for these acetylcholine binding proteins than for the muscarinic receptors. These findings, together with the all-to-none photolabelling efficiency observed for a quinuclidine derivative, substituted either by an azido or a diazonium group, are discussed. Finally, the apparent lack of binding selectivity of these new photo-affinity probes towards muscarinic receptor affinity states or subtypes should allow comparative studies of the acetylcholine binding site on different muscarinic receptor proteins, obtained either through purification procedures or expression of separate gene products.

65 patients with interstitial lung diseases were subdivided into two groups: idiopathic pulmonary fibrosis (IPF) and other interstitial pulmonary diseases (OIP) according to histopathological, immunological and follow-up findings. Arterial blood gases and pulmonary hemodynamics at rest and during steady-state exercise were compared in these two groups (IPF = 31 patients, OIP = 34 patients). The resting PaO2 was significantly lower in the IPF group (p less than 0.001) and regularly worsened during exercise in this group (from 69.6 +/- 11.6 to 56.0 +/- 9.4 mm Hg, p less than 0.001) whereas it did not vary significantly in the OIP group (from 79.2 +/- 13.1 to 75.3 +/- 14.1 mm Hg, NS). Pulmonary artery mean pressure (PPA) was higher in the IPF group (p less than 0.001) as were all indices of pulmonary vascular resistance (PVR). During exercise, PPA markedly increased in the IPF group (from 21.7 +/- 7.8 to 45.3 +/- 16.2 mm Hg) but modestly in the OIP group (from 15.5 +/- 3.7 to 28.3 +/- 9.8 mm Hg). The best relationships were found between PPA, PVR and PaO2, which suggests that pulmonary arterial hypertension in these diseases is not only due to anatomical factors but also to alveolar and arterial hypoxia. Arterial blood gases and pulmonary hemodynamics at rest and during exercise may be of interest for the discrimination of 'true' interstitial fibrosis (IPF) from other interstitial lung diseases (OIP).

Calcium ions are ubiquitous messengers of numerous cellular functions. Under normal conditions, they translate the membrane signal into specific cellular activity by electromechanical or electrosecretory coupling. An enhancement of the transmembrane calcium influx results in exaggerated cellular function, such as increased vascular contractility. Therefore, a reduction of transmembrane calcium influx by calcium antagonists effectively reduces high blood pressure (BP). It has been shown that the long-term treatment of genetically hypertensive rats with dihydropyridine calcium antagonists ameliorates the tissue damage that occurs in association with high BP in various organs. This tissue protection is not secondary to the reduction of hypertension as it can be demonstrated in the absence of BP reduction. This favourable effect may be attributed to the prevention of intracellular calcium overload which results in an exhaustion of energy-rich phosphates, excessive activation of proteolytic and phospholytic enzymes, membrane destruction and cellular death. In acute ischaemia experiments, inhibition of excessive transmembrane calcium influx by the dihydropyridine calcium antagonists prevents vascular and parenchymal damage. Moreover, long-term treatment with dihydropyridine calcium antagonists prevents vascular and parenchymatous damage in advanced or accelerated hypertension. In accordance with this concept, calcium antagonists have been shown to exert protective effects against acute ischaemic damage in both the heart and the kidney.

The cardioselectivity and specificity of diacetolol, the major metabolite of the beta-adrenoceptor blocking drug acebutolol, was studied in the isolated right atrium of the guinea-pig and rat and the papillary muscle and trachea of the guinea-pig. The beta-adrenoceptor blocking potency of diacetolol is about ten times lower than that of acebutolol. Like acebutolol, diacetolol was a more effective isoprenaline antagonist in the heart than in the trachea, thus showing relative cardioselectivity. The high water solubility of diacetolol and acebutolol led to a much faster disappearance of the beta-blockade after washout than the blockade by the lipid soluble agents propranolol and penbutolol. Like acebutolol, diacetolol had a weak intrinsic sympathomimetic activity. Cardiac depressant effects, e.g. decrease of maximum upstroke velocity and duration of the action potential and reduction in force of contraction, occurred with concentrations 100-1000 times higher than those needed for beta-blockade, thus indicating relative specificity.