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Many drug targets are intracellular. To access them, a drug molecule must pass through the cell membrane, a process often facilitated or impeded by transporters. Once in the cytoplasm, basic molecules may become concentrated in organelles. To predict the pharmacologic effect accurately, there must be data concerning the concentration at the target, which is difficult to measure. Techniques that combine mass spectrometry and imaging techniques (matrix-assisted laser desorption/ionization, secondary ion mass spectrometry (SIMS), and nanoSIMS) have promise in addressing this problem.

The effects of isoprenaline and salbutamol administered orally, by inhalation, or by intravenous infusion were compared in 13 asthmatic patients. Bronchodilator activity was assessed by serial measurement of specific airways conductance (SGaw). Log-dose response curves were obtained for both drugs and showed them to be equipotent as bronchodilators. Cardiovascular effects were variable, but in general, isopenaline caused greater rise in pulse rate and a greater change in blood pressure than the same dose of salbutamol.Cardiorespiratory measurements during continuous intravenous infusion of increasing doses of both drugs suggested a greater effect of isoprenaline than the same dose of salbutamol on metabolic rate, pulmonary ventilation, pulmonary gas exchange, cardiac output, and heart rate. The effect of salbutamol on the heart rate was about 10 times less than that of isoprenaline but lasted longer.

The title of this article may raise a smile from colleagues in the field of basic pharmacology. To them, pharmacology has always been about molecular interactions, and this title may simply confirm a suspicion that clinical pharmacology is mainly about semi-quantitative observations that have only a limited foundation in hard science. They are partly right, at least regarding a communication problem. In a discussion about systems biology, an exasperated engineer once remarked that biologists and physicians do not even use the same routine software packages that engineers do. Similarly, a basic pharmacologist might note that, whereas he measures drug concentrations in micromoles, the clinical pharmacologist uses micrograms per milliliters. Nevertheless, as clinical pharmacologists seek to make more quantitative observations at the molecular level in living humans, our colleagues in basic pharmacology are delving into cellular signal transduction systems governed by complex protein-protein interactions and regulated by positive and negative feedback loops. In seeking to understand these systems, they face problems that are similar to the challenge of measurement in intact humans.

The sequencing of the human genome has already had an enormous impact on medicine, particularly with single-gene changes that predispose to a serious disease such as cystic fibrosis or the overexpression of Her2 in about one-third of breast cancers. Genetic technology has led to some very important therapeutic innovations, including the use of imatinib mesylate (Gleevec) in BCR-ABL chronic myeloid leukemia and of trastuzumab (Herceptin) in Her2-positive breast cancer, but the much anticipated explosion of new effective treatments has been more modest than expected.

Lapatinib is a clinically important component of the treatment for HER2-positive metastatic breast cancer and has an acceptable safety profile. Lapatinib-associated Hy's Law cases have been characterized using human leukocyte antigen (HLA) DQA1*02:01/DRB1*07:01 and Gilbert's syndrome UGT1A1*28/*28 genotypes. The HLA-positive cases had higher alanine aminotransferase (ALT) elevation, whereas the HLA-negative cases had a higher incidence of Gilbert's syndrome. The findings of our study, which extend this HLA association to lapatinib-associated serious liver injury, emphasize the importance of Gilbert's syndrome in the interpretation of Hy's Law and may lead to methods for enhancing patient safety.

The distribution of atrial natriuretic peptide (ANP) clearance receptors in rat kidney was investigated by in vitro autoradiography using des[Gln18,Ser19,Gly20,Leu21,Gly22]-ANP-(4- 23) (C-ANP) and 125I-Tyr0-ANP-(5-25) as relatively specific ligands of this receptor. Alpha-125I-ANP (100 pM) bound reversibly but with high affinity to glomeruli, outer medullary vasa recta bundles, and inner medulla. C-ANP (10 microM) inhibited greater than 60% of this glomerular binding but did not inhibit the binding of alpha-125I-ANP to medullary tissues. Alpha-125I-ANP also bound reversibly to the renal arteries up to the glomerulus. This arterial binding was only partly inhibited by 10 microM C-ANP. In the presence of 10 microM C-ANP, increasing concentrations of alpha-125I-ANP bound to a residue of glomerular sites with apparent dissociation constants of 0.82 +/- 0.16 to 2.73 +/- 1.20 nM at different cortical levels. 125I-Tyr0-ANP-(5-25) bound significantly to glomeruli and intrarenal arteries but not to vasa recta bundles or inner medulla. This glomerular binding also occurred with nanomolar dissociation constants. It was completely inhibited by 1 microM alpha-ANP and 10 microM C-ANP, but not by unrelated peptides such as gastrin. These results suggest that renal ANP clearance receptors are restricted in vivo to the glomeruli and renal arterial system of the rat.

The Systolic Hypertension in Europe (Syst-Eur) trial proved that blood pressure (BP) lowering therapy starting with nitrendipine reduces the risk of cardiovascular complications in older (or = 60 years) patients with isolated systolic hypertension (systolic BPor = 160 mm Hg and diastolic BP95 mm Hg). After the completion of the Syst-Eur trial on 14 February 1997, 3506 consenting patients (93.0% of those eligible) were enrolled in phase 2 of the Syst-Eur trial. This open follow-up study aims to confirm the safety of long-term antihypertensive therapy based on a dihydropyridine. To lower the sitting systolic BP below 150 mm Hg (target BP), the first-line agent nitrendipine (10-40 mg/day) may be associated with enalapril (5-20 mg/day), hydrochlorothiazide (12.5-25 mg/day), both add-on study drugs, or if required any other antihypertensive agent. On 1 November 1998, 3248 patients were still being followed, 86 patients had proceeded to non-supervised follow-up, and 43 had died. The median follow-up in Syst-Eur 2 was 14.3 months. At the last available visit, systolic/diastolic BP in the patients formerly randomised to placebo (n = 1682) or active treatment (n = 1824), had decreased by 13.2/5.2 mm Hg and by 4.6/1.6 mm Hg, respectively, so that the between-group BP difference was 1.7 mm Hg systolic (95% Ci: 0.8 to 2.6 mm Hg; P0.001) and 0.9 mm Hg diastolic (95% Cl: 0.4 to 1.5 mm mm Hg; P0.001). At the beginning of Syst-Eur 2, the goal BP was reached by 25.4% and 50.6% of the former placebo and active-treatment groups; at the last visit these proportions were 55.9% and 63.1%, respectively. At that moment, 45.9% of the patients were on monotherapy with nitrendipine, 29.3% took nitrendipine in combination with other study drugs. Until the end of 2001, BP control of the Syst-Eur 2 patients will be further improved. Cardiovascular complications and adverse events, such as cancer or gastro-intestinal bleeding, will be monitored and validated by blinded experts.

Isolated systolic hypertension occurs in about 15% of people aged 60 years or older. In 1989, the European Working Party on High Blood Pressure in the Elderly investigated whether active treatment could reduce cardiovascular complications of isolated systolic hypertension. Fatal and non-fatal stroke combined was the primary endpoint.All patients (60 years) were initially started on masked placebo. At three run-in visits 1 month apart, their average sitting systolic blood pressure was 160-219 mm Hg with a diastolic blood pressure lower than 95 mm Hg. After stratification for centre, sex, and previous cardiovascular complications, 4695 patients were randomly assigned to nitrendipine 10-40 mg daily, with the possible addition of enalapril 5-20 mg daily and hydrochlorothiazide 12.5-25.0 mg daily, or matching placebos. Patients withdrawing from double-blind treatment were still followed up. We compared occurrence of major endpoints by intention to treat.At a median of 2 years' follow-up, sitting systolic and diastolic blood pressures had fallen by 13 mm Hg and 2 mm Hg in the placebo group (n = 2297) and by 23 mm Hg and 7 mm Hg in the active treatment group (n = 2398). The between-group differences were systolic 10.1 mm Hg (95% CI 8.8-11.4) and diastolic, 4.5 mm Hg (3.9-5.1). Active treatment reduced the total rate of stroke from 13.7 to 7.9 endpoints per 1000 patient-years (42% reduction; p = 0.003). Non-fatal stroke decreased by 44% (p = 0.007). In the active treatment group, all fatal and non-fatal cardiac endpoints, including sudden death, declined by 26% (p = 0.03). Non-fatal cardiac endpoints decreased by 33% (p = 0.03) and all fatal and non-fatal cardiovascular endpoints by 31% (p0.001). Cardiovascular mortality was slightly lower on active treatment (-27%, p = 0.07), but all-cause mortality was not influenced (-14%; p = 0.22).Among elderly patients with isolated systolic hypertension, antihypertensive drug treatment starting with nitrendipine reduces the rate of cardiovascular complications. Treatment of 1000 patients for 5 years with this type of regimen may prevent 29 strokes or 53 major cardiovascular endpoints.

Leukotriene synthesis may be increased in a variety of inflammatory diseases. Urinary leukotriene E4 is a stable metabolite of leukotrienes C4 and D4 which has previously been found to be increased in exacerbations of severe asthma and after antigen inhalation. Levels of urinary LTE4 in seven patients during and after a severe flare of atopic dermatitis were measured by high-performance liquid chromatography (HPLC) and radioimmunoassay (RIA). Mean urinary LTE4 levels (+/- SEM) were not increased during (16.7 +/- 3.7 pg/mumol) or after (16.9 +/- 4.8 mumol) the acute exacerbation of atopic dermatitis when compared with the normal range (mean = 23.8 [95% confidence interval 19.9-28.2] pg/mumol creatinine). These findings do not provide evidence of cysteine leukotriene involvement in the pathogenesis of atopic dermatitis.

The objectives of this study were to compare the effects of two centrally-acting antihypertensive drugs on measures of quality of life in a three-month double-blind trial of hypertensive patients randomized to methyldopa (n = 79) or rilmenidine (n = 78). We studied men and women aged over 21 y attending eight hospital out-patient clinics in the United Kingdom. They had average diastolic blood pressures between 95 and 110 mm Hg and systolic pressures below 210 mm Hg after a 4-week placebo run-in period. The doses ranged from 1 to 2 mg daily of rilmenidine and 500 mg to 1 g of methyldopa. Hydrochlorothiazide (25 mg daily) was added after 8 weeks when the diastolic blood pressure remained at 90 mm Hg or more in 29% of patients on rilmenidine and 35% of those on methyldopa. Quality of life was assessed from self-completed questionnaires using standardized instruments. Both drugs reduced blood pressure, but at the end of the trial the fall in the methyldopa group (19.3/13.0 mm Hg) was significantly greater than in the rilmenidine group (13.2/10.0 mm Hg). Ten patients in the methyldopa group withdrew from the trial compared with three in the rilmenidine group, primarily because of adverse effects. In both groups there was a significant increase in the overall reporting of adverse effects. Reports of dry mouth increased on both drugs, and sleepiness on rilmenidine but not methyldopa. There was no significant difference between the drugs in the overall reporting of adverse effects or of individual adverse effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Three doses of radiolabeled leukotriene C4 (0.2 to 15 muCi) were infused into three subjects to investigate its metabolism and routes of elimination during 4 days. Between 12% and 20% of the infused dose was recovered in the urine within 24 hours, of which a substantial and relatively constant proportion (4.1% to 6.3% total dose) appeared as leukotriene E4 (LTE4), mainly in the first 4 hours. Polar omega-oxidation products, N-acetyl LTE4, and tritiated water were also present. Fecal elimination accounted for a further 30% to 40% of the infused dose. In the absence of altered metabolism or biliary excretion, urinary LTE4 may be a useful measure of whole body production of the cysteinyl leukotrienes.

Platelets produce a range of bronchoconstrictor mediators. Measurements of plasma factors have implicated platelet activation in allergic asthma, and sensitised guinea pigs challenged with ovalbumin show pulmonary platelet aggregation accompanying bronchoconstriction. To investigate this further we injected autologous platelets labelled with indium 111 and red cells labelled with technetium 99m into three young volunteers with atopic asthma and three non-asthmatic volunteers and, after equilibration of platelets between blood and splenic pool, monitored lung 99mTc and 111In activities continuously. Comparison with the corresponding activities in blood samples allowed calculation of pulmonary platelet to red cell transit time ratio (tp/tr). This ratio was 0.9, 1.02, and 0.98 in the non-asthmatic subjects compared with 1.04, 0.97, and 1.17 in the asthmatic subjects. This argues against the existence of an intrapulmonary platelet pool in normal subjects; transpulmonary transit time was slightly prolonged in one asthmatic subject. Bronchial challenge with Dermatophagoides pteronyssinus was performed in the asthmatic subjects and monitoring continued for a further 30 minutes. Antigen induced falls in FEV1 of 20-50% were accompanied by small decreases in the 111In but not in the 99mTc lung signal. In line with this tp/tr fell to 0.89, 0.89, and 1.05. Antigen induced bronchoconstriction was therefore not accompanied by intrapulmonary platelet accumulation. Platelet survival was normal at 10.2 days in both groups of subjects.

The plasma concentrations of free alpha-methyldopa and methyldopa sulphate conjugate were measured in 7 hypertensive patients with normal renal function following alpha-methyldopa (1 g) orally. Five of these patients subsequently received alpha-methyldopa ethyl ester (250 mg) (methyldopate) intravenously and two further patients received 250 mg of alpha-methyldopa intravenously. After oral administration a large amount of total plasma alpha-methyldopa was present as sulphate conjugate. There were wide interindividual differences in the ratio of free: conjugated alpha-methyldopa in plasma (ratio at 4 hours ranged from 3.73-0.83) suggesting that individual differences in the extent of sulphate conjugation may occur. There was no close correlation between the degree of conjugation and the fall in arterial pressure. At all time intervals examined, plasma concentrations were higher following intravenous alpha-methyldopa than alpha-methyldopate. The plasma concentration of alpha-methyldopa (free and esterified) 60 minutes after i.v. alpha-methyldopate was 1.7+/-0.3 mug/ml while at the same time after the same dose of methyldopa by the same route the mean concentration was 5.9 mug/ml. Although small amounts of sulphate conjugate were detected after i.v. alpha-methyldopate, insignificant quantities of conjugate were found after i.v. alpha-methyldopa. The average fall in mean arterial pressure was 27 mm/Hg following i.v. alpha-methyldopa but only 2.7 mm Hg following alpha-methyldopate. These results suggest that sulphate conjugation of alpha-methyldopa occurs in the gastrointestinal tract during absorption. Hydrolysis of alpha-methyldopa ethyl ester does not appear to be instantaneous and pharmacokinetic differences between the ester and free alpha-methyldopa have been demonstrated.

The effect of an oral angiotensin I converting enzyme inhibitor, SQ 14225 (Captopril) on blood pressure and plasma renin activity (PRA) was studied in deoxycorticosterone-salt (DOCA/salt) hypertensive rats. Intraperitoneal (ip) injection of captopril (1 mg/kg) produced a significant fall in systolic blood pressure (23.4 ± 5.0 mm Hg, p < 0.001) whereas no significant change in blood pressure occurred in control rats. Indomethacin (IDM) (2.5 mg/kg ip) pretreatment significantly (p < 0.01) attenuated the hypotensive action of captopril in DOCA/salt rats. PRA was markedly suppressed in DOCA/salt rats (0.3 ± 0.1 mg/ml/hr) when compared with the normotensive controls (4.4 ± 2.2 ng/ml/hr, p < 0.001) at baseline. Captopril induced a significant rise in PRA in both groups of rats. These responses were not significantly altered by IDM pretreatment. The hypotensive effect of captopril in the DOCA/salt model may be mediated by prostaglandins since their synthesis is inhibited by indomethacin.

The development of fluorescein angiography has stimulated a great deal of interest in the vascular physiology of the retina and choroid by providing a method for examining different aspects of the ocular circulation in vivo. Of particular interest is the role of the blood supply to the optic disc in the production of field defects in glaucoma, and its relationship to pathological disc cupping (Hayreh, I969, 1970; Blumenthal, Best, Galin, and Toyofuku, 1971; Goldmann and Blok, 197I). A number of experiments in animals and man have been carried out to demonstrate the influence of acute and chronic rises in the intraocular pressure on the choroidal supply to the disc and peripapillary region (Blumenthal, Gitter, Best, and Galin, I970; Swietliczko and David, 1970; Blumenthal, Best, and Galin, 197I). In these conditions of high intraocular pressure, whether pathological or experimental, several observations have been made on the accompanying reduction of blood velocity in the retinal arteries but, apart from the studies by Dollery, Henkind, Kohner, and Paterson (I968), little quantitative data exists on this relationship between altered perfusion pressure and retinal blood flow. The present series of experiments was designed as an extension of the work of Dollery and his co-workers to investigate the changes in retinal blood flow velocity and retinal blood flow at different intraocular pressures, and to study the effects of measures used to treat retinal artery obstructions in man.

Human alpha-atrial natriuretic peptide (h-alpha ANP) makes the urine of dehydrated volunteers hypotonic to plasma despite high circulating concentrations of antidiuretic hormone. Urinary dilution with h-alpha ANP also occurs in subjects receiving indomethacin. Therefore, h-alpha ANP antagonises effects of antidiuretic hormone on distal tubular V2-receptors in man, probably without involving prostaglandins.

In man, circulating adrenaline has little or no direct effect on the control of blood pressure. A small proportion of adrenaline secreted by the adrenal medulla is accumulated in sympathetic nerve endings and may be re-released by sympathetic nerve stimulation. Recent pharmacological studies have suggested that adrenaline acts on a presynaptic beta-receptor on sympathetic nerve endings to facilitate noradrenaline release, and it has been proposed that adrenaline re-released from these nerve endings is therefore a functionally important "co-transmitter". Intermittently elevated secretion of adrenaline from the adrenal medulla could therefore lead indirectly to a sustained increase in neuronal release of noradrenaline and hence to hypertension.

The levels of 6-oxo-prostaglandin F1α (6-oxo-PGF1α) were measured in cord blood and in peripheral venous blood in newborns using gas chromatography coupled with negative ion chemical ionization mass spectrometry. The plasma concentrations of 6-oxo-PGF1α in cord blood increased significantly between delivery and placental expulsion (P < .005). In newborns, the circulation levels of 6-oxo-PGF1α after four hours of life were low and comparable to adult levels. Large quantities of prostacyclin are produced by the uteroplacental unit during parturition, but only small amounts are transmitted to the newborn during a normal delivery. The low plasma concentrations of 6-oxo-PGF1α in newborns suggest that prostaglandin I1 is not a circulating vasodilator during the first week of life.

Centrally-administered opioid peptides produce elevations in levels of catecholamines in plasma in conscious rats. To investigate the opioid receptor involved in mediating this response, morphine (3.5-105 nmol), [D-Ala2-D-Leu5]enkephalin (DADL, 1.05-35 nmol) and U50, 488H (35-1160 nmol), relatively selective ligands for the mu, delta and kappa receptors respectively, were injected intracerebroventricularly into conscious rats and the levels of catecholamines in plasma determined at the peak of the response. Each agonist produced dose-dependent elevations in levels of noradrenaline and adrenaline, the order of potency being DADL approximately equal to morphine greater than U50,488H. These results exclude involvement of the kappa receptor but do not distinguish between an effect mediated by a mu or delta receptor. The responses to morphine were blocked in the presence of 300 nmol naloxone but were not altered by 41.5 nmol RX 781094, a selective alpha 2-adrenoceptor antagonist. The elevation in levels of adrenaline in plasma produced by small doses of the agonists was not related to behavioural changes.

The decision to request intravenous urography in a hypertensive patient has been examined, together with the abnormalities discovered and the resulting changes in clinical management. The records of 405 hypertensive patients newly referred to a single clinic, were examined for the years 1955, 1965 and 1971. Intravenous urography was requested more frequently in younger than in older patients, and the number of requests increased with the level of diastolic blood pressure. The more recent the date of presentation, the more often was the investigation requested. Thirty-five patients had IVU abnormalities against 185 with a normal urogram. The urograms reported in 1971 were reviewed without the knowledge of the previous report and the non-agreement between the standard report and the review is discussed. Nine per cent of the patients who had an IVU in 1971 had a change in medical management as a result of the investigation. When an abnormality was detected on urography the plasma urea and presenting blood pressure were significantly higher and the patients age (adjusted for blood pressure and plasma urea) significantly lower than when the urogram was normal. Based on these results a multiple regression equation is discussed relating the presence of an abnormality ( Y ) to plasma urea, age and systolic blood pressure as independent variables. A value of Y can be found which would detect most of the significant abnormalities and avoid the request in several of the patients without an abnormality. These decision rules require testing in a prospective study.

1. The function of angiotensin converting enzyme was investigated in twenty-four healthy men. Forearm blood flow was measured under basal conditions and during administration of enalaprilat (a converting enzyme inhibitor) and/or peptide substrates of converting enzyme into the left brachial artery. Blood flow was compared in the two arms. 2. Enalaprilat had no effect on basal blood flow. The concentration of enalaprilat in venous blood from the control arm was low, and plasma renin activity was not increased, indicating that systemic inhibition of converting enzyme did not occur. 3. Effects of angiotensin and of bradykinin, administered intra-arterially, were limited to the infused arm. Enalaprilat (13 nmol min-1) inhibited converting enzyme in the infused arm, in which it caused approximately a 100-fold reduction in sensitivity to angiotensin I, while having no effect on the vasoconstriction caused by angiotensin II. Enalaprilat increased vasodilatation caused by bradykinin. 4. Aspirin, an inhibitor of cyclo-oxygenase, did not inhibit vasodilatation caused by bradykinin whether infused alone or with enalaprilat, indicating that these responses are not mediated by prostaglandins. 5. We conclude that under basal conditions neither conversion of angiotensin I to angiotensin II nor degradation of bradykinin determines resistance vessel tone in the human forearm. Converting enzyme may affect vascular tone in situations in which intravascular concentrations of peptides are increased over those present under basal conditions.

A slightly modified Middlesex Hospital Questionnaire was given to 946 patients with hypertension who were receiving treatment at two hospital clinics. The response rate was 90%. Compared with previously published results for the general population the hypertensive patients scored significantly higher for free-floating anxiety, phobic anxiety and depression. Male hypertensive patients, but not female patients, also scored higher for obsession and hysteria. The high scores for hypertensive patients could not be closely correlated with any particular drug therapy with the possible exception of phobic anxiety and propranolol in women but not in men. There was a weak but statistically significant correlation between systolic blood pressure and both somatic complaint rate and phobic anxiety.

The response to a standard dose of heparin was studied in 20 patients with venous thromboembolism. The heparin regimen consisted of intravenous injection of 70 units per kg, followed after 90 minutes by a maintenance dose of 400 units per kg per 24 hours given by continuous infusion. Plasma heparin activity and the activated partial thromboplastin time (APTT) were measured at intervals to determine clearance of the initial injection and the response to maintenance dose. Large inter-individual variations were found in the anticoagulant effect and these were due in part to differences in heparin clearance and in part to differences in the APTT response to given amounts of heparin (heparin effect index). The heparin half-life was 63 +/- 15 minutes when plasma heparin activities were used for this calculation and 84 +/- 71.5 minutes when the APTT was used. These results are similar to values previously reported in normal volunteers. Four of the 20 patients had pulmonary embolism and in these heparin half-life was significantly shortened (P less than 0.005).

Branch and hemisphere vein occlusion were produced in rhesus monkeys by argon laser photocoagulation. The following observations were made: (1) Immediately after occlusion there was venous dilatation, delayed filling of the artery, delayed drainage by the occluded vein, and capillary leakage. (2) Two patterns of evolution were identified within the first week. In some animals the fundus changes resolved and the retina returned to normal, while in others there was progressive retinal capillary closure. (3) Those animals destined to have capillary closure had diffuse or cluster retinal haemorrhages at 24 hours. (4) Capillary closure took place over 1 week and was usually complete over large areas of retina. (5) Retinal atrophy and major vessel changes occurred over several weeks. (6) Retinal revascularisation occurred in those areas of closure, though this was often limited. It was concluded that the early changes mimicked those seen in human retinal vein occlusion, though persistent retinal oedema and preretinal neovascularisation were not identified.

Serial retinal photographs have been taken of a fourteenyear-old girl with long-standing, poorly controlled diabetes mellitus who presented with severe hypercholesterolemia. Selective fluorescence contrast photography revealed masses of dilated hairpin capillary loops in the retina. Over a period of eight months of strict diabetic control the retinal vasculature returned to normal. The findings are discussed with reference to the origin and reversibility of retinal vascular changes in diabetes.

Effects of changes in pulmonary arterial (Pa), venous (Pv), and alveolar (Pa) pressures on the over-all pressure-blood flow relations of an isolated dog lung have been re-examined. In the preparation used, the distribution of blood flow was predictable from previous measurements with radioactive gases. The results showed that the pressure-flow relations of the whole lung were greatly affected by the distribution of blood flow within it. For example, the pulmonary vascular resistance (PVR) of the lung depended on whether all the lung was perfused with blood or not, and thus whether there was an unperfused zone at the top of the lung where Pa was less than Pa ( zone 1). Again the pressure-flow relations of the lung were shown to depend on how much of the lung had a Pv less than Pa ( zone 2), and how much had a Pv which exceeded Pa ( zone 3). The effects on PVR of changing Pv or Pa could be explained on this basis. No evidence of a critical closing pressure in the vessels of the expanded lung was found. It was concluded that although the over-all pressure-flow relations of the whole lung were complicated, the flow through individual vessels could be accounted for by the simple mechanical effects of pressures inside and outside the vessels. hydrostatic effect; pulmonary vascular resistance; Starling resistor; vascular waterfall; critical closing pressure Submitted on May 4, 1964

A self-administered symptom questionnaire was completed by 477 patients in a hypertension clinic. The complaints of the patients were analysed according to the type of therapy being given and the dose of drug taken. Methyldopa therapy was associated with sleepiness, weakness of the limbs, sleeping longer at night, and rising more frequently at night to pass urine. Diarrhoea, impotence, failure of ejaculation, blurred vision, depression, and the symptoms of postural hypotension were not related to methyldopa therapy. Bethanidine administration was related to postural hypotension, impotence, and failure of ejaculation but not to weakness of the limbs, blurred vision, depression, or diarrhoea. Patients receiving guanethidine complained of postural hypotension, failure of ejaculation, and had their bowels open more frequently. Similarly, patients receiving propranolol had an increased frequency of defaecation but also tended to complain of weakness of the limbs. Considering each drug individually, 5% of patients failed to take the prescribed dose of diuretic whereas