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To evaluate the impact of a toxicology service on a major metropolitan teaching hospital.A descriptive comparative study of all patients presenting with poisoning or suspected poisoning 12 months before and after the commencement of a toxicology service. Data on length of stay in the emergency department, disposition, length of stay of admitted patients and substance(s) involved were examined.A total of 1,316 poisoned patients were studied. There was a statistically significant increase in self-poisonings from 612 to 704 (P = 0.002) and in the number of admissions from 113 to 192 (P0.05). There was no significant change in emergency department length of stay. The average length of stay for patients admitted under the care of the toxicology service decreased, especially for complicated patients.In the first 12 months of operation the toxicology service treated more patients than the 12-month period prior to commencement, achieving a decrease in average length of stay for those patients admitted to the service. The emergency department length of stay was not altered. We surmise that by decreasing average length of stay for the patients under the care of the toxicology service, the net increase in the general pool of unoccupied beds improves bed access for all emergency department patients.

In vitro lipolysis stimulated by low (-)-isoprenaline concentrations (or =30 nM) in epididymal white adipocytes from Sprague-Dawley rats was inhibited at least 60-80% by the specific beta1-antagonists LK 204-545 and CGP 20712A (1 microM), suggesting that at these low (10 nM) concentrations of (-)-isoprenaline lipolysis was primarily (80%) but not solely mediated via beta1-adrenergic receptors. Low concentrations (100 nM) of (-)-noradrenaline and formoterol also confirmed a role for beta1-adrenergic receptors in mediating lipolysis at low concentrations of these agonists. At higher agonist concentrations, beta3-adrenergic receptors were fully activated and were the dominant beta-adrenergic receptor subtype mediating the maximum lipolytic response, and the maximum response was not affected by the beta1-antagonists, demonstrating that the beta3-receptor is capable of inducing maximum lipolysis on its own. Studies of lipolysis induced by the relatively beta2-selective agonist formoterol in the presence of beta1-blockade (1 microM CGP 20712A) demonstrated the inability of the beta2-selective antagonist ICI 118-551 to inhibit the residual lipolysis at concentrations of ICI 118-551or = 1 microM. Higher concentrations of ICI 118-551 inhibited the residual formoterol-induced lipolysis competetively, but with low affinity (approximately 500-fold lower than its beta2-adrenergic receptor pA2, 7.80 +/- 0.21), suggesting that formoterol was not acting via beta2-adrenergic receptors. These data are consistent with beta1-adrenergic receptors playing an important role in lipolysis at physiological but not pharmacological concentrations of catecholamines and that beta2-adrenergic receptors play no obvious direct role in mediating beta-adrenergic receptor agonist-induced lipolysis in vitro. Finally, racemic-SR 59230A, unlike the pure (S, S)-isomer (a beta3-selective antagonist), was found to be a nonselective antagonist at the three beta-adrenergic receptor subtypes, showing that the other enantiomers have different selectivity.

To establish reliability and ease of use of the Cambridge Neuropsychological Test Automated Battery (CANTAB) in assessing changes in cognitive function induced by antihypertensive drugs.Standard neuropsychological testing was combined with CANTAB in a double-blind 18-week cross-over study in elderly hypertensives taking perindopril or hydrochlorothiazide/triamterene (HT). Cognitive effects were assessed by employing tests of attention, visuospatial and verbal memory, learning, reasoning, planning, problem solving, speed and coordination. Affect was assessed using two different depression-rating scales.Perindopril and the diuretic had no adverse effects on the various aspects of cognitive function. Mood, as assessed by the Hamilton Depression Rating Scale and the Beck Depression Inventory, was improved on Perindopril, and the error rate in the motor screening test was lower. Ambulatory blood pressure monitoring showed both drugs achieved effective 24-h control.The ease of use and the ability to adjust the level of testing to the requirements of individual patients, together with the reliability of longitudinal test/re-test results, indicates that CANTAB is an important addition to the methods available to quantitate adverse central nervous system drug effects. The other purpose of the study was to assess any adverse cognitive effects of perindopril against a drug HT believed to have no adverse central nervous system effects. In this context, perindopril was free of adverse effects in all the objective tests employed. In addition, there was a benefit seen in two independent assessments of depression (the Hamilton and the Beck rating scales).

We have previously reported that in rat brain membranes, [3H]rilmenidine, in addition to labelling alpha2-adrenoceptors and the I2B-subtype of imidazoline receptor binding site (I2B-RBS), may label an additional I-RBS population, distinct from previously classified I1-RBS and I2-RBS. In this study, using crude or fractionated rat brain membranes we examined the possible association of [3H]rilmenidine-labelled I-RBS with the A- and B-isoforms of monoamine oxidase (MAO) by studying the inhibition of [3H]rilmenidine binding by a number of MAO inhibitors; and comparing the maximal binding density (Bmax) and subcellular distribution of [3H]rilmenidine binding sites with that of MAO-A and MAO-B catalytic sites labelled by [3H]RO41-1049 and [3H]RO19-6327 and 12-RBS labelled by [3H]2-BFI. Inhibition of [3H]rilmenidine binding by all MAO inhibitors tested produced very shallow curves (slope 0.29-0.56). Clorgyline and moclobemide (selective MAO-A inhibitors) displayed moderate affinities (60-140 nM), while pargyline (non-selective MAO-inhibitor), RO41-1049 (selective MAO-A inhibitor) and RO19-6327 (selective MAO-B inhibitor) exhibited very low affinities (2 microM) for 50-75% of [3H]rilmenidine-labelled I-RBS in crude brain membranes and even lower affinity for the remaining binding. Under identical buffer conditions, the Bmax of [3H]rilmenidine-labelled I-RBS (1.45+/-0.14 pmol/mg protein) was considerably lower than those of MAO-A (13.10+/-0.15 pmol/mg) and MAO-B (10.35+/-0.50 pmol/mg) sites. These results suggest that [3H]rilmenidine does not interact directly with the active catalytic site of either MAO enzyme and could at best only associate with a subpopulation of MAO molecules. Binding studies on five fractions of rat cortex homogenates-nuclear (N), heavy (M) and light (L) mitochondrial, microsomal non-mitochondrial (P), and soluble cytosolic (S) fractions-revealed that 45% of total [3H]rilmenidine binding was present in the P fraction cf. 20 and 23% in the M and L fractions, in contrast to [3H]RO19-6327 and [3H]2-BFI which bound 11-13% in the P fraction and 36-38% and 35-44% in the M and L fractions, respectively. Binding of all ligands in the N fraction was 6-15% of total. These studies reveal that [3H]rilmenidine-labelled I-RBS, unlike the I2-RBS, are not predominantly associated with mitochondrial fractions containing the MAO enzymes (and cytochrome oxidase activity), but appear to be distributed in both the mitochondrial and plasma membrane fractions in rat cerebral cortex.

The distribution and relative densities of imidazoline-receptor binding sites (I-RBS) and monoamine oxidase (MAO)-A and -B enzyme(s) in rat and rabbit kidney were compared autoradiographically using fixed nanomolar concentrations of [3H]rilmenidine and [3H]2-(benzofuranyl)-2-imidazoline ([3H]2-BFI) to label I-RBS, and [3H]RO41-1049 and [3H]RO19-6327 to label MAO-A and -B isoenzymes, respectively. In rat kidney, high densities of I-RBS labelled by [3H]rilmenidine were observed in the cortex and outer stripe (120-280 fmol/mg tissue), in contrast to low I-RBS densities labelled by [3H]2-BFI (4 fmol/mg). A relatively high density of [3H]RO41-1049 binding to MAO-A enzyme was present in all regions of the rat kidney (160-210 fmol/mg) compared with a low density of [3H]RO19-6327 binding to MAO-B (25 fmol/mg). Comparison of MAO-A and -B distributions with that of [3H]rilmenidine-labelled I-RBS strongly suggests a lack of association in rat kidney. Similarly, the extremely low densities of [3H]2-BFI-labelled I2-RBS in rat kidney contrasts with the density of MAO-A, but is consistent with the low density of MAO-B. Rabbit kidney cortex and outer stripe contained high relative densities of [3H]rilmenidine-labelled I-RBS (200-215 fmol/mg) and [3H]2-BFI-labelled I2-RBS (45-60 fmol/mg) with lower densities in the inner stripe and inner medulla (or = 100 and 30 fmol/mg respectively). A high density of MAO-A binding was observed in the inner stripe (515 fmol/mg) with lower levels in the cortex and outer stripe (100-240 fmol/mg), while high densities of MAO-B binding were observed in the cortex and outer stripe (290-450 fmol/mg) with lower levels in the inner stripe (65 fmol/mg). The correlation between the localization of [3H]rilmenidine-labelled I-RBS and [3H]RO19-6327-labelled MAO-B in rabbit kidney (r = 0.87, P = 0.057) suggest that [3H]rilmenidine may label a binding site co-existent with MAO-B, but not MAO-A (n.s.), in this tissue, but rilmenidine did not inhibit [3H]RO41-1049 or [3H]RO19-6327 binding. The distribution of [3H]2-BFI-labelled I2-RBS overlapped the combined distributions of both MAO-A and -B isoenzymes, suggesting that [3H]2-BFI may label sites on both enzymes in the rabbit, but [3H]2-BFI binding only correlated with [3H]RO19-6327 (r = 0.84, P = 0.07), not [3H]RO41-1049 binding (n.s.). Moreover, 2-BFI only inhibited [3H]RO19-6327, not [3H]RO41-1049 binding. These data are consistent with reports that I2-RBS are located on MAO-B and allosterically influence the catalytic site. The relationship of [3H]rilmenidine- and [3H]2-BFI-labelled I-RBS and the identity of non-MAO-associated [3H]rilmenidine-labelled I-RBS requires further investigation.

This longitudinal study examines the sensitivity of 2 computerized neuropsychological tests, delayed matching to sample and paired associate learning, to early dementia of the Alzheimer type (DAT). Normal controls, patients in the early stages of DAT, and individuals with questionable dementia (QD) were studied. At 6 and 12 months after initial presentation, almost half of the QD group exhibited lower scores on the computerized subtests, maintaining their scores on standard testing. Over the same period NC subjects maintained their performance levels, while DAT patients continued to deteriorate. Linear discriminant function analyses of the computerized subtests at 6 and 12 months correctly classified 100% of the early DAT patients. Eighty-four and 79 percent of normal controls were correctly classified at 6 and 12 months respectively. Further development of these subtests for the detection of early dementia and the documentation of ongoing change in DAT is warranted. The findings are discussed in terms of the special sensitivity of these tests to the neuropathology of Alzheimer's Disease.

2-(2-Benzofuranyl)-2-imidazoline (2-BFI) has recently been characterised as a selective ligand for the I2-type of imidazoline-receptor binding site(s) (I2-RBS). The present studies determined the relative levels of specific [3H]2-BFI binding to membrane homogenates of brain and kidney from rat, guinea pig and rabbit and identified the pharmacological characteristics of [3H]2-BFI binding sites in rabbit kidney membranes. Rabbit kidney membranes had the highest relative density of specific [3H]2-BFI binding of all tissues studied (2000 fmol/mg protein). Rabbit brain and guinea pig kidney had moderate levels of specific [3H]2-BFI binding (350-500 fmol/mg protein), while rat kidney and guinea pig and rat brain displayed much lower densities of binding (40-65 fmol/mg protein). Studies of [3H]2-BFI binding kinetics in rabbit kidney homogenates revealed binding to two distinct sites with Kd values of 0.10 +/- 0.01 nmol/l and 1.00 +/- 0.36 nmol/l respectively. Equilibrium saturation studies were also consistent with the presence of two binding sites-[3H]2-BFI (0.01-20 nmol/l) bound to sites with affinities of 0.10 +/- 0.01 nmol/l and 0.92 +/- 0.13 nmol/l and binding densities of 470 +/- 80 and 840 +/- 60 fmol/mg protein (n = 3), representing 36 and 64% respectively. Drug inhibition studies revealed that L-adrenaline; alpha 1-adrenoceptor drugs (prazosin, L-phenylephrine) and alpha 2-adrenoceptor drugs (rauwolscine, methoxyidazoxan, 2-(2,4-(O-methoxyphenyl)-piperazin-1-yl)-ethyl-4, 4-dimethyl-1,3-(2H,4H)-isoquinolindione (ARC-239) had extremely low affinities for [3H]2-BFI binding sites (IC50or = 10 mumol/l). Putative I1-RBS compounds, p-aminoclonidine, moxonidine, imidazole-4-acetic acid and cimetidine, inhibited [3H]2-BFI binding to rabbit renal membranes with low to very low affinities (Ki values 3 toor = 100 mumol/l), suggesting [3H]2-BFI does not label I1-RBS in rabbit kidney membranes. I2-RBS compounds-2- (4,5-dihydroimidaz-2-yl)-quinoline (BU224), 2-(4,5-dihydroimidaz-2-yl)-quinoxaline (BU239), idazoxan and cirazoline-potently inhibited [3H]2-BFI binding (Ki values 0.37-1.6 nmol/l), confirming the labelling of I2-RBS. Inhibition of [3H]2-BFI binding by certain compounds was consistent with their interaction with two binding site populations-for example (drug, Ki values) guanabenz, 0.65 nmol/l and 0.17 mumol/l; naphazoline, 0.94 nmol/l and 2.8 mumol/l; amiloride, 76 nmol/l and 26 mumol/l rilmenidine, 150 nmol/l and 50 mumol/l; and clonidine, 230 nmol/l and 70 mumol/l. The high affinity of amiloride for a high proportion (85%) of the binding is consistent with the presence of the I2A-subtype of I-RBS in rabbit kidney. These results demonstrate that [3H]2-BFI is a highly selective and high affinity radioligand for I2-RBS which should be useful for the further characterisation of these sites in mammalian tissues.

Epidemiological evidence has linked essential hypertension with impaired tissue sensitivity to insulin (i.e. insulin resistance) and actions which could contribute to elevated blood pressure include renal sodium and water retention, sympathetic nervous system stimulation and effects on vascular smooth muscle cell growth and cation balance. Although insulin has pressor effects in some animal models, similar changes in human studies have only been demonstrable with supraphysiological insulin concentrations. We have recently measured finger blood pressure during a two stage hyperinsulinaemic euglycaemic clamp that produced insulin concentrations within the 'physiological' range. The plasma insulin concentration increased from 7.0 +/- 0.3 mu U.ml(-1) to 28.9 +/- 0.6 mu U.ml(-)and then to 101 +/-1.7 mu U.ml(-1) during the procedure and was associated with an increase in fingers but not arm systolic blood pressure during both low dose (i.e.+ 9.9 +/- 1.9 mmHg vs + 7.5 +/- 2.7 mmHg with control,p0.05) and high dose insulin (21.9 +/- 2.3 mmHg vs 14.6 +/- 3.1 mmHg, p0.01). Thus it appears that 'physiological' concentrations of insulin have pressor effects on finger systolic blood pressure that are not detectable more proximally and it is possible that such changes could contribute to the development of sustained elevations of blood pressure.

Anomalously low affinities for the beta-1-adrenoceptor are seen for members of a series of para-substituted N-isopropylphenoxypropanolamines in which the substituent is able to conjugate with the aromatic ring. The energy of conjugation was calculated using the AM1 semiempirical molecular orbital method and appears to correlate with the loss of binding energy, and hence affinity for the receptor. This suggests that binding is associated with movement of the substituent out of the plane of the aromatic ring due to steric interference with the receptor. A previously unrecognized binding site for aromatic groups off the para position is also identified.

The secondary structure of bacteriorhodopsin (bacR) is predicted using the Chou and Fasman method in conjunction with the hydropathic index of Kyte and Doolittle. The predicted bacR structure was compared with the structure determined by Henderson et al. (1990) using electron diffraction and was found to correlate extremely well. The secondary structure of bovine rhodopsin (bovR) was then predicted using the same techniques. The proposed transmembrane regions of bovR were then examined and found to have sequence similarity with those transmembrane regions of bacR.

The activity of baroreceptor reflexes and cardiopulmonary reflexes was examined in conscious spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto (WKY) rats. The baroreceptor heart rate reflex, elicited by phenylephrine- and nitroprusside-induced changes in blood pressure, had a reduced range and lower heart rate plateau in SHR than in WKY rats, which suggests impaired vagal control of the heart rate in SHR. Cardiopulmonary receptor reflex activity was assessed by intravenous injections of phenyldiguanide which evoke the Bezold-Jarisch reflex. Phenyldiguanide elicited dose-dependent bradycardic and hypotensive responses in WKY rats, but these were significantly attenuated in SHR. This is the first demonstration of impaired Bezold-Jarisch responses in conscious SHR and provides evidence of both impaired vagally mediated arterial baroreceptor activity and impaired cardiopulmonary receptor activity in this rat strain.

The spontaneously hypertensive rat (SHR) is the most commonly used animal model of hypertension. For many years, it has been widely accepted that the most appropriate control strain is the Wistar-Kyoto (WKY) rat to which SHR rats are genetically related. However, recent concerns have been raised about genetic differences between the various colonies of SHRs and, in particular, genetic differences between colonies of WKY rats. It has been further emphasized that the only way to establish that a genetic trait is an etiological factor in the development of hypertension is through studies of F2 backcrosses between SHR and WKY rats. The present article details the history of the SHR and WKY strains and demonstrates why there is high likelihood of genetic variability between rats of both strains from different colonies around the world. It suggests that the WKY strain is not the most suitable for backcross studies because of the incidence of spontaneous hypertension and the somewhat higher levels of blood pressure in these rats. A central reference strain is proposed using SHRs inbred at Kyoto University, where brother/sister inbreeding has continued for more than 80 generations.

Reserpine (Fig. 1), an alkaloid derived from the roots of certain species of Rauwolfia, was isolated in 1952, and about 50 Rauwolfia alkaloids are known. Extracts of Rauwolfia, a plant genus belonging to the Apocynaceae family, were used by the Hindus for a variety of diseases including snake bites because of the resemblance of the roots to a snake (Rauwolfia serpentina). It was also used for the treatment of cardiovascular diseases, insomnia, and insanity (Weiner 1985). Reference to the medical use of Rauwolfia alkaloids appeared in the Western literature as early as 1563 (Bein 1956). In 1931 Sen and Bose reported in the Indian Medical Journal that the whole root could be used for the treatment of hypertension and psychosis. Widespread interest in their use for the treatment of hypertension, however, was aroused much later after Vakil (1949) published his findings on the use of Rauwolfia alkaloids in the British Heart Journal. Parental usage became popular for hypertensive emergencies but has a tendency to produce excessive sedation.

Guanethidine and related compounds have collectively been called adrenergic blocking drugs because their major pharmacological action is to prevent the release of noradrenaline from postganglionic neurons in response to sympathetic nerve stimulations. Guanethidine has other actions on catecholamine metabolism (see Sect. 2) and can cause significant tissue depletion of catecholamines. It does not, however, interfere with release of catecholamines from the adrenal medulla and does not produce parasympathetic blockade.

The pharmacokinetic properties of captopril were studied in two groups of hypertensive patients; (1) those who had never taken captopril (acute group), and (2) those who had been taking captopril for at least 6 months (chronic group). It was found that after 100 mg of captopril orally, the mean peak plasma level in the chronic group was three times higher than that in the acute group while the area under the curve was twice as high in the chronic group. These data suggest that bioavailability increases with chronic administration, and thus it may be possible to reduce the dosage of captopril and still maintain blood pressure control while reducing side effects.

The treatment of hypertension by costly new drugs such as the angiotensin converting enzyme inhibitors, means that careful monitoring of health care expenditure is essential. If drugs like simvastatin come to be widely used, costs will mount even more. New drugs cannot be used indiscriminately.

The antihypertensive and side effects of guanfacine and clonidine were compared in 24 patients with essential hypertension in a single-blind crossover study. After four weeks of active treatment, both guanfacine and clonidine were equally effective in reducing blood pressure. After six weeks of active therapy, recumbent, but not standing, blood pressures were statistically higher (P < 0.01) when patients were taking guanfacine. Side effects were noted in all 24 patients, and resulted in the withdrawal of five patients (three of whom were receiving clonidine, one was receiving guanfacine and one was taking placebo). There were no significant changes in biochemical or haematological parameters during the trial. There was no evidence of "rebound" hypertension, but withdrawal symptoms did occur in one patient after therapy with guanfacine was discontinued.

A sensitive and specific high pressure liquid chromatographic procedure for ranitidine estimation is described and pharmacokinetic studies in six healthy volunteers reported. Each subjects received 20 mg of ranitidine i.v.; 20 mg, 40 mg and 100 mg orally having fasted overnight and 100 mg with a standard meal. Following the i.v. dose, ranitidine plasma concentrations fell biexponentially with a distribution half-life of 6.1 +/- 0.9 min and a terminal elimination half-life of 1.9 +/- 0.1 h. The volume of distribution was 115 +/- 7 1 and the systemic plasma clearance 709 +/- 62 ml/min. After 20 mg oral doses the systemic availability was high (88 +/- 10%). Bioavailability was unaffected by food and AUC increased linearly with dose to 100 mg. Renal excretion of unchanged ranitidine was between 50 and 70% and a further 1-3% was excreted as desmethylranitidine. In separate studies, the inhibitory action of cimetidine and ranitidine on pentagastrin stimulated gastric acid output was compared in seven duodenal ulcer patients. Results so far indicate that ranitidine 150 mg i.v. produces a more pronounced and more prolonged suppression of pentagastrin stimulated gastric acid output than cimetidine 200 mg i.v. (p less than 0.001). Ranitidine produced a sustained near total (greater than 90%) suppression in acid output in the period 60 to 120 min after drug administration, whereas acid output with cimetidine was less and fell from 82 to 54% in the same period.

We describe a modified high-performance liquid-chromatographic method for the simultaneous analysis of carbamazepine andits biologically active metabolite, carbamazepine-10, 11-epoxide. Concentrations of both these compounds in the plasma of 35 epileptic patients receiving chronic carbamazepine therapy are presented. Concentrations of carbamazepine in plasma were related to those of carbamazepine-10, 11-epoxide (r - 0.495, P less than 0.05). Total daily doses of carbamazepine were better correlated with plasma concentrations of carbamazepine-10, 11-epoxide (r = 0.714, P less than 0.001) than of carbamazepine (r = 0.269, P greater than 0.05). Close correlations were found between results of the three assay procedures we used to measure plasma carbamazepine concentrations: high-performance liquid chromatography, gas-liquid chromatography, and enzyme immunoassay. Correlation coefficients exceeded 0.97 and regression slopes were near unity, indicating that all three procedures were individually specific for the quantification of plasma carbamazepine.

Echocardiographic assessment of left ventricular function was performed in twenty-two unselected patients on stable, chronic maintenance dialysis. The statistically significant abnormalities were enlargement of the left ventricular cavity (end diastolic internal dimension or "diameter" 5.4 +/- 0.2 cm, normal 4.4 +/- 0.3 cm), thickening of the left ventricular wall (end diastolic thickness 1.1 +/- 0.05 cm, normal 0.9 +/- 0.03 cm) and a reduction in myocardial contraction (fractional shortening 28.2 +/- 2.0%, normal 35.7 +/- 0.9%). Myocardial impairment could not be attributed to the effects of hypertension or to ischemic heart disease. There was, however, a significant negative correlation between fractional shortening and total plasma catecholamines (r = 0.45, P less than 0.05) suggesting that excessive catecholamines may contribute to the decreased myocardial contraction seen in uremic patients.

Phœochromocytomas have many pathological and clinical features of interest. The present case report concerns a patient with two tumours, one of which was present in the middle mediastinum. This is only the second time that such an occurrence has been reported. Only one of the tumours (that in the right adrenal gland) secreted adrenaline, and difficulty was experienced in localising the mediastinal tumour. It was found that direct adrenal venous sampling proved misleading for purposes of localisation.

An open study of the effectiveness of metoprolol in reducing the blood pressures of 13 hypertensive patients was conducted. It was found that metoprolol reduced the patients' blood pressure satisfactorily, and is well tolerated within the dose range of 100 mg to 400 mg daily.

1. Urinary sodium excretion and plasma renin activity have been measured in a group of persons with untreated mild hypertension and in a control normotensive group. 2. Preliminary analyses of the data indicate that the daily sodium excretion was significantly higher in the hypertensive group but the plasma renin activity did not correlate significantly with the urinary excretion of sodium. 3. These findings suggest that sodium intake was significantly greater in a population with mild hypertension than in a comparable normotensive group.

The effect of nitroglycerin (NTG)-induced tolerance on the spasmolytic effects of a series of vasodilators was determined to establish potential sites of tolerance. Concentration-effect curves to vasodilators were completed concurrently in U46619-contracted bovine isolated coronary artery rings pre-exposed to 100 microM NTG for 10 min (NTG-tolerant rings) and in control rings not pre-exposed to NTG. Compared to control rings, NTG-tolerant rings were markedly less responsive (P less than .01, n = 8-10) to the spasmolytic actions of NTG, isosorbide dinitrate, sodium nitroprusside (SNP) and 3-morpholinosydonimine (SIN-1), whereas the spasmolytic actions of S-nitroso-N-acetylpenicillamine and nitric oxide were only marginally attenuated in NTG-tolerant rings. On the other hand, no significant difference in the relaxant responses of NTG-tolerant and control coronary artery rings were observed to either the endothelium-dependent vasodilator, A23187 or the guanylate cyclase-independent vasodilator, theophylline. In additional cross-tolerance studies, relaxations to the organic nitrate vasodilator, NTG were significantly more attenuated (P less than .05, n = 5) by tolerance induced by NTG, than by either SNP or SIN-1, whereas the actions of the non-nitrate vasodilators, SNP and SIN-1 were attenuated more by SNP-and SIN-1-induced tolerance than by NTG-induced tolerance (P less than .05, n = 5). We conclude that, in this isolated coronary artery preparation, NTG-induced tolerance affects at least two major sites in the cascade of events between the initial site of NTG action and guanylate cyclase activation.(ABSTRACT TRUNCATED AT 250 WORDS)

When adult male Wistar-Kyoto rats had been injected intra-peritoneally with a dose of 100 mg/kg of cyclophosphamide (CP), their urinary bladders showed changes of thickening and haemorrhage visible macroscopically, and oedema, necrosis and haemorrhage of the mucosa visible microscopically. There was an increase in bladder weight from an average of 60 mg in untreated control rats to an average of 125 mg in the CP-treated rats. When in addition they had been given 400 mg/kg of a thiol drug, namely either penicillamine or its disulphide, or N-acetylcysteine (NAC) or its S-carboxymethyl derivative carbocysteine, the increase in bladder weight and the histologic changes of haemorrhagic cystitis were found to be prevented by the co-administration of penicillamine or NAC but not by penicillamine disulphide or carbocysteine. The leucopenia caused by CP was not prevented by co-administration of these thiol drugs. It is concluded that penicillamine, like NAC, is effective in preventing CP-induced cystitis but not at the expense of reducing the cytotoxicity of CP. The inefficacy of penicillamine disulphide and carbocysteine suggests that significant dissociation of the disulphide does not occur in vivo and that the thiol moiety is important in preventing the cystitis. Penicillamine, a thiol compound with anti-rheumatic and possible anti-tumour effects, may thus prove to be a very useful adjunct to CP therapy.

Mitochondrial abnormalities are reported in four cases of phaeochromocytoma. These abnormalities include swelling and scant cristae, intramitochondrial dense bodies, septate-like junctions, intercristal fusion plus spheroidal bodies, and intramitochondrial rodlets. These structural mitochondrial changes are associated with reduction in activity of the mitochondrial enzymes, monoamine oxidase and succinic dehydrogenase.

1 The role of central beta-adrenoceptors in the anticonvulsant effect of beta-adrenoceptor antagonists has been examined. 2 Oral administration of (-)- and (+)-propranolol (0.05-1 mg/kg) and (+/-)-pindolol (0.025-0.5 mg/kg) produced a dose-dependent decrease in duration of convulsions produced by pentylenetetrazol (PTZ 50 mg/kg, i.p.) in rats. 3 At the EC50 level, (-)-propranolol is seven times more effective than the (+)-isomer. 4 Oral administration of (-)-, (+)- or (+/-)-practolol (1-10 mg/kg) or (-)- or (+)-timolol (1-10 mg/kg), two beta-adrenoceptor antagonists that do not penetrate the blood brain barrier, had no significant effect on the duration of PTZ-induced convulsions. 5 Intracerebroventricular administration of (-)-propranolol (0.5 microgram/kg) or (-)-timolol (0.25 microgram/kg) produced highly significant anticonvulsant effects whereas the (+)-isomers at the same dose level were ineffective. (+/-)-Pindolol (0.25 microgram/kg) was also much more effective given by this route than when given orally. The (+)- and (-)-isomers of the beta 1-adrenoceptor selective antagonist practolol (10 microgram/kg) exerted only weak anticonvulsant effects. 6 This study provides evidence that beta-adrenoceptor antagonists exert an anticonvulsant effect through central beta 2-adrenoceptors. At high dose levels, additional anticonvulsant activity is associated with membrane stabilization in those antagonists which possess this property.

Studies using a sensitive radioenzymatic assay for plasma noradrenaline suggest there is a selective overactivity of the sympathetic nervous system in essential hypertension. Methodology which allows the study of local sympathetic turnover in CNS nuclei and peripheral blood vessels is described. This approach has been used to study the non-innervated sympathetic turnover phaeochromocytoma. It is suggested that studies of local regulatory mechanism in neurotransmitter release are required to give a greater understanding of the central and peripheral role of the sympathetic nervous system in the pathogenesis of hypertension.

alpha-Adrenoceptors in brain can be studied readily by radioligand binding techniques. This provides valuable information not only on the distribution of receptors in brain regions, but also on the regulation of receptors. The usefulness of this technique is dependent in part on a radioligand with high specificity for the receptor under study. Our studies have shown that 3H-clonidine does not bind exclusively to alpha 2-adrenoceptor subtypes, but also interacts with alpha 1-adrenoceptors. In contrast, 3H-guanfacine labels a high affinity alpha 2 subtype with good selectivity, but 3H-lofexidine probably labels with both alpha 2 and alpha 1-adrenoceptor binding sites.

Tritium-labeled preparations of the selective alpha 2-adrenoceptor agonist, clonidine, and the selective alpha 1-adrenoceptor antagonists, prazosin and WB 4101, were examined for their suitability as ligands for receptor assay. In the rat brain, 3H-clonidine bound specifically with high affinity to membrane sites, and drug displacement studies indicated that these were alpha 2-adrenoceptors. The structural requirements for this receptor were defined by examining a range of clonidine analogues. 3H-Clonidine binding to peripheral tissues of the rat was very low, although peripheral tissues from guinea pig exhibited higher binding. Specific 3H-clinidine binding was not reduced after chemical sympathectomy, suggesting that the binding site, although having characteristics of an alpha 2-adrenoceptor, was not located presynaptically. Studies with 3H-WB 4101 in rat cerebral cortex indicated that this ligand bound to an alpha 1-adrenoceptor which was independent of the 3H-clonidine-binding site. 3H-Prazosin was a ligand for alpha 1-adrenoceptors in guinea pig brain and also in membranes from seminal vesicle. However, in the latter tissue, characterization of the binding site was hampered by a high degree of nonspecific binding (50% of total binding).

1. The combined use of alpha-methyldopa and L-alpha-methyldopa hydrazine (a peripheral decarboxylase inhibitor) has been studied, in a double-blind cross-over comparison, with alpha-methyldopa and L-alpha-methyldopa hydrazine placebo in the treatment of eight patients with essential hypertension. 2. L-alpha-methyldopa hydrazine did not enhance the antihypertensive effect of alpha-methyldopa. This suggests that because methyldopa can inhibit its own decarboxylation, peripheral decarboxylation is not an important metabolic pathway for methyldopa and elevated brain levels of methyldopa do not necessarily result in elevated brain levels of methyldopamine.