Differences between zofenopril and ramipril, two ACE inhibitors, on cough induced by citric acid in guinea pigs: role of bradykinin and PGE2

Dry and persistent cough is one of the commonest side effects experienced by patients treated with angiotensin-converting enzyme (ACE) inhibitors for the therapy of hypertension and congestive heart failure. The present study investigated the effect of zofenopril and ramipril on cough induced by citric acid in guinea pig and the involvement of bradykinin (BK) and prostaglandin E2 (PGE2) in mediating the responses of these drugs. Zofenopril (10 mg/kg) or ramipril (3–10 mg/kg), which is threefold more potent than zofenopril, on a mg basis, in lowering blood pressure, was orally administered daily in drinking water for 2 weeks. At the end of this period, aerosol of citric acid solution (0.1 M) was performed and the number of cough counted for 10 min. The role of the kinin B₂ receptor was also investigated. BK and PGE2 levels in the bronchoalveolar lavage (BAL) fluid were measured after repeated oral treatment with zofenopril or ramipril (10 mg/kg). Ramipril (3–10 mg/kg) increased citric acid-induced cough by 40% and 60%, respectively, as compared to the vehicle control group (15.0?±?1.8), while zofenopril (10 mg/kg) was without effect. The enhancement of citric acid-induced cough caused by ramipril (10 mg/kg) was reduced by the kinin B₂ receptor antagonist MEN16132 (0.25 mg/kg ip). BK and PGE2 levels in the BAL fluid were increased, in comparison to the control group, after ramipril treatment, while they were unchanged after zofenopril administration. Zofenopril, contrary to ramipril, did not affect either citric acid-induced cough in the guinea pigs or BK and PGE2 production in the airways.     

A comparison between ATP and bradykinin as possible mediators of the responses of smooth muscle to non-adrenergic non-cholinergic nerves

The effects of ATP, bradykinin (BK) and electrical stimulation of intramural non-adrenergic non-cholinergic nerves (NS) were compared in four smooth muscle preparations. In the guinea-pig taenia caeci and rat duodenum, ATP (10^?7-5 × 10^?5 M) and BK (5 × 10^?10-10^?7 M) closely mimicked the response to NS. The relaxations to BK, but not to ATP or NS, were inhibited by carboxypeptidase B (3–15 U/ml) and apamin (10^?8-5 × 10^?8 M) prevented the relaxations to all three stimuli. BK contracted the guinea-pig distal colon whereas ATP and NS caused inhibition. In the guinea-pig bladder, ATP and NS induced rapid phasic contractions whereas BK caused tonic contractions. In the latter two preparations, incubation with indomethacin failed to reveal any BK relaxationic In view of its failure to mimic the nerve-mediated response in two of the tissues, and of its selective inhibition by carboxypeptidase B in the other two, BK is less likely than ATP to be the transmitter in non-adrenergic non-cholinergic nerves supplying smooth muscle.     

Some neurochemical properties of a new antidepressant,bupropion hydrochloride (Wellbutrin™)

Bupropion is a novel antidepressant agent. In the present study, an attempt was made to gain some insight into the mechanism of the drug's antidepressant activity. In vitro studies revealed that bupropion was a weak, competitive inhibitor of norepinephrine (NE) uptake into rat hypothalamic synaptosomes and of dopamine (DM) uptake into rat striatal synaptosomes, having IC50 values of 6.5 ± 0.6 × 10^?6 M and 3.4 ± 0.4 × 10^?6 M, respectively. At 1 × 10^?5 M, the drug produced a 20 ± 3% inhibition of serotonin (5-HT) uptake into rat hypothalamic synaptosomes. The drug was also a weak inhibitor of the ATP-Mg⁺² stimulated uptake of NE and DM into synaptic vesicles of whole rat brain, having IC50 values of 3.3 × 10^?5 M and 6.0 × 10^?5 M, respectively. Bupropion had no dose-dependent effect on the spontaneous release of NE, DM, and 5-HT from these synaptosomal preparations in concentrations as high as 1 × 10^?4 M. Brain monoamine oxidase (MAO) activity in vitro was not affected by concentrations of the drug ranging from 10^?7 M to 10^?5 M. Bupropion was also without effect on brain MAO, 1 hr after i.p. doses in rats as high as 100 mg/kg. The ED50 value for bupropion necessary to inhibit the uptake of ³H-catecholamines by 50% into synaptosomes incubated in the serum from rats treated with the drug was 40 mg/kg i.p., while its ED50 value for antidepressant activity, as judged by the ability of bupropion to reverse the immobile posture of “helpless” rats, was 8 mg/kg i.p. These neurochemical properties of bupropion on uptake of biogenic amines and on MAO activity serve to distinguish it from other antidepressant drugs of the tricyclic and MAO inhibitor classes.     

Lack of interaction between ramipril and simvastatin

Twenty two healthy males participated in a randomised, placebo-controlled, double blind, cross-over study to investigate the influence of simvastatin on the pharmacokinetics of ramipril and its active metabolite (ramiprilat), and on the ACE-inhibiting effect of ramiprilat. During two study periods, each of 7 days, subjects received daily either simvastatin 20 mg at 19.00 h or placebo; ramipril (5 mg) was given on Day 5 of each of the periods. Plasma concentrations of ramipril and ramiprilat and ACE-activity were measured in sequential blood specimens, and ramipril and ramiprilat concentrations were measured in urine. Blood and urine collections for pharmacokinetic and pharmacodynamic assessment were made up to 72 h after the dose of ramipril. The mean AUC of ramipril for ramipril+placebo (R+P) and ramipril+simvastatin (R+S) was 22.2 and 21.3 ng.h.ml^?, respectively; for ramiprilat the corresponding figures were 61.3 and 57.6 ng.h.ml^?. The urinary excretion of ramipril+metabolites for (R+P) and (R+S) was 25.2 and 24.1% of dose. The maximum percentage inhibition of ACE-activity for (R+P) was 94.6%, and for (R+S) it was 94.1%. It is concluded that concomitant administration of simvastatin and ramipril has no clinically relevant effect on the pharmacokinetics or ACE-inhibition of the latter drug and its metabolites.     

Ramipril prevents the detrimental sequels of chronic NO synthase inhibition in rats: hypertension,cardiac hypertrophy and renal insufficiency

Inhibition of the angiotensin converting enzyme (ACE) with ramipril was studied in male Wistar rats during long-term inhibition of nitric oxide (NO) synthase by N^G-nitro-l-arginine methyl ester (l-NAME). Chronic treatment with l-NAME in a dose of 25 mg/kg per day over 6 weeks caused myocardial hypertrophy and a significant increase in systolic blood pressure (245 ± 16 mmHg) as compared to controls (155+4 mmHg). Animals receiving simultaneously l-NAME and ramipril were protected against blood pressure increase and partially against myocardial hypertrophy. L-NAME caused a significant reduction in glomerular filtration rate (GFR: 2.56+0.73 ml·kg^–1·min^–1) and renal plasma flow (RPF: 6.93±1.70ml·kg^–1·min^–1) as compared to control (GFR: 7.29±0.69, RPF: 21.36±2.33ml·kg^–1·min^–1). Addition of ramipril prevented l-NAME-induced reduction in GFR and renal plasma flow. l-NAME produced an elevation in urinary protein excretion and serum creatinine and a decrease in potassium excretion which was antagonised by ramipril. L-NAME-induced increase in plasma renin activity (PRA) was further elevated with ramipril treatment. Isolated hearts from rats treated with l-NAME showed increased post-ischaemic reperfusion injuries. Compared to controls duration of ventricular fibrillation was increased and coronary flow reduced. During ischaemia the cytosolic enzymes lactate dehydrogenase and creatine kinase, as well as lactate in the venous effluent were increased. Myocardial tissue values of glycogen, ATP, and creatine phosphate were decreased, whereas lactate was increased. Coadministration of ramipril reversed these effects. l-NAME treatment reduced the cyclic GMP content in urine and renal arteries, and was not changed by additional ramipril-treatment. In the kidney hyalinosis of arterioles and of glomerular capillaries, as well as mesangial expansion and tubular atrophies seen after long-term inhibition of NO synthase were reduced by coadministration of ramipril. In conclusion, long-term ACE inhibition by ramipril prevented l-NAME-induced hypertension and cardiac hypertrophy, and attenuated functional and morphological changes in the kidneys. In addition, cardiac-dynamic and -metabolic deterioration induced by L-NAME was normalised by co-treatment with ramipril. Correspondence to: Max Hropot at the above address     

Estrogenic behavior of 2(o-chlorophenyl)-2-(p-chlorophenyl)-1,1,1-trichloroethane and its homologues.

Eight chlorinated hydrocarbons were tested for their ability to compete with ³H-estradiol-17β for specific binding proteins in uterine cytoplasm from immature rats. The binding was assayed on 5–20% sucrose density gradients. 2(o-Chlorophenyl)-1,1,1-trichloroethane (o,p′-DDT) and 2(o-chlorophenyl)-2-(p-chloropenyl)-1,1-dichloroethylene (o,p′-DDE) (1·4 × 10^?4M) competed with ³H-estradiol-17β (8·7 × 10^?9 M) for binding to the “8 S receptor” in the cytomplasm. 2,2-Bis-(p-chlorophenyl)-1,1,1-trichloroethane (p,p′-DDT), 2,2-bis-(p-chlorophenyl)-1,1-dichloroethylene (p,p′-DDE), 2,2-bis-(p-chlorophenyl)-1,1-dichloroethane (p,p′-DDD), 2(m-chlorophenyl)-2-(p-chlorophenyl)-1,1-dichloroethane (m,p′-DDD), 2(o-chlorophenyl)-2-(p-chlorophenyl)-1,1-dichloroethylene (o,p′-DDD) and bis-(p-chlorophenyl)-1,1-dichloroacetate (DDA) did not compete at 1sd4 × 10^?4 M. Transfer of the receptor-bound compounds into the nuclei was examined using similar competition techniques. o,p′-DDT and o,p′-DDE competed with estradiol binding in the nuclei. These studies indicate that o,p′-DDT and o,p′-DDE at high concentrations act as estrogens as measured by their ability to compete with estradiol-17β for binding to the uterine cytopoasmic receptor and in the transfer and binding of estradiol in the nuclei of uterine cells.     

The effect of pentobarbital on the carbohydrate metabolism of glial cells in culture

Hamster astroblast glial cells (clone NN) and dissociated glial cells from newborn rat brains in primary culture were exposed to from 5 × 10^?5 to 1 × 10^?3 M pentobarbital-Na and 1 × 10^?4M or 2.5 × 10^?4 M morphine hydrochloride. After various periods of time the following enzymatic activities were measured in the cell culture: fructose-diphosphate-aldolase (ALD), pyruvate kinase (PK.), lactate dehydrogenase (LDH), glutamate dehydrogenase (GDH), malate dehydrogenase (MDH) and NADH cytochrome c reductase (CCR). The long-term exposure to pentobarbital resulted in increases in LDH, MDH and GDH activities and a consistent decrease in PK activity. Continuous exposure to morphine resulted in minor, uniformly depressive changes. When neuroblastoma cells (clone M1) or rat fibroblasts in primary culture were exposed to pentobarbital no specific changes could be detected. The results are interpreted to suggest that barbiturates affect the carbohydrate metabolism of glial cells in a drug- and cell-dependent fashion.     

Thaliporphine protects ischemic and ischemic‐reperfused rat hearts via an NO‐dependent mechanism

In ischemia or ischemia‐reperfusion (I/R), nitric oxide (NO) can potentially exert several beneficial effects. Thaliporphine, a natural alkaloid with Ca²⁺ channel‐activating and Na⁺/K⁺ channel‐blocking activities, increased NO levels and exerted cardioprotective action in ischemic or I/R rats. The role of NO in the cardioprotective actions of thaliporphine was assessed. The severity of rhythm disturbances and mortality in anesthetized rats with either coronary artery occlusion for 30 min, or 5 min followed by 30‐min reperfusion, were monitored and compared in thaliporphine‐ vs. placebo‐treated groups. Thaliporphine treatment significantly increased NO and decreased lactate dehydrogenase (LDH) levels in the blood during the end period of ischemia or I/R. These changes in NO and LDH levels by thaliporphine were associated with a reduction in the incidence and duration of ventricular tachycardia (VT) and ventricular fibrillation (VF) during ischemic or I/R period. The mortality of animals was also completely prevented by 1 × 10^–8 moles/kg of thaliporphine. In animals subjected to 4 h of left coronary artery occlusion, 1 × 10^–7 moles/kg of thaliporphine dramatic reduced cardiac infarct zone from 46 ± 6% to 7.1 ± 1.9%. Inhibition of NO synthesis with 3.7 × 10^–6 moles/kg of N^ω ‐nitro‐L‐arginine methyl ester (L‐NAME) abolished the beneficial effects of thaliporphine during 30 min or 4 h myocardial ischemia. However, the antiarrhythmic activity and mortality reduction efficacy of thaliporphine during reperfusion after 5 min of ischemia was only partially antagonized by L‐NAME. These results showed that thaliporphine efficiently exerted the cardioprotections either in acute or prolonged coronary artery occlusion or occlusion‐reperfusion situations. The fact that thaliporphine induced cardioprotective effects were abrogated by L‐NAME indicates that NO is an important mediator for the cardioprotective effects of thaliporphine in acute or prolonged ischemia, whereas antioxidant activities may contribute to the protection of I/R injury. Drug Dev. Res. 52:446–453, 2001. © 2001 Wiley‐Liss, Inc.     

Stimulatory effect of platinum (IV) ion on the production of superoxide radical from xanthine oxidase and macrophages.

Superoxide radical (^.O^?₂) production was measured spectrophotometrically using NADH and lactate dehydrogenase (LDH) in a xanthine oxidase(XOD) plus hypoxanthine (HX) system and in an isolated guinea pig macrophages system. Sodium platinum (IV) chloride (Na₂PtCl₆: 2.5 × 10^?4?1 × 10^?3M) enhanced the production of ^.O₂^? in both systems (2–10 times). The degree of the enhancement was dependent on incubation time, basal level of ^.O₂^? production and concentration of Na₂PtCl₆. The stimulated ^.O₂^? production in the XOD system was inhibited by luminol (O-aminophtalhydrazide) and that in the macrophages was inhibited by an anti-inflammatory drug, Diclofenac sodium (Dc). These results show that platinum (IV) ion is either a potent stabilizer of ^.O₂^? or a stimulator of ^.O₂^? production as are paraquat or streptonigrin. This specific character of platinum (IV) ion may explain its bactericidal and inflammation-inducing properties.     

Inhibition of superoxide anion production in non-stimulated guinea pig peritoneal exudate cells by anti-inflammatory drugs.

Inhibitory effects of anti-inflammatory drugs on the production of superoxide anion (·O₂^? by isolated non-treated guinea pig peritoneal exudate cells (PEC) was studied spectro-photometrically using NADH and lactate dehydrogenase (LDH). Values of ID₅₀ were; diclofenac sodium (2 × 10^?5M), indomethacin (3 × 10^?5M), oxyphenbutazone (8 × 10^?5M), fenamic acid (1 × 10^?4M), ibuprofen (1 × 10^?4M), benzydamine (3 × 10^?4M), aspirin (10^?3M<) and dexamethasone (10^?3M<). The mechanism of inhibition seemed to block plasma membrane associated NAD(P)H oxidase(s) activity which produces ·O₂^? ID₅₀ values of other drugs; superoxide dismutase (SOD, 2 × 10^?8M), cytochalasin B(1 × 10^?7M) and NEM (6 × 10^?6M). d-Mannitol radical scavenger), 1,3-diphenyl-isobenzofuran (singlet oxygen scavenger) and sodium azide (mitochondrial electron transport inhibitor and singlet oxygen scavenger) were negative.Superoxide radical itself or oxygen-centered radical(s) derived from ·O₂^? is supposed recently as a rate-limiting factor for prostaglandin (PG) synthetase. Whether the inhibition of non-steroidal anti-inflammatory drug (NSAID) on ·O₂^? production is linked directly to PG biosynthesis or not, ·O₂^? was already demonstrated in our laboratory to make a role for the development of rat carageenan foot oedema. It may serve as a new in vitro sceening method of NSAID, to check the inhibitory potency of a compound on ·O₂^? production by guinea pig PEC.     

Cardiovascular effects induced by N-(4'-dihydro)-piperoylthiomorpholine in normotensive rats

Objectives We have tested the cardiovascular effects of N‐(4′‐dihydro)‐piperoylthiomorpholine (LASSBio 365) on rats using an in‐vivo and in‐vitro approach. Methods LASSBio 365 (0.025, 0.05, 0.1, 0.25, 0.5 or 1 mg/kg, randomly injected) was administered to conscious unrestrained rats and the mean arterial pressure and heart rate were measured. The effects of LASSBio 365 (3 × 10^?6–3 × 10^?4m ) on rat isolated aortic rings with and without endothelium were investigated. Key findings LASSBio 365 induced a dose‐dependent decrease in mean arterial pressure and heart rate (ED50 = 158 ± 53 µg/kg). The effects evoked by LASSBio 365 (0.5 mg/kg) were inhibited by pretreatment with atropine. In anaesthetized rats, electrocardiogram recordings revealed second/third degree sinoatrial and atrioventricular blockade induced by the compound, which were completely inhibited after cardiac muscarinic blockade or cervical bilateral vagotomy. In rat isolated aortic rings, LASSBio 365 (3 × 10^?6–3 × 10^?4m ) was capable of antagonizing the contractile effects induced by phenylephrine (1 µm ) or KCl (80 mm ) (IC50 = 107 ± 6; 92 ± 6 µm , respectively). This effect was not inhibited after removal of the vascular endothelium (IC50 = 84 ± 4; 92 ± 10 µm , respectively). LASSBio 365 (10^?6–10^?4m ) antagonized CaCl₂‐induced contractions in a concentration‐dependent manner. Furthermore, LASSBio 365 (98 µm ) inhibited contractions produced by noradrenaline (1 µm ), but not those induced by caffeine (20 mm ). Conclusions These results suggested that LASSBio 365 produced negative chronotropism and reduced peripheral resistance that were probably due to the stimulation of cardiac muscarinic pathways. Peripheral vasodilation was probably linked to voltage‐dependent Ca²⁺‐channel blockade and/or specific inhibition of Ca²⁺ release from noradrenaline‐sensitive intracellular stores.     

Pharmacokinetics and pharmacodynamics of ramipril and piretanide administered alone and in combination

The pharmacokinetics and pharmacodynamics of single oral doses of 5 mg ramipril and 6 mg piretanide administered separately and in combination were determined in a single blind, randomised, 3-period cross-over study in 24 healthy male volunteers.The peak plasma concentrations of ramipril and ramiprilat increased slightly (from 11.9 to 14.8 ng/ml, and from 6.39 to 8.96 ng/ml, respectively) as did the area under the plasma concentration-time curve of ramipril (0–4 h) and ramiprilat (0–24 h) (from 15.8 to 19.8 ng·ml^–1·h, and from 63.4 to 74.6 ng·ml^–1·h, respectively). The urinary excretion of ramiprilat also rose (from 6.82 to 7.73 % of dose) following simultaneous treatment with piretanide. These effects were probably due to reduced first-pass metabolism of ramipril/ramiprilat to inactive metabolites. The blood pressure lowering effect, the time course of inhibition of ACE activity in plasma and the concentration-response relationship for the inhibition of plasma ACE activity were not affected by piretanide.The peak plasma concentration of piretanide was somewhat reduced (from 285 to 244 ng/ml) following simultaneous treatment with ramipril. No other pharmacokinetic parameter was affected. Piretanide increased urine flow, and sodium, chloride and potassium excretion, especially during the first 2 hours following administration. These pharmacodynamic parameters were not affected by ramipril.Thus, simultaneous administration of single oral doses of ramipril and piretanide caused modest changes in the peak and average plasma concentrations of both drugs, which did not lead to detectable alterations in the pharmacodynamic parameters measured in healthy volunteers.     

Effects of 2,3-dimethoxy-5-methyl-6-(10'-hydroxydecyl)-1,4-benzoquinone (CV-2619) on myocardial energy metabolism in the hypertrophied heart of spontaneously hypertensive rats

Effects of CV-2619 (10 and 30 mg/kg/day, p.o.) or ubiquinone-10 (Q-10, 10 mg/kg/day, p.o.) treatment for 5 weeks on systolic blood pressure (SBP) and myocardial energy metabolism were studied in spontaneously hypertensive rats of 20 weeks of age. The systolic blood pressure was about 205 mmHg at the start of the experiment, and a slight increase was noted thereafter in the control (vehicle) group. CV-2619, but not Q-10, inhibited the increase in the blood pressure. At 25 weeks of age, cardiac hypertrophy was noted to the same extent in either treated group. Myocardial contents of glycolytic intermediates (glycogen, glucose, pyruvate and lactate) and creatine phosphate (Cr-P), ATP, ADP, and AMP were not significantly influenced by CV-2619 or Q-10 treatment. CV-2619, however, significantly increased the energy charge, an index of myocardial energy state, with higher dose and lowered the lactate/pyruvate ratio with either dose. These results suggest that CV-2619 has a mild antihypertensive effect and improves the myocardial energy state in the hypertrophied heart during the sustained phase of hypertension in SHR rats.     

Inhibition by (−)-Deprenyl of Agonist-Evoked Contractions in Rabbit Aorta

Abstract: The effect of (?)-deprenyl, a relatively selective MAO-B inhibitor, was examined for its ability to inhibit the contractions of rabbit isolated aorta evoked by various agonists and potassium. (?)-Deprenyl (10^?5?3 × 10^?4 M) antagonized the contractions evoked by noradrenaline (10^?8?3 × 10^?4 M); pA₂: 5.10. The antagonism was reversible. It was attenuated by cocaine (3x M); pA₂: 4.38, unchanged by corticosterone (4 × 10^?5 M); pA₂ 4.79 and enhanced by cocaine (3 × 10^?5 M) plus corticosterone (4 × 10^?5 M); pA₂: 5.48. (+)-Deprenyl (10^?6?10^?4 M) did not alter the contractions evoked by noradrenaline (3 × 10^?9?10^?4 M). Clorgyline (10^?5 and 10^?4 M) antagonized the noradrenaline-evoked contractions. Pargyline (10^?4 and 3 × 10^?4 M) had no effect. (?)-Deprenyl (10^?5?3 × 10^?4 M) antagonized the contractions evoked by phenylephrine (10^?8?10^?4 M); pA₂: 5.10. Removal of the endothelium did not alter the antagonism; pA₂: 5.35. (?)-Deprenyl (10^?5?3 × 10^?4 M) antagonized the contractions evoked by either 5-hydroxytryptamine (3 × 10^?8?3 × 10^?4 M); pA₂: 4.61 or by histamine (10^?6?3 × 10^?2 M); pA₂: 4.84. (?)-Deprenyl (3 × 10^?4 M) caused a non-competitive antagonism of the contractions evoked by potassium (1.5-5.5 × 10^?2 M). It is concluded that (?)-deprenyl is a weak inhibitor of postjunctional α-adrenoceptors, 5-hydroxytryptamine (5-HT₂) receptors, and histamine (H₁) receptors.     

On the Role of Cyclic Nucleotides in the Regulation of Cardiac Contractility and Glycolysis During Hypoxia *

Abstract: A possible involvement of cyclic nucleotides (cAMP and cGMP) in the regulation of cardiac contractility and glycolysis during hypoxia was examined in spontaneously beating rat atria. A reduction of the high oxygen saturation (HiOxSa) of the incubation medium from 95–100% to half produced a rapid decline of the amplitude. The deterioration of 50% was seen after 30 sec. of hypoxia. The decline was partly antagonized by noradrenaline (NA, 1×10^?6 M) or hypercalcaemia (5.7×10^?3 M instead of 1.9×10^?3 M). The cAMP level remained unchanged during the first 12 min. of hypoxia, but the cGMP content increased gradually and reached a significantly increased level in 4–8 min. Paradoxically, the production of lactate decreased, after 30 sec. of hypoxia, but accelerated then 2–4 min. after the onset of hypoxia. The depletion of creatine phosphate and ATP stores was initiated after 2 min. of hypoxia. The atrial content of the active forms of phosphofructokinase and lactate dehydrogenase gradually rose during hypoxia. Sodium nitroprusside (SNP, 1×10^?4 M) and NA produced increases in cGMP and cAMP levels, respectively, both in HiOxSa and hypoxia. SNP induced a slight and NA a marked increase in the amplitude in HiOxSa. Verapamil (1×10^?6 M) decreased the contractility, but did not affect the levels of cAMP or cGMP. Both SNP and verapamil decreased the lactate production, but they could not resist the NA-induced increase in the atrial lactate level. Hypercalcaemia increased the amplitude but slightly reduced the lactate production in HiOxSa. ⁴⁵Ca-uptake was reduced to about 35 per cent of control as measured between 5 and 10 min. of hypoxia. It is concluded that the lack of oxygen could have direct and parallel effects on the sarcolemma and on the mitochondria. The former could result in the deterioration of contractility and the latter in the termination of aerobic energy production. Cyclic nucleotides are not involved in either of these phenomena. However, at the low rate of anaerobic glycolysis, e.g. in HiOxSa or at the very early stage of hypoxia, cGMP could inhibit and cAMP accelerate the lactate production.     

The preclinical antipsychotic evaluation of HRP 913, a novel benzisoxazole derivative

HRP 913 {1-[3-(6-fluoro-1,2-benzisoxazole-3-yl)propyl]-4-(2-oxo-1-benzimidazolinyl)} piperidine demonstrated preclinical antipsychotic activity with features that may provide a clinical advantage over current therapy. It was effective in blocking amphetamine stereotypy in rats (ED₅₀ = 0.4 mg/kg, i.p.), amphetamine circling in SN-lesioned rats (ED₅₀ = 0.3 mg/kg, i.p.), apomorphine stereotypy in rats (ED₅₀ = 0.8 mg/kg, i.p.), but not apomorphine circling in SN-lesioned rats (up to 10 mg/kg, i.p.). It also blocked Sidman avoidance in rats (ED₅₀ = 0.17 mg/kg, i.p.) and monkeys (ED₅₀ = 0.2 mg/kg, p.o.) and blocked intracranial self-stimulation in rats (0.09 mg/kg, i.p.). A unique biphasic effect on catalepsy was found. Monkey EPS studies demonstrate a potential for EPS that is lower than some existing clinical standards. HRP 913 displaced ³H-spiroperidol from rat striatal sites (IC₅₀ = 6.0 × 10^?9 M) and inhibited WB-4101 binding (IC₅₀ = 2.6 × 10^?8 M) with only slight effect on QNB binding. HRP 913 does not appear to have marked α-blocking properties in vivo. HRP 913 is a potent dopamine antagonist and is predicted to have less side effects than current therapy.     

Predicting health risk from exposure to trihalomethanes in an Olympic-size indoor swimming pool among elite swimmers and coaches

ABSTRACT

Disinfection by-products (DBP) such as trihalomethanes (THM) are formed when chlorine and bromine interact with natural organic materials in chlorine-treated swimming pools. Epidemiological evidence demonstrated an association between exposure to swimming pool environment and adverse health effects. Therefore, this study aimed to assess carcinogenic and non-carcinogenic risk of long-term exposure of elite swimmers and their coaches. In an Olympic-size indoor chlorinated swimming pool, THM levels were determined in water (21–69 µg/L), in the boundary layer above the water surface (59–397 µg/m³), and in the air surrounding the pool (28–390 µg/m³). These values were used to predict multi-pathway chronic daily intake (CDI), cancer risk (CR) and hazard index (HI). Oral and dermal CDI for swimmers were 2.4 × 10^?6 and 2.0 × 10^?8, respectively. The swimmers’ inhalation CDI (1.9 × 10^?3 mg/kg/day) was estimated to be sixfold higher than levels obtained for coaches (3.3 × 10^?4 mg/kg/day). According to guidelines, the HI was acceptable, but CR exceeded the recommended limit for both, coaches (CR: 5.5 × 10^?7–8.5 × 10^?5; HI: 6.5 × 10^?4–1 × 10^?1) and swimmers (CR: 1.4 × 10^?5–3.6 × 10^?4 HI: 1.6 × 10^?2–4.3 × 10^?1). Our findings provide further support to the need to develop comprehensive guidelines to safeguard the health of individuals involved in elite swimming.     

Nitrosation of quaternary ammonium compounds in vivo in the Wistar rat

1. Animals dosed orally with nitrite (1.5 × 10^?3 mol/kg) and nonyl dimethylbenzylammonium bromide (2.9 × 10^?4 mol/kg) exhibit liver damage within two hours; cetyl trimethylammonium bromide plus nitrite was not significantly hepatotoxic.

2. Both nonyl dimethylbenzyl ammonium bromide and cetyl trimethylammonium bromide were demethylated by rat-liver microsomal preparations; substrate concentrations of 1 mM or more were inhibitory.

3. Bile from rats given i.p. doses of cetyl trimethylammonium bromide, nonyl dimethylbenzylammonium bromide or dodecyl dimethylbenzylammonium bromide contains only metabolites, no unchanged compounds were detected.     

Contribution by bradykinin to the natriuretic response to the angiotensin converting enzyme inhibitor ramiprilat in spontaneously hypertensive rats

Summary It is well documented that angiotensin converting enzyme inhibitors decrease blood pressure, which is associated with natriuresis in humans and certain animal models of hypertension. However, it is not clear whether these beneficial effects are due solely to blockade of angiotensin-II production and/or also involves any contribution by kinins. The present study was performed in Inactin^® (5-ethyl-5-(1-methylpropyl)-2-thio-barbiturate sodium)-anesthetized spontaneously hypertensive rats aged 10–13 wks to examine the relative influence of the angiotensin receptor antagonist losartan (2-n-butyl-4-chloro-5-hydroxymethyl-1- [(2-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl] imidazole potassium salt) and the bradykinin receptor 2 antagonist HOE 140 (D-Arg-[Hyp3, Thi5, D-Tic7, Oic8] bradykinin) on renal and hemodynamic responses to the angiotensin converting enzyme inhibitor ramiprilat. We found that ramiprilat (1 mg/kg, i.v.) caused sustained reduction in mean blood pressure, marked increases in urine output and urinary sodium excretion without alteration in glomerular filtration rate. In a separate group of animals, it was found that losartan (1 mg/kg, i. v.) decreased blood pressure to a similar degree as ramiprilat and the magnitude of blood pressure fall seen following the combined administration of ramiprilat and losartan was similar to that caused by either compound alone. However, the increase in urinary sodium excretion seen following losartan administration was significantly smaller than that following ramiprilat or ramiprilat plus losartan. It was also found that HOE 140 (50 g/kg, i.v.), which did not significantly affect both hemodynamic and renal parameters when administered alone, significantly attenuated the natriuretic and diuretic, but not the antihypertensive effect of ramiprilat. These results indicate that inhibition of angiotensin II formation accounts for the major portion of antihypertensive, diuretic and natriuretic effects of ramiprilat and that the accumulation of kinins contributes significantly to renal but not the acute antihypertensive effects of ramiprilat. Correspondence to: M. F. Lokhandwala at the above address     

Inhibition of superoxide anion production in macrophages by anti-inflammatory drugs.

The inhibition by anti-inflammatory drugs of the production of Superoxide anions (O₂^?) by isolated guinea pig macrophages was studied spectrophotometrically using NADH and lactate dehydrogenase. id₅₀ values were: 4 × 10^?7M (diclophenac sodium), 1 × 10^?6M (oxyphenbutazone), 1 × 10^?5M (indomethacin), 4 × 10^?5M (phenylbutazone), 7 × 10^?5M (mefenamic acid), 8 × 10^?5 M (flufenamic acid), 8 × 10^?5M (colchicine), 3 × 10^?4M (aspirin), 3 × 10^?4M (benzydamine), 10^?3M < (dexamethasone) and 10^?3M < (gold sodium thiomalate). They seemed to block the cell membrane-associated mechanism to produce Superoxide anions, since most of them did not abolish the generation of superoxide anions from the xanthine oxidase plus hypoxanthine system. Cytochalasin B, pyrogallol, ascorbate, NEM, l-epinephrine and chlorpromazine also inhibited, the production of Superoxide anion, but many non anti-inflammatory drugs were ineffective. This technique was evaluated as a screening method in vitro for nonsteroidal anti-inflammatory drugs.