Showing papers in "Pharmacology in 1986"
TL;DR: Acetyltransferase with p-aminobenzoic acid (PABA) as substrate was investigated in the cytosolic fraction of the placenta, liver, adrenals, lungs, kidneys, intestine from human fetuses and the liver, lung, kidneys and intestinal mucosa from adult subjects.
Abstract: Acetyltransferase with p -aminobenzoic acid (PABA) as substrate was investigated in the cytosolic fraction of the placenta, liver, adrenals, lungs, kidneys, intestine from human fetu
127 citations
TL;DR: Results, together with the fact that PmP is biochemically and pharmacologically active, suggest that the metabolite may contribute significantly to the central effects of the parent drug.
Abstract: Buspirone (BP), a newly developed antianxiety agent, forms 1-(2-pyrimidinyl)-piperazine (PmP) during its biotransformation in rats and man. After oral administration of pharmacologically effective dos
115 citations
TL;DR: Simultaneous measurements of intracellular membrane potential and tension developed by coronary smooth muscle precontracted with Ach showed that the smooth muscle relaxation by substance P is accompanied by membrane hyperpolarization, which indicates that substance P and mechanical stimulation act by releasing from the endothelium a humoral factor that produces arterial smooth Muscle relaxation.
Abstract: Mechanical stimulation, substance P and vasoactive intestinal polypeptide (VIP) were found to relax the transversal strip of anterior descending branches of pig coronary arteries precontracted by acetylcholine. The effects of mechanical stimulation and substance P required the presence of intact endothelium, while VIP did not. The effect of VIP did not appear to be mediated by catecholamines. Simultaneous measurements of intracellular membrane potential and tension developed by coronary smooth muscle precontracted with Ach showed that the smooth muscle relaxation by substance P is accompanied by membrane hyperpolarization. In contrast VIP relaxed the same tissue without affecting the membrane potential. In a cascade experiment, the fluid perfused intraluminally in intact segments of coronary arteries was dropped over a de-endothelialized strip which relaxed in response to substance P and mechanical stimulation. This indicates that substance P and mechanical stimulation act by releasing from the endothelium a humoral factor that produces arterial smooth muscle relaxation.
79 citations
TL;DR: Heterogeneity in mast cells from different locations is shown to vary in their histochemical, ultrastructural, cytochemical and functional properties.
Abstract: Mast cells from different locations are shown to vary in their histochemical, ultrastructural, cytochemical and functional properties The clinical consequences of this heterogeneity and possible reasons for its origin are discussed
77 citations
TL;DR: The results suggest that the polyol pathway is implicated in diabetic-induced proteinuria and inhibition of aldose reductase may represent a therapeutic approach for management of diabetic nephropathy.
Abstract: Proteinuria was diminished by concomitant oral administration of sorbinil, an aldose reductase inhibitor to streptozotocin-induced diabetic rats. Animals were placed in one of three groups: control, d
74 citations
TL;DR: It is concluded that gastric wall mucus depletion is likely to play an important role in stress ulcer formation; the antiulcer action of verapamil could partly be due to the preservation of mucus.
Abstract: The effects of verapamil on gastric wall mucus and ulceration were studied in rats which were restrained and exposed to 4 degrees C (stress). Stress for 2 h significantly depleted stomach wall mucus and produced marked gastric glandular ulcers. Verapamil pretreatment (2, 4, 8 or 16 mg/kg), injected intraperitoneally 30 min before experimentation, significantly prevented stress-induced mucus depletion and gastric ulceration; however, it did not itself influence stomach wall mucus levels in nonstressed animals. Intragastric administration of carbenoxolone (100 or 200 mg/kg), also given 30 min before stress, exhibited similar actions as verapamil. A 15% solution of N-acetylcysteine (10 ml/kg), given orally, strongly decreased the mucus content in both nonstress and stress conditions; it induced ulcers in nonstressed rats, and worsened stress ulceration. These effects were not reversed by verapamil pretreatment. The influence of multiple-dose pretreatment with verapamil or carbenoxolone on mucus content and ulceration in the gastric glandular mucosa during stress is also discussed. It is concluded that gastric wall mucus depletion is likely to play an important role in stress ulcer formation; the antiulcer action of verapamil could partly be due to the preservation of mucus.
73 citations
TL;DR: Among the four tachykinins, a significantly dose-dependent histamine release from rat mast cells and a flare response in human skin was observed only with substance P, indicating the possible implication of histamine in this response and a dissociation of effects and possibly of receptors.
Abstract: Substance P and two recently identified neurokinins, substance K and neuromedin K as well as the nonmammalian tachykinin kassinin were compared for (a) histamine-releasing abilities from rat mast cells, (b) plasma extravasation effects on rat skin, and (c) wheal and flare responses on human skin. Among the four tachykinins, a significantly dose-dependent histamine release from rat mast cells and a flare response in human skin was observed only with substance P, indicating the possible implication of histamine in this response. On the other hand, the four peptides were similarly active on the wheal response (plasma extravasation produced by increased permeability of capillaries and venules) in human skin and on the plasma extravasation in the rat skin, suggesting a dissociation of effects and possibly of receptors.
72 citations
TL;DR: Considering that substance P and related peptides are active only at very high concentrations, it cannot be affirmed that these agents activate specific receptors, since substance K is inactive.
Abstract: Chemotactic and chemoluminescent activities of substance P, substance K, kassinin and the substance P fragments SP 4-11, SP 7-11, SP 1-4 have been investigated in order to identify the minimum active
72 citations
TL;DR: It is concluded that the antiulcer mechanisms of zinc sulphate and PGE2 may be different, and protection by the former drug could be due partly to preservation of mucus adhering to the gastric mucosa.
Abstract: The aetiology of ethanol-induced gastric ulceration, and its interaction with zinc, were studied in rats. Oral administration of ethanol (40, 50 or 80%) to conscious rats reduced the stomach mucus content and increased gastric ulcer formation in a concentration-dependent manner. Histological examination indicated that mucus, both on the surface and within the epithelium, was depleted because of epithelium being shed from the gastric mucosa. Zinc sulphate abolished mucus loss and ulcer formation in the ethanol-treated animals. Using an ex-vivo gastric chamber preparation in anaesthetised animals, it was found that an ethanol (50%)-HCl (100 mmol/l) solution produced severe glandular haemorrhagic ulceration, elevated Na+, K+ and protein levels in the luminal solution, and reduced the H+ content in this fluid. Zinc sulphate pretreatment dose-dependently prevented all these changes. On the other hand, prostaglandin E2 (PGE2) administration only antagonised ethanol ulceration and H+ loss from the chamber; it did not significantly influence the Na+ and K+ fluxes and protein leakage into the luminal solution. It is concluded that the antiulcer mechanisms of zinc sulphate and PGE2 may be different. Protection by the former drug could be due partly to preservation of mucus adhering to the gastric mucosa. The possibility of the membrane-stabilising action of zinc contributing to the observed effects is also discussed.
50 citations
TL;DR: The potency of drugs to inhibit irreversibly sickled cell formation was related to the potency of inhibition of calmodulin-activated phosphodiesterase.
Abstract: Nitrendipine, nifedipine and verapamil inhibit the in vitro formation of irreversibly sickled cells. Using a method of forming both dehydrated cells and irreversibly sickled cells in vitro by repeated cycles of sickling and unsickling, the effects of several drugs in inhibiting the formation of these cells were studied. Drugs known as Ca2+ channel antagonists, such as nitrendipine, nifedipine and verapamil were found to inhibit these reactions. Other types of calcium channel blockers, such as lanthanum and zinc, did not inhibit the formation of these cells. The potency of drugs to inhibit irreversibly sickled cell formation was related to the potency of inhibition of calmodulin-activated phosphodiesterase.
44 citations
TL;DR: Results suggest that either the maintenance or the strengthening or even the replacement of the gastric nonwettable hydrophobic lining between the damaging agent and the Gastric mucosa may contribute to the cytoprotective mechanism of certain compounds.
Abstract: The role of the gastric nonwettable hydrophobic layer (surfactant) was investigated in the mucosal protection against the damage induced by ethanol in the rat. Although aluminium hydroxide inhibited t
TL;DR: The present findings suggest that histamine-induced relaxation of rat mesenteric arteries is dependent upon endothelial cell processes which are enhanced in arteries from STZ-diabetic rats.
Abstract: Diabetes mellitus is known to produce alterations in vascular reactivity. In the present study we have examined the effects of short-term diabetes on histamine-induced relaxation of isolated mesenteric arteries, and the role of the endothelial cell layer in this response. Removal of the endothelium completely abolished the histamine relaxation effect in both diabetic and age-matched control rats. In contrast, vessels isolated from streptozotocin-diabetic rats were supersensitive to histamine, and this relaxation was mediated only through the H1-receptors. The present findings suggest that histamine-induced relaxation of rat mesenteric arteries is dependent upon endothelial cell processes which are enhanced in arteries from STZ-diabetic rats.
TL;DR: Tifluadom, a benzodiazepine with purported opioid receptor-related analgesic properties, was studied in regard to its acute effects on power spectra of the EEG to demonstrate vigilance changes and somatosensory-evoked potentials were derived to evaluate its effect on the propagation of impulses in sensory nerve fibers.
Abstract: Tifluadom, a benzodiazepine with purported opioid receptor-related analgesic properties, was studied in regard to its acute effects on power spectra of the EEG to demonstrate vigilance changes. Additionally, somatosensory-evoked potentials (SEP) were derived to evaluate its effect on the propagation of impulses in sensory nerve fibers. In order to demonstrate stereospecificity, the two enantiomers of tifluadom (KC-5911 and KC-6128) were given in graded doses (20, 40, 80, 160 µg/kg i.v.) to awake, unrestrained and trained dogs at 10-min intervals. KC-6128, but not its optical counterpart KC-5911, induced synchronization of the EEG at 20 µg/kg with an increase of power (pW) in the delta (1–4 Hz; + 300%), theta (4–8 Hz; +450%), and alpha (8–13 Hz +90%) bands. This was accompanied by a reduction of power in the fast beta domain (13–30 Hz; –95%). Vigilance changes were reflected in the beta/delta quotient which dropped from 3.7 (control) to 0.8 (20 µg/kg) and to 0.3 (40 µg/kg). A further increase in the dose resulted in saturation. At the highest dose (160 µg/kg) there was an additional reduction of the beta/delta quotient to 0.1. In order to unmask the receptor population, possibly mediating the observed changes, a benzodiazepine antagonist and opioid antagonists were given. Ro 15-1788 (240 µg/kg) had no effect and naloxone (20 µg/kg) induced a short term (5 min) arousal. Only the kappa antagonist Mr 2266 (20 µg/kg) induced a reversal of the beta/delta quotient back to 5.5. KC-5911 induced an insignificant drop in the beta/delta quotient which was reversed by Ro 15-1788. In somatosensory-evoked potentials, only KC-6128 induced a dose-related suppression of amplitude and an increase of latency of the late N100 potential by -76 and +36%, which peaked at 160 und 80 µg/kg, respectively. Mr 2266 reversed the suppression of amplitude and the increase of latency back to control. Thus, slowing of EEG activity, increase of latency and suppression of amplitude of the N100peak in the SEP induced by KC-6128 seems to be mediated by the opioid kappa receptor. KC-5911-induced EEG changes are related to benzodiazepine receptor interaction.
TL;DR: It is concluded that activation of muscarinic receptors in the pancreatic beta-cells results in mobilization of calcium from more than one intracellular pool.
Abstract: Exposure to carbachol resulted in a biphasic stimulation of 45Ca efflux when beta-cell-rich pancreatic islets from ob/ob mice were perifused with a Ca2+-deficient medium. The pattern of stimulated 45Ca efflux was markedly modified by glucose. Whereas the initial carbachol-stimulated phase was conditional on previous exposure to glucose, the subsequent phase was completely suppressed by 20 mmol/l of the sugar. The stimulatory could be clearly separated also on the basis of a Na+ dependence. Removal of extracellular Na+ resulted in a disappearance of the second phase, but it was still possible to induce a prominent initial peak if depletion of intracellular K+ was prevented when Na+ was omitted. It is concluded that activation of muscarinic receptors in the pancreatic beta-cells results in mobilization of calcium from more than one intracellular pool. Whereas the second phase of stimulated efflux can be explained in terms of an increased entry of Na+ into the beta-cells, the initial stimulation may be due to receptor-mediated breakdown of polyphosphoinositides.
TL;DR: A self-limiting abstinence syndrome was observed in all dogs, consisting of behavioral alterations (listlessness, wet dog shakes, dorsal recumbency), tremor, a severe clonic-tonic seizure in 1 case, hyperthermia, and weight loss.
Abstract: Six dogs were, under constant environmental conditions, treated for 7 weeks with clonazepam (0.5 mg/kg b.i.d. orally). Already after 1 week of treatment, slight symptoms of withdrawal could be elicite
TL;DR: Results suggest that reduced beta-adrenergic responsiveness in estrogen-treated rats may have resulted from down-regulation of beta- adrenoceptors associated with increased secretion of catecholamines induced by chronic estrogen treatment.
Abstract: Chronic treatment with an estrogenic agent is known to reduce the responsiveness to β-adrenergic stimulation in rats.To assess the possibility that endogenously produced catecholamines may play a role
TL;DR: There was a marked and significant worsening of sleep above baseline levels (rebound insomnia) on the third night as well as significant increases in tension and anxiety the next day following drug withdrawal.
Abstract: Lorazepam, an anxiolytic drug, was evaluated in a 2-mg dose using a 16-night protocol including 7 nights of drug trial. Initially and with continued use the drug was moderately effective in inducing and maintaining sleep. Side effects included episodes of memory impairment and confusion in 2 subjects and group mean increases in daytime anxiety and tension with continued drug use. Following drug withdrawal, there was a marked and significant worsening of sleep above baseline levels (rebound insomnia) on the third night as well as significant increases in tension and anxiety the next day. The peak degree of withdrawal sleep disturbance was several times the peak degree of sleep improvement with drug administration.
TL;DR: A two-compartment open model was found to describe best the experimental data and galanthamine hydrobromide (Nivalin) pharmacokinetics was carried out on male Wistar rats following single intravenous and oral administration.
Abstract: A study on galanthamine hydrobromide (Nivalin®) pharmacokinetics was carried out on male Wistar rats following single intravenous and oral administration. Plasma samples were collected after decapitat
TL;DR: It is suggested that tizanidine-mediated gastric mucosal protection may prevent gastric ulcers induced by anti-inflammatory agents.
Abstract: The effects of a novel imidazoline derivative (tizanidine) on experimental ulcers and glycoproteins in the gastric mucosa and juice of rats were examined and compared with that of clonidine. Tizanidin
TL;DR: A role for histamine H2 receptors in the secretion of PRL and T4 is suggested after a significant rise in post-TRH T4 after cimetidine and ranitidine administration is suggested.
Abstract: Cimetidine (400 mg bd), ranitidine (150 mg bd) and placebo were administered for 1 week to 6 healthy male volunteers in a randomized double-blind cross-over fashion Hormonal concentrations before and after a TRH test were assessed before and after each treatment A spontaneous decrease in the hormonal response to TRH was observed after placebo treatment Both cimetidine and ranitidine induced a significant increase in basal prolactin (PRL) values Neither TSH nor T3 were modified by cimetidine or by ranitidine The basal concentration of reverse T3 was increased during cimetidine treatment There was a significant rise in post-TRH T4 after cimetidine and ranitidine administration These results suggest a role for histamine H2 receptors in the secretion of PRL and T4 Moreover, cimetidine affects the hepatic metabolism of thyroid hormones
TL;DR: Transport activity of the Na+/K+-ATPase was studied in rat and rabbit aorta under basal and agonist-stimulated conditions.
Abstract: Transport activity of the Na+/K+-ATPase was studied in rat and rabbit aorta under basal and agonist-stimulated conditions. Basal ouabain-sensitive 86Rb+ upt
TL;DR: 3H-muscimol was bound by sections of ovary in a manner consistent with the existence of specific GABA receptors, and was reversible, saturable, of high affinity, and inhibited by GABA receptor interfering drugs.
Abstract: The distribution of 3H-muscimol within guinea pig ovary was studied using combined radioreceptor binding studies and histoautoradiographic technique performed on frozen sections of ovary mounted on microscope slides. 3H-muscimol was bound by sections of ovary in a manner consistent with the existence of specific GABA receptors. The binding was reversible, saturable, of high affinity (KD was 38 ± 6 nmol/l and Bmax was about 378 ± 61 fmol/mg protein, and inhibited by GABA receptor interfering drugs. 3H-muscimol binding sites were found in the blood vessel wall, in the follicle and in the oocytes. The number of oocyte and follicular receptors gradually decreases during the development of ovarian follicles.
TL;DR: The sensitivity of the aortic smooth muscle to potassium chloride, phenylephrine and serotonin increased with increasing preload; whereas the calcium chloride concentration-response curves of K+-depolarized strips were unaffected by preload.
Abstract: Concentration-response curves to potassium chloride, phenylephrine, serotonin and calcium chloride were obtained from rat aortic strips subjected to preloads of 0.75, 1.5 or 3.0 g. The sensitivity of the aortic smooth muscle to potassium chloride, phenylephrine and serotonin increased with increasing preload; whereas the calcium chloride concentration-response curves of K+-depolarized strips were unaffected by preload. These results demonstrate that the sensitivity of rat aortic smooth muscle to many vasoactive agents is a function of preload and also indicate that an alteration in the influx of external Ca2+ is not sufficient to explain the effect of preload on sensitivity.
TL;DR: Data point to an age-related decrease in sulfation and increase in glucuronidation of acetaminophen and further emphasize that the major conjugated metabolites are excreted by renal transport processes that operate under separate control.
Abstract: The effects of aging on acetaminophen metabolism and elimination in male Fischer 344 rats were examined after intravenous injection of 300 mg/kg. Age as a variable had only a small effect on the total clearance of acetaminophen. However, the fraction of administered dose recovered from urine as acetaminophen sulfate and the partial clearance to acetaminophen sulfate decreased while the fraction recovered as acetaminophen glucuronide and the partial clearance to acetaminophen glucuronide increased with increasing age. Renal clearances of acetaminophen and acetaminophen glucuronide were unchanged while that of acetaminophen sulfate decreased. These data point to an age-related decrease in sulfation and increase in glucuronidation of acetaminophen and further emphasize that the major conjugated metabolites are excreted by renal transport processes that operate under separate control. Moreover, they raise the possibility that advancing age may be accompanied by a general decline in processes that govern sulfate conjugate formation and elimination.
TL;DR: Suggestions have been made for rescheduling the dosage of the drug in PEM based on observations of single-dose concentration profiles after 10 mg/kg of carbamazepine, which showed lower plasma peak levels.
Abstract: The pharmacokinetics of carbamazepine was studied in 6 children with protein energy malnutrition (PEM) and in 6 healthy children. Plasma carbamazepine was estimated by enzyme multiplied immunoassay technique. Single-dose concentration profiles after 10 mg/kg of the drug showed lower plasma peak levels. The systemic availability (AUC 0–48 h) of the drug in PEM was also reduced. Based on these observations, suggestions have been made for rescheduling the dosage of the drug in PEM.
TL;DR: GTN and DZ appear to interfere with different components of Ca++ entry through slow channels and intracellular Ca++ release, whereas DZ primarily blocks the influx of Ca ++ from the extracellular space, whereas GTN appears to act by inhibiting Ca++ movements at an intrace cellular site.
Abstract: The inhibitory effects of glycerol trinitrate (GTN) and diltiazem (DZ) on contractions produced by submaximal concentrations (ED 75) of norepinephrine (NE) and potassium chloride (KCl) were studied in isolated canine renal artery rings. In addition, the site of action of these compounds in blocking NE-induced contractions was determined by using zero calcium (Ca++) buffer + 2 mM EGTA (calcium-free solution). GTN was more potent than DZ in relaxing KCl-induced contractions (potential-operated calcium channels) as well as NE-induced contractions (receptor-operated calcium channels). In a Ca++-free buffer, the response to NE was reduced to approximately 20-25% of the response in normal Ca++ (1.25 mM) buffer. GTN (1 X 10(-9)-1 X 10(-4) M) produced a marked inhibition of NE-induced contractions in Ca++-free buffer, whereas DZ had no inhibitory effect even at very high concentrations (1 X 10(-4) M). Thus, GTN and DZ appear to interfere with different components of Ca++ entry through slow channels and intracellular Ca++ release. DZ primarily blocks the influx of Ca++ from the extracellular space, whereas GTN appears to act by inhibiting Ca++ movements at an intracellular site.
TL;DR: The effect of morphine, fentanyl, pethidine and pentazocine was studied in gerbils against air blast-induced seizures to point to a role of other receptors (or processes) besides the mu-receptor for this drug.
Abstract: The effect of morphine, fentanyl, pethidine and pentazocine was studied in gerbils against air blast-induced seizures. Major, generalized seizures were suppressed by morphine (ED50 = 4.0 mg
TL;DR: The results indicated that Bay K 8644 and cholinergic stimuli are strong activators of the duodenal motility in vitro and suggested a novel site of action of this compound in the gastrointestinal muscle.
Abstract: The contractile effect of the dihydropyridine analogue Bay K 8644, recently described as a Ca2+-agonist, has been evaluated in the rat isolated duodenal muscle in comparison with that of ac
TL;DR: The Tyr-induced changes observed in these studies include a chronic increase in free dopamine, and a transient decrease in norepinephrine, excretion, which are significantly prolonged while alpha 2-adrenoceptor number was reduced in rats receiving Tyr.
Abstract: The antihypertensive effect of chronic administration of L-tyrosine (Tyr) was investigated in a two-part study. In the first experiment, adult male Sprague-Dawley rats were assigned to 1 of 4 treatmen
TL;DR: There were genetic differences in brain regional levels of NE, dopamine (DA) and serotonin (5-HT) between DR and DS rats and the cardiovascular implications of these genetic and salt-related changes in peripheral and central nervous system monoamines were discussed.
Abstract: Monoamine and metabolite levels were determined in brain regions and in the kidney, heart and adrenals taken from Dahl salt-sensitive (DS) and salt-resistant (DR) rats on either normal (NS) or high (HS) (8.5% NaCl) salt diets. The HS diet significantly (p