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Biomedical subjects

A Giachetti

Publications and source records attributed to A Giachetti.

At least 109 records · Page 6Linked to original sources
PubMed1987

N-butyl hyoscine exerts local spasmolytic effect in the small and large bowel of the conscious dog.

The spasmolytic activity of N-Butyl Hyoscine (NBH) (1) has been investigated in conscious dogs provided with ileal or colonic Thiry fistulas in which motility was stimulated by intraluminal distension. In ileal motility experiments, phasic motility index (PMI), intestinal tonus, contraction frequency and heart rate were monitored. Intravenous administration of NBH (10 to 100 micrograms/kg) depressed PMI (ED50 35.1 micrograms/kg) and the other motility parameters. Heart rate increases were observed at 100 micrograms/kg. Application of NBH directly into the fistula (300 to 3000 micrograms/kg) caused a long-lasting, potent inhibition (31-72%) of PMI; tonus and contraction frequency were only slightly affected, while heart rate was not altered. When NBH was administered into an ileal fistula adjacent to the one from which motility was recorded, changes of PMI and other parameters were observed only after a massive dose of the drug (10000 micrograms/kg). In colonic fistula experiments, intraluminal NBH administration (300 to 3000 micrograms/kg) depressed colonic motility (39-59%), without affecting heart rate. It is concluded that NBH present in the intestine, although poorly absorbed, exerts local spasmolytic action.

Animals↗
PubMed1987

Spontaneous and conditioned behavior of Wistar and Long Evans rats.

Spontaneous behavior (locomotion, feeding, drinking, and exploration in a two box apparatus) as well as conditioned behavior (passive and active avoidance responding, and freezing in the light-dark box apparatus) were studied in naive male Wistar and Long Evans rats. Concerning spontaneous behavior, Long Evans rats were more active during both light and dark periods, and showed better exploratory performance than Wistar rats. Concerning conditioned behavior, Long Evans rats acquired and retained better active and passive avoidance responses, and exhibited longer initial freezing than Wistar rats in the range of 0.6-1.4 mA footshocks. The results better define the important behavioral differences existing between the two strains, Long Evans rats showing consistently a higher level of alertness and a better conditioned performance.

Animals↗
PubMed1986

Cardioselective profile of AF-DX 116, a muscarine M2 receptor antagonist.

AF-DX 116 (see chemical name below) is a competitive antagonist of muscarine receptors in peripheral organs. In contrast to pirenzepine, its behaviour in functional experiments indicates selectivity for the M2 muscarinic subtype. In pithed rats AF-DX 116 inhibits vagally-induced bradycardia, an M2 response, (ED50 32 micrograms/kg i.v.) in preference to the M1-mediated pressor response to McN-A-343 (ED50 211 micrograms/kg i.v.). AF-DX 116 further discriminates among M2 receptors, showing a high affinity for the cardiac muscarine receptors. In isolated preparations, AF-DX 116 has a tenfold higher affinity for the muscarine receptors of the heart (pA2 7.33) than for those in smooth muscles (pA2 6.39-6.44). The same profile appears from animal studies, where the compound is a more potent antagonist of either endogenously or exogenously activated cardiac muscarine responses as compared to vascular, smooth muscle or secretory responses. In general, the ratios of potencies (ED50) observed in cardiac vs. other muscarine mediated functions ranged between 30 and 50. Atropine showed no discrimination, inhibiting all muscarine responses in the same range of doses. In the conscious dog intravenous AF-DX 116 increased basal heart rate, and completely reversed the reflex bradycardia induced by clonidine. Tachycardia was dose-related (ED50 79 micrograms/kg i.v.), and occurred independently of background sympathetic tone. AF-DX 116 clearly distinguishes between M1- and M2-mediated responses; it also emphasizes the long-recognized heterogeneity among the peripheral M2 subtypes. AF-DX 116, for its pronounced cardioselectivity, may have a therapeutic potential in the treatment of sinus bradycardia.

Animals↗
PubMed1986

Effect of pirenzepine and PGE2 on taurocholic acid-induced gastric lesions.

Cytoprotective activity of Pirenzepine (PZ) and Prostaglandin E2 (PGE2) was investigated in the gastric damage induced by taurocholic acid (TA) in the rat. Gastric mucosal potential difference (PD) and gross mucosal erosions were measured. Intravenous PZ (18 mg/kg) and PGE2 (5 micrograms/kg) prevented both the sharp decrease of PD and the gastric lesions caused by intragastric TA (40 mM). When TA administration preceeded drug treatment, both compounds reversed the PD fall but only PZ was able to restore gross mucosal integrity. It is thought that TA causes gastric damage by producing back-diffusion of H+ ions across the mucosal layer. It is speculated that antimuscarinic, such as PZ, might reduce gastric damage either by preventing, at the submucosal level, the spreading of cytolesive process triggered by H+ retro-diffusion and/or by inhibition of acid secretion in the depth of the gastric glands.

Animals↗
PubMed1986

Some factors influencing conditioned and spontaneous behavior of rats in the light-dark box test.

Step-through and exit latencies in the light-dark box test were used to examine the effects of unconditioned exploration, the physical characteristics of the apparatus and detention on passive and active avoidance. Experiment 1, in which the subjects (Ss) received inescapable shocks in the dark chamber, shows that omission of the free exploration of the apparatus does not significantly affect acquisition and retention of either of the learned responses. Further, passive avoidance, compared with active avoidance is, by far, the better consolidated response. Experiment 2, which is the reverse of Experiment 1, (the dark chamber becomes the safe box, and the punishments are administered in the light chamber) emphasizes the role played by the physical characteristics of the two chambers of the apparatus. This role is shown by the improvement of the active avoidance response. Experiment 3 confirms the importance of detention in influencing the behavior of conditioned and control Ss. These results underscore the basic differences of active and passive avoidance responses.

Animals↗
PubMed1986

Binding and functional profiles of the selective M1 muscarinic receptor antagonists trihexyphenidyl and dicyclomine.

The selectivity profiles of the muscarinic receptor antagonists dicyclomine and trihexyphenidyl have been examined in binding and functional studies and compared with those of pirenzepine and atropine. Dicyclomine, trihexyphenidyl and pirenzepine demonstrated the highest affinity for the M1 muscarinic receptor subtype as revealed in competition experiments against [3H]-pirenzepine labelling of cortical membranes. Their affinity values lay in a narrow range (3.7-14 nM) approaching that of atropine (1.6 nM). Competition experiments against [3H]-N-methylscopolamine in cardiac and glandular (salivary) membranes revealed differences between the drugs examined. Dicyclomine, trihexyphenidyl and pirenzepine displayed low affinity for the cardiac and intermediate affinity for the glandular receptors. Thus, the drugs appeared to discriminate between the M1 (cortical) and the peripheral muscarinic subtypes (cardiac and glandular). However, atropine displayed similar affinities for either subtype with IC50s varying only slightly (1.6-4.6 nM). The rank order of selectivity was: pirenzepine greater than dicyclomine greater than trihexyphenidyl greater than atropine. Mirroring the binding data, pirenzepine, dicyclomine and trihexyphenidyl showed a tenfold greater ability at inhibiting M1-receptor mediated ganglionic responses (McN A-343 pressor effect in pithed rats and nictitating membrane contraction in cats) than at inhibiting peripheral muscarinic responses in the heart and cardiovascular smooth muscle (vagal bradycardia in rats and cats and vagally-induced vasodilatation in cats). The muscarinic antagonists so far examined can be categorized into two groups. Trihexyphenidyl, dicyclomine and pirenzepine, included in one group, are characterized by a higher affinity for the neuronal (M1) muscarinic receptor, hence they antagonize functional responses mediated by the M1 subtype. Atropine, a member of the other group, shows essentially no selectivity. 6 Differentiation of M1 and peripheral muscarinic receptor subtypes appears to be a property not confined to tricyclics such as pirenzepine but shared by diverse chemical structures. Both trihexyphenidyl and dicyclomine appear to be useful pharmacological tools in the classification of muscarinic receptor subtypes.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed1985

Cholinergic control of gastric acid secretion.

In the perfused stomach preparation of the anaesthetized rat the cholinergic agonists acetylcholine (ACh) and bethanechol stimulated gastric acid secretion. Both agonists produced similar maximal acid output (70 mumols/15 min) when infused intravenously. However, bethanechol was more potent, eliciting half maximal stimulation at 1.98 mumols/kg/h, while the corresponding dose of ACh was 10.95 mumols/kg/h. Secretory responses to either agonist were antagonized in a dose related fashion by blockade of muscarinic receptors with atropine. In contrast, inhibition of nicotinic receptors with hexamethonium produced a striking potentiation of ACh stimulated secretion whilst the bethanechol elicited secretion remained unaffected. In the presence of full nicotinic receptor blockade the ACh response curve was shifted to the left sixfold, half maximal stimulation being produced at 1.79 mumols/kg/h. Cimetidine partially inhibited the secretory responses elicited by either ACh or bethanechol while blockade of adrenoceptors (alpha and beta) did not affect acid output induced by cholinergic agonists. Secretion elicited by ACh is interpreted as being the composite effect of pro-secretory action and an inhibitory mechanism due to the activation of nicotinic receptors. Hexamethonium, through nicotinic receptor blockade, inhibits the restricting mechanism and thus reveals the full stimulatory action of ACh.

Acetylcholine↗
PubMed1985

Evaluation of novel compounds interacting with H2-histamine receptors: effect on histamine-sensitive adenylate cyclase activity in guinea-pig gastric mucosa.

The activity of a number of compounds belonging to the novel class of N-imidazolylphenyl-N'-alkyl-formamidines on histamine-sensitive adenylate cyclase was evaluated. All substances inhibited histamine-dependent adenylate cyclase activation. The compounds which were investigated in a wider concentration range, i.e. DA 4360, DA 4577, and DA 4626, behaved as simple competitive antagonists, yielding apparent KB values comparable with those estimated in conventional H2-receptor assays. These results provide further evidence for the highly selective H2-receptor antagonism of these new molecules, and confirm the suitability of the histamine-stimulated adenylate cyclase assay in guinea-pig gastric cells as a functionally reduced system for the study of H2 antagonists.

Adenylyl Cyclase Inhibitors↗
PubMed1985

Pharmacological profile of mifentidine: a novel H2-receptor antagonist.

Mifentidine, a representative compound of a novel class of H2-antagonists, has been investigated for its ability to interact with H2-receptors and to inhibit gastric acid secretion. Affinity estimates (KB) of mifentidine obtained from in vitro studies on cardiac and gastric mucosal histamine (H2) receptors were in the 20-50 nM range. Mifentidine appeared to be endowed with strong anti-secretory properties against histamine-stimulated secretion in the anaesthetized rat and in the conscious dog. Distinct features of mifentidine were considerable bioavailability and duration of anti-secretory effect.

Animals↗
PubMed1985

Pharmacology of mifentidine, a novel H2-receptor antagonist.

N1-[(4-Imidazolyl)-phenyl]-N2-isopropylformamidine (mifentidine, DA 4577 is a potent and selective H2 antagonist, representative of a new class of compounds, the imidazolylphenyl-formamidines, characterized by a semi-rigid structural conformation. Mifentidine appeared to be a specific and competitive antagonist of several histamine-mediated responses. Thus, in isolated guinea pig atria and ventricles it antagonized histamine chronotropic and dimaprit inotropic effects in a competitive manner providing affinity estimates (pA2) of 7.66 and 7.74, respectively. Mifentidine exerted potent antisecretory effects in: the isolated mouse stomach where it antagonized the acid promoting activity of histamine (EC50 3.28 mumol/l) but not that of bethanechol or db-cAMP (adenosine 3',5'-monophosphate); the lumen perfused stomach of the anaesthetized rat, inhibiting histamine (ED50 0.1 mumol/kg i.v.) and pentagastrin (ED50 0.2 mumol/kg i.v.) stimulated secretion; the pylorus ligated rat (ED50 1.35 mumol/kg i.v.); the gastric fistula dog, reducing the secretagogue effect of pentagastrin (ED50 96 nmol/kg i.v.); the conscious dog equipped with the Heidenhain pouch, where it was effective both following intravenous (ED50 119.7 nmol/kg) and oral administration (ED50 323.8 nmol/kg) in antagonizing histamine action. Mifentidine antisecretory effect, examined in the dog, appeared to last for a significantly longer time than that of ranitidine. Mifentidine was free of cardiovascular effects (on aortic blood pressure and heart rate) when administered repeatedly to the conscious dog at doses far above those needed to suppress acid secretion.

Animals↗
PubMed1985

Mifentidine: evaluation of antiandrogen effects and kidney function studies.

Among a number of investigations aimed at evaluating the safety profile of a new antihistamine (H2), N1-[(4-imidazolyl)-phenyl]-N2-isopropyl-formamidine (mifentidine), its effects on male accessory sexual organs and on kidney function were studied in greater detail because of the known propensity of H2-antagonists to cause antiandrogenic activity and to alter renal function. Mifentidine (190 and 380 mg/kg p.o.) was compared to cimetidine (475 and 950 mg/kg p.o.) for its ability to affect growth of seminal vesicles and prostate of immature castrated rats treated either with testosterone (TP) or 5-alpha-dihydrotestosterone (DHT). Lower doses of mifentidine were investigated because, in terms of H2-antagonistic activity, it was shown to be several times (15 to 30) as potent as cimetidine. Cimetidine at the highest dose (950 mg/kg) reduced prostate growth sustained by TP, and the DHT-promoted growth of seminal vesicles and prostate. Mifentidine had no effect on hormone promoted growth of male accessory sexual organs. Renal function studies after repeated (7 days) administration of mifentidine (150 and 600 mg/kg p.o.) and cimetidine (1500 mg/kg p.o.) revealed a significant increase of the excreted fraction of filtered sodium (FeNa) and potassium (FeK) only after cimetidine, indicating altered tubular reabsorption. Creatinine and urea clearances were unchanged by either drug treatment. Thus mifentidine appears to be devoid of antiandrogenic activity and renal effects.

Androgen Antagonists↗
PubMed1985

Cimetropium: characterization of antimuscarinic and spasmolytic properties.

Cimetropium displaced 3H-NMS binding from membranes derived from gastrointestinal smooth muscle. The affinity of cimetropium for intestinal muscarinic receptors was in the range 70-100 nM. The competitive antagonism of cimetropium was demonstrated in guinea-pig ileum and taenia coli stimulated by bethanechol. Comparing pA2 values, cimetropium (8.19 and 7.91, resp.) was 0.3 times as potent as atropine (8.52 and 8.41, resp.). Cimetropium displayed strong inhibitory effects towards BaCl2 and 5-hydroxytryptamine induced contractions of the guinea-pig ileum. The compound was devoid of antihistaminic or Ca++ channel blocking activity. A binding study performed in vivo confirmed the ability of i.v. cimetropium to displace 3H-N-methylscopolamine binding from muscarinic receptors in peripheral organs. In addition, when injected into ileal loops, cimetropium displaced 3H-NMS binding solely from the surrounding tissue of the loop, indicating a topical effect of the compound.

Animals↗
PubMed1985

Active and passive avoidance learning in homozygous D.I. Brattleboro rats.

In homozygous D.I. rats and in Long-Evans controls the contemporaneous evolution of learning and retention of active and passive avoidance responses was studied by means of the light-dark box test. Passive avoidance performance of homozygous D.I. rats was almost equal to that of control subjects, while their active avoidance performance showed a significant deficit. Also, in homozygous D.I. rats the duration of the first freezing after being placed in the apparatus was consistently longer than in control Ss. The longer duration of this inhibitory behavior has been taken as an indication of a diminished ability of homozygous D.I. rats to respond to stress. The possible role of this diminished response to stress in determining the active avoidance deficit is discussed.

Animals↗
PubMed1984

Passive and active avoidance behavior in the light-dark box test.

The temporal evolution of passive and active avoidance behaviors has been followed in rats, using the light-dark box test, by measuring step-through and exit latencies. The employed schedule consisted of three 7 day periods (free exploration, reinforced learning, forced extinction-retention). The data show clearly that the two learned behaviors are both rapidly established and exhibit significant differences only during extinction, active avoidance apparently depending on close temporal reinforcement. The diverse role of several behavioral and neurological mechanisms is hypothesized.

Animals↗
PubMed1984

(Imidazolylphenyl)formamidines. A structurally novel class of potent histamine H2 receptor antagonists.

Structure-activity considerations of N alpha-guanylhistamine, the first compound found with detectable H2-antagonist activity, led to the synthesis of a series of conformationally rigid guanylhistamine analogues, namely, (imidazolylphenyl)guanidines, imidazolylbenzamidines, and (imidazolylphenyl)formamidines. It was found that in the guanidine and benzamidine classes, the meta-substituted derivatives (3, 4, 7, and 8) possessed H2-antagonist activity, whereas in the class of formamidines, only the para-substituted derivative 10 was found active. A subsequent increase in the size of the substituent at the formamidino group of 10 led to compounds (15-20) of high H2-antagonist affinity, which was related to the gastric antisecretory effect. Members of this structurally novel class of H2 antagonists were 20- to 50-fold more potent than cimetidine both "in vitro" and "in vivo". Structure-activity relationships are discussed in terms of ionization properties, partitioning behavior, conformational aspects of the selected compound 17, and of possible modes of interaction with the histamine H2 receptor. It was found that the formamidine moiety was an important structural feature and that H2-antagonist activity requires correct steric and electronic properties. Compound 17 (DA 4577), owing to its pharmacological profile and demonstrated safety in animals, was selected to be clinically investigated.

Amidines↗
PubMed1984

Arbitrary time unit counts as a mean to evaluate animal activities.

The quantitative assessment of the temporal distribution of animal activities (locomotion, feeding and drinking), which is of interest for behavioral studies, can be effected in several ways when observations last for long periods of time. One fairly widely used method is based on the scoring of segments of varying length of continuous ink on paper records (arbitrary activity counts), although, as far as we know, no proof has been given of the validity of this method. The relationship between the data obtained from the scoring process (arbitrary activity counts) and the absolute numerical data obtained from readings of activity counters has been tested by means of statistical analysis. The results show that there is an excellent fit between the two sets of data, thus proving the reliability of this method of assessing animal activities.

Animals↗
PubMed1983

Properties of cytosolic proteins that confer vasoactive intestinal polypeptide-sensitivity to rat brain adenylate cyclase.

Rat brain cortex, caudate nucleus and cerebellum contain one or more factors that confer Vasoactive Intestinal Polypeptide (VIP)-, dopamine (DA)- and norepinephrine (NE)-sensitivity to adenylate cyclase in the absence of added GTP. These factors also stimulate the basal activity of the enzyme. The activity is found in a 100 000 X g supernatant; has an apparent molecular weight greater than 450 000 daltons; is inactivated by pronase, alkaline phosphatase and ammonium sulphate, and partially degraded by trypsin; and is stable to heat and acidic treatment. The effect of the factors is additive with that of guanosine-5'-triphosphate (GTP), and is not abolished by guanosine 5'-0-(2-thiodiphosphate) (GDP-beta-S). These results suggest that stimulation of adenylate cyclase by VIP, and most likely by DA and NE, can be modulated by soluble proteins.

Adenylyl Cyclases↗