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Biomedical subjects

E Grana

Publications and source records attributed to E Grana.

At least 37 records · Page 2Linked to original sources
PubMed1991

Effects of cromakalim (BRL 34915) on mechanical responses of rat vas deferens to noradrenaline and naphazoline.

The contractile responses produced by noradrenaline were compared to those produced by naphazoline in the rat isolated vas deferens, a preparation which is usually quiescent. The responses to noradrenaline were biphasic: prominent spontaneous contractile activity was superimposed on contractions produced by naphazoline. After removal of naphazoline the rat vas deferens displayed periodic spontaneous activity. The effects of cromakalim and verapamil were compared on contractions induced by noradrenaline and naphazoline and on spontaneous activity induced by exposure to naphazoline. Cromakalim (1-10 x 10(-7) M) shifted to the right the cumulative concentration-response curve of naphazoline but not that of noradrenaline; at the same range of concentrations, cromakalim inhibited naphazoline-induced periodic spontaneous activity. Verapamil (3-30 x 10(-8) M) flattened in a dose-dependent manner the concentration-response curves of noradrenaline and naphazoline; higher concentrations of verapamil (3-30 x 10(-6) M) were required to modify periodic spontaneous activity. It was concluded that naphazoline but not noradrenaline can block K+ channel(s) and that this property can represent an important difference between imidazolines and phenethylamines.

Animals↗
PubMed1991

Potentiating actions of tranylcypromine and moclobemide on the sympathomimetic activity of dopamine.

Ex vivo investigations were carried out to study the potentiating actions of the MAOIs moclobemide and tranylcypromine on peripheral alpha- and beta-adrenergic effects of dopamine. Isolated rat vas deferens and atria were used. Preliminary experiments showed that both moclobemide and tranylcypromine did not affect the response to noradrenaline, while they enhanced the response to tyramine. By comparison of the responses to dopamine in control and reserpinized rats, it was shown that dopamine acts in a direct and indirect manner on both the tissues tested. Two concentrations (20, 40 mg/kg, i.p.) of moclobemide were tested and administered at different time periods (2, 5 or 24 h) before the animals were sacrificed. Two concentrations (2, 20 mg/kg, i.p.) of tranylcypromine were tested at different intervals of time (2, 24 h). The results obtained pointed out that: (1) Moclobemide 20 mg/kg potentiated the alpha-adrenergic response to dopamine only 2 h after administration while 40 mg/kg exerted a potentiation which was evident not only 2 but also 5 h after administration. Both doses were ineffective 24 h after administration. (2) Moclobemide 20 and 40 mg/kg potentiated the beta-adrenergic response to dopamine. The effect was present 2 and 5 h after administration but it was absent 24 h after. (3) Tranylcypromine 20 mg/kg potentiated the alpha-adrenergic response to dopamine: this effect was present after 2 h from pretreatment and was still evident after 24 h. The lower concentration of tranylcypromine (2 mg/kg) enhanced the response to dopamine only after 24 h from pretreatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Muscarinic inhibition of acetylcholine release from a novel in vitro preparation of the guinea-pig trachea.

An isolated preparation of the guinea-pig trachea is described which allows the simultaneous measurement of acetylcholine release and smooth muscle contraction. Incubation of the epithelium-free preparation with [3H]choline resulted in the formation of [3H]acetylcholine. Electrical stimulation caused the release of [3H]acetylcholine and a contractile response. Tetrodotoxin and omission of calcium from the medium abolished both the evoked release and contractions. The muscarinic agonists oxotremorine, carbachol and pilocarpine concentration-dependently inhibited the electrically evoked acetylcholine release and contracted the tracheal smooth muscle. Pre- and postsynaptic EC50 values for a given agonist were not different. Atropine (100 nmol/l) significantly facilitated the evoked acetylcholine release. A concentration of 10 nmol/l atropine did not change the evoked release but antagonized the inhibitory effect of oxotremorine. It is concluded that presynaptic muscarine autoreceptors inhibit the release of acetylcholine from parasympathetic nerves of the guinea-pig trachea.

Acetylcholine↗
PubMed1990

Nitrile oxides in medicinal chemistry. 3. Synthesis and bioenantioselectivity of (+)- and (-)-2-methyl-5-[(dimethylamino)-methyl]-3-oxo-isoxazolidine methiodide.

The two enantiomers of the potent muscarinic ligand 2-methyl-5[(dimethylamino)methyl]-3-oxo-isoxazolidine methiodide [(+/-)-V] were synthesized in a very high enantiomeric excess (98.8 and greater than 99%). The muscarinic activity of the two enantiomers was assayed on the isolated guinea pig ileum and atria, and on rat jejunum and urinary bladder and the nicotinic activity was evaluated on the frog rectus abdominis muscle. (R)-(-)-V, the most potent enantiomer in the muscarinic tests, has the same absolute configuration as [2R,5R]-muscarone and, like muscarone, has a low eudismic ratio (ER: 2.5-10.4). In the nicotinic assay, (S)-(+)-V was found to be the eutomer (ER: 3.5).

Animals↗
PubMed1989

Prejunctional effects of muscarinic agonists on 3H-acetylcholine release in the rat urinary bladder strip.

The inhibitory effects of some muscarinic agonists on tritiated acetylcholine release evoked by field stimulation were investigated in the rat urinary bladder strip. The acetylcholine stores of the preparation were labelled with 3H-choline. Electrical field stimulation caused an outflow of tritium, reflecting the release of 3H-acetylcholine. The release of 3H-acetylcholine was decreased in a concentration-dependent manner by all the agonists tested: oxotremorine, muscarone, muscarine, carbachol and methylfurtrethonium. On the contrary, only muscarine and muscarone enhanced the basal efflux of tritium in a concentration-dependent fashion. Concentration-response curves were determined both at 2 Hz and at 1 Hz by using intermittent administration of the drugs. Maximal depression in release (by 78-82%) was observed in experiments at 1 Hz. A similar inhibition was obtained at 2 Hz frequency only when a low concentration of calcium (0.6 mM) in the medium was used. Oxotremorine was the most potent among the tested compounds with the same intrinsic activity as the other drugs. In contrast to the other agonists investigated, oxotremorine showed in about 10-fold greater potency at pre- than at postjunctional muscarine receptors in the rat urinary bladder. This difference might depend either on heterogeneity of muscarine receptors or on different mechanism(s) relating to the transducing properties of receptors at the pre- and postjunctional level. A comparison between the relative prejunctional potencies in the rat urinary bladder and in the guinea pig myenteric plexus (data from the literature) suggests that prejunctional muscarine receptors are similar in these tissues. Furthermore, the findings obtained with a low concentration of calcium in the medium may support the view that intraneuronal availability of calcium plays a significant role in modulating the prejunctional negative feed-back mechanism in the rat urinary bladder.

Acetylcholine↗
PubMed1989

Distribution of dissociation constant values of muscarinic agonists.

The frequency distributions of dissociation constant values of some muscarinic agonists (carbachol, muscarone and cis-2-methyl-5-trimethylammoniummethyl-1,3-oxathiolane) obtained on guinea-pig ileum and atria and rat urinary bladder have been examined to see if the means of the dissociation constant values and the statistical tests for their significance, should be based on geometric rather than on arithmetic means. For the three compounds the distributions on a logarithmic scale did not significantly deviate from normality while the distributions on an arithmetic scale tended to deviate from normality.

Animals↗
PubMed1988

Formation and release of [3H]acetylcholine in the rat urinary bladder strip.

The relationship between different frequencies of loading stimulation and [3H]acetylcholine (ACh) formation and release from nerve terminals has been investigated in extratrigonal strips of the urinary bladder of the rat. An increase in frequency (0.2, 0.4 and 0.8 Hz) for the 30 min incubations with [3H]choline produced an enhancement of storage of [3H]ACh from 19.5 to 34% of total tritium content in the tissue. Higher frequencies (1.6 and 3.2 Hz) failed to increase storage further on. The [3H]choline content did not vary significantly. Electrical field stimulation at 2 Hz (360 shocks) produced a release of tritium. The evoked outflow was higher when the strip was loaded at 0.8 Hz than at the other frequencies tested. Both [3H]ACh and [3H]choline were measured in the perfusate of strips preloaded at 0.8 Hz. Most of the induced outflow was found to be [3H]ACh, as in previous experiments carried out using 0.2 Hz as a loading frequency. The findings suggest that in the rat urinary bladder strip loading at 0.8 Hz is suitable for increasing the formation and the resulting release of [3H]ACh during electrical stimulation.

Acetylcholine↗
PubMed1987

Determination of dissociation constants and relative efficacies of some potent muscarinic agonists at postjunctional muscarinic receptors.

This study was undertaken to determine dissociation constants (KA and relative efficacies (er) of seven muscarinic agonists (methylfurtrethonium; dioxolane, oxathiolane, carbachol, muscarine, muscarone and oxotremorine) in three isolated tissues (guinea-pig ileum and atria and rat urinary bladder). The rank order of affinities (-log KA) of the various compounds varied depending on the tissue used. er values for the different agonists did not differ significantly from each other in any of the three tissues, except that the er of muscarine in the guinea-pig ileum was higher than those of the other compounds and that of oxotremorine in the rat urinary bladder was lower than those of the other agonists. Comparisons among tissues show that KA and er values were the same in different tissues for some compounds (muscarone, muscarine and methylfurtrethonium), while significant differences were found for the other compounds. This suggests the existence of a discrete receptor population recognized by some but not all agonists. For oxotremorine er as well as -log KA, is greater in atria than in smooth muscle: these factors combine to determine the cardioselectivity of this compound which can now ascribed to receptor selectivity.

Animals↗
PubMed1987

Determination of dissociation constants and relative efficacies of some muscarinic agonists at nicotinic receptors.

Dissociation constant and relative efficacy values of six cholinergic agents endowed with a high muscarinic activity (carbachol, methylfurtrethonium, cis-2-methyl-4-trimetylammoniummethyl-1,3-dioxolane, cis-2-methyl-5-trimethylammoniummethyl-1,3-oxathiolane, muscarone, oxotremorine) have been determined on the frog rectus abdominis nicotinic receptors. The results obtained point out that: a) the nicotinic receptor reserve of the frog rectus abdominis is very little if any, b) there are no appreciable variations in the relative efficacy values of all the compounds tested, c) it is instead possible to establish a rank order of affinity. The comparison of the affinity values towards nicotinic receptors, herewith reported, and those towards ileal muscarinic receptors, previously reported could be useful to shed some light on the differences between muscarinic and nicotinic receptors.

Animals↗
PubMed1986

Comparative studies of the postjunctional activities of some very potent muscarinic agonists.

This study was undertaken to determine the potencies of seven muscarinic agonists (methylfurtrethonium, dioxolane, oxathiolane, carbachol, muscarine, muscarone and oxotremorine) on the postjunctional muscarinic receptors of seven isolated preparations (guinea pig taenia-coli, ileum, jejunum, trachea and atria and rat jejunum and urinary bladder). The results indicate that the rank order of sensitivity of the preparations varies independently of the potency of the agonist used and it is almost the same for all the compounds with the exception of oxotremorine. Muscarone was the most potent compound in all the tissues. Intergroup comparisons in each preparation and the evaluation of the equieffective molar ratios relative to muscarone revealed that carbachol possesses a certain degree of cardioselectivity and oxathiolane, on the other hand, is much less active on the cardiac tissue than on the others. Oxotremorine is a peculiar compound endowed with cardioselectivity.

Animals↗
PubMed1986

The influence of verapamil and papaverine on the calcium- and epinephrine-induced responses of isolated guinea-pig atria.

The effects of papaverine and verapamil on Ca2+ - and epinephrine evoked responses were investigated on spontaneously beating atria of the guinea-pig. Papaverine showed a non competitive antagonism against epinephrine but was ineffective against Ca2+; verapamil antagonized both the action of epinephrine and Ca2+ in a different manner but at the same concentrations. The pharmacological prerequisite to classify an anti-Ca2+ substance as a blocker of Ca2+ entry (that is the ability to selectively antagonize the Ca2+ -induced contraction relative to those of norepinephrine in vascular smooth muscle) was not met by the results obtained in the cardiac tissue. The behaviors of verapamil and papaverine with regard to Ca2+ response suggest another criterion for classifying a substance as a Ca2+ entry blocker based on the ability or inability to inhibit the response of the atrial preparation to Ca2+.

Animals↗
PubMed1986

Study of the nicotinic activity of very potent muscarinic agents.

The nicotinic activity of seven cholinergic agents endowed with a very high muscarinic activity (carbachol, methylfurtrethonium, cis-2-methyl-4-trimethylammoniummethyl-1,3-dioxolane, cis-2-methyl-5-trimethylammoniummethil-1,3-oxathiolane, muscarine, muscarone, oxotremorine) has been studied on the frog rectus abdominis. Carbachol is the most active compound with an EC50 value of 1.98 X 10(-6) M; the ratio between nicotinic and muscarinc activity is 67. Methylfurtrethonium and oxotremorine are the least potent and also behave as "partial agonists". Muscarine is devoid of activity. It is concluded that the nicotinic component does not interfere with the evaluation of the muscarinic potency of the compounds under investigation.

Animals↗
PubMed1986

QSAR in a series of muscarinic agents. Note VI. Five-membered cyclic ligands.

Proceeding in our study on the muscarinic receptor site, a refinement of its topology by means of Quantitative Structure-Activity Relationships has been carried out. Specific key structures have been selected considering not only muscarine and the corresponding desether derivative, but also a set of cyclopentenyltrimethylammoniummethyl salts. These derivatives, considered in a correlation equation extended to all of the five-membered cyclic structures previously examined, significantly improve understanding of contributions of critical ligand substructures to the overall interaction. The results obtained reinforce the reliability of correlation equations in structure-activity studies.

Chemical Phenomena↗
PubMed1986

Presynaptic inhibitory muscarinic receptors modulating [3H] acetylcholine release in the rat urinary bladder.

The occurrence of presynaptic muscarinic receptors inhibiting the release of acetylcholine (ACh) from nerve terminals was investigated in the rat urinary bladder. Strips from the extratrigonal area were preincubated with [3H]choline and stimulated at 0.2 Hz. Both [3H]ACh and [3H]choline content were measured in the tissue. The uptake of tritiated choline was prevented by hemicholinium-3. The field stimulation at 2 Hz (360 shocks) produced a release of tritium. Most of the induced outflow was found to be [3H]ACh. Both tetrodotoxin treatment and calcium omission from the medium prevented such an evoked-outflow of tritium. When two electrical stimulations (S1 and S2) at 2 Hz (360 shocks) were carried out at 45-min intervals, an S2/S1 ratio of 0.82 was found. Physostigmine reduced the evoked-release of [3H]ACh whereas atropine increased it in a concentration-dependent manner. Atropine antagonized the inhibitory effect of physostigmine, so that the S2/S1 ratio did not vary significantly from control experiments. Both carbachol and muscarine strongly decreased the [3H]ACh evoked outflow. Muscarine increased the spontaneous outflow of tritium also. These findings suggest that the urinary bladder of the rat is equipped with presynaptic inhibitory muscarinic receptors modulating ACh release from cholinergic postganglionic neurons.

Acetylcholine↗
PubMed1986

Analysis of the relaxing effect of dopamine on the isolated rat jejunum.

The relaxing effect of dopamine on the rat isolated jejunum has been studied. Dopamine was found 170 times less potent than noradrenaline and 3 times more potent than tyramine. The relaxing effect of dopamine does not show the tachyphylaxis phenomenon, is present in preparations from rats pretreated with reserpine and is not influenced by cocaine. These results indicate that dopamine has a direct action. To characterize the receptor(s) through which dopamine causes intestinal relaxation the alpha-blocker phentolamine, the beta-blocker propranolol and the dopamine receptor blockers haloperidol and cis-alpha-flupenthixol, alone or in combination have been tested. 40% of inhibition of the response to dopamine was obtained with phentolamine, 25% with propranolol and 30% with haloperidol or cis-alpha-flupenthixol. Combining together three antagonists acting on three different receptors it was possible to obtain 70% of inhibition of the responses to dopamine. It is concluded that alpha and beta adrenoceptors and specific dopamine receptors are involved in the direct relaxing action of dopamine.

Animals↗
PubMed1985

Differential sensitivity to prazosin and yohimbine blockade of tyramine and noradrenaline.

Previous researches demonstrated that in the rat vas deferens the effects of noradrenaline released by tyramine were more easily affected than those induced by exogenous noradrenaline by the non selective alpha-blockers, phentolamine and dihydroergocristine. The investigation has now been extended to the effects of selective alpha-blockers, prazosin and yohimbine with the aim to see whether the major sensitivity of tyramine to alpha-blockade correlates with the type of receptor activated. The results obtained with the two antagonists which selectively block alpha 1 and alpha 2 receptors strongly resemble each other and those previously obtained with the non selective alpha-adrenoceptor blockers. Thus, the peculiar sensitivity to alpha-blockade of noradrenaline released by tyramine with respect to exogenous noradrenaline does not seem to be dependent on the type (alpha 1 or alpha 2) of receptor involved.

Animals↗