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A Giachetti

Publications and source records attributed to A Giachetti.

At least 73 records · Page 4Linked to original sources
PubMed1990

Further studies on the response of the guinea-pig isolated bronchus to endothelins and sarafotoxin S6b.

Endothelin-1 (ET-1), endothelin-3 (ET-3) and sarafotoxin S6b (SRFTX) produced a concentration-dependent contraction of the guinea-pig isolated bronchus. In untreated preparations, SRFTX was about 10 times more potent than ET-1 or ET-3 and produced a greater maximal effect. Mechanical removal of the bronchial epithelium (rubbing) or the addition of indomethacin (5 microM) increased the potency of all peptides, ET-3 being enhanced more than ET-1 or SRFTX. Further, the activity of ET-3 was enhanced by a mixture of peptidase inhibitors (thiorphan, captopril, bestatin, 1 microM each). When the three potentiating factors were combined (rubbed bronchi in presence of indomethacin and peptidase inhibitors), the following order of potency was found, ET-3 congruent to SRTFX greater than ET-1. For comparison, the activity of the three peptides was also studied in the rubbed rat isolated aorta in the presence of indomethacin and peptidase inhibitors and the following rank order of potency was found: ET-1 greater than SRFTX greater than ET-3. When the activity of the peptides was compared in these two preparations, ET-1 was 4 times more potent in the aorta than in the bronchus, while SRFTX and ET-3 were 8.7 and 133 times more potent in the bronchus than the aorta, respectively. These findings indicate that, in the guinea-pig bronchus, the contractile activity of these peptides is attenuated by the concomitant production of epithelium-derived relaxant factor(s), prostanoid production via the cyclooxygenase pathway and, possibly, enzymatic inactivation of added peptides. Further, the existence of multiple receptors mediating the contractile response to these peptides is suggested.

Animals↗
PubMed1990

A highly selective NK-2 tachykinin receptor antagonist containing D-tryptophan.

The classical approach used in the development of substance P (SP) antagonists, i.e. the introduction of multiple D-tryptophan (D-Trp), was successfully extended to neurokinin A (NKA). Thus, a new NK-2-selective tachykinin receptor antagonist, namely [Tyr5, D-Trp6,8,9, Arg10]NKA-(4-10), was developed that had pA2 values of 5.2, 7.9 and 4.9 in three monoreceptor in vitro assays for NK-1, NK-2 and NK-3 tachykinin receptors, respectively.

Amino Acid Sequence↗
PubMed1990

Human isolated ileum: motor responses of the circular muscle to electrical field stimulation and exogenous neuropeptides.

(1) Circularly-oriented muscle strips from the human ileum responded to electrical field stimulation (1-50 Hz) with frequency-related primary relaxation at low frequency and primary contractions at high frequencies of stimulation. Both responses were abolished or markedly reduced by tetrodotoxin (1 microM). (2) Atropine (3 microM) or omega conotoxin (0.1 microM) reduced but dit not abolish contraction to electrical field stimulation and enhanced the relaxation. Omega conotoxin (0.1 microM) did not affect carbachol-induced contraction nor isoprenaline-induced relaxation. (3) Neurokinin A and substance P (1 nM-1 microM) produced a concentration-dependent contraction. The NK-1 receptor selective agonist, [Pro9]SP sulfone and the NK-2 receptor selective agonist [beta Ala8]NKA(4-10) produced a contraction superimposable to that of substance P and neurokinin A, respectively. On the other hand, [MePhe7]-neurokinin B, an NK-3 receptor selective agonist was ineffective up to 1 microM. The response to substance P or neurokinin A was unaffected by atropine (3 microM). (4) Galanin, up to 0.1 microM, produced a weak and inconsistent contraction. (5) Vasoactive intestinal polypeptide (10 nM-1 microM) produced a concentration-dependent relaxation while human alpha calcitonin gene-related peptide exerted a weak and inconsistent relaxant effect. (6) These findings indicate that both cholinergic excitatory and non-cholinergic inhibitory nerves affect the motility of the circular muscle of the human small intestine. Transmitter release from excitatory nerves seems largely mediated by activation of omega conotoxin-sensitive (N-type) calcium channels. Tachykinins exert a potent contractile effect, independently of cholinergic nerves, via NK-1 and NK-2 receptors.

Aged↗
PubMed1990

The rat's right-left preference during free exploration of a multiple Y-maze.

The right-left preference of Wistar, Sprague-Dawley, and Long Evans rats of both sexes was investigated in a multiple Y-maze in which the animals had to perform three consecutive right-left choices in order to go from the common starting point to one of the eight goal arms. The rats were free to explore the maze without being subjected to punishments or rewards. Care was taken to minimize inhibitory influences on exploration (low illumination, no handling to return the rats to home cage). The statistical analysis of the total right-left choices performed by the rats showed that three groups (Wistar females, Sprague-Dawley females, and Long Evans males) exhibited a preference for the right. This preference was not related either to sex or strain, but was possibly a species characteristic.

Animals↗
PubMed1990

Effect of endothelin-1, endothelin-3 and C-terminal hexapeptide, endothelin (16-21) on motor activity in rats.

Intracerebroventricular administration of ET-1 (12.5 and 25 pmol/rat) and ET-3 (25 and 50 pmol/rat) induced the loss of the righting reflex and barrel-rolling behaviour in rats. The C-terminal hexapeptide ET(16-21) did not produce these effects. The automated recording of motor activity revealed that, unlike ET (16-21), both ET-1 and ET-3 evoke a dose-regulated increase of the immobility time. Pretreatment with peptidase inhibitors did not modify the activity of subthreshold doses of peptides. Since ET (16-21) display full agonist properties at ETB but does not interact with ETA receptors, the present data suggest that the behavioural syndrome induced by centrally administered ET-1 and ET-3 may be mediated by stimulation of ETA receptors.

Animals↗
PubMed1990

Motor response of the human isolated colon to capsaicin and its relationship to release of vasoactive intestinal polypeptide.

The aim of this study was to obtain indirect evidence of the presence of capsaicin-sensitive afferents in the human colon by studying the motor response to capsaicin of longitudinal strips from the human isolated taenia coli in parallel to the ability of capsaicin or KCl to induce peptide release from the human superfused colon. Capsaicin (1 microM) evoked a relaxation of the taenia, approaching 60-80% of the response to isoprenaline. Tachykinins evoked contractions of the taenia, while calcitonin gene-related peptide induced a relaxation. Neither tachyphylaxis to calcitonin gene-related peptide nor preincubation with an anti-calcitonin gene-related peptide serum did block the response to capsaicin which was also unaffected by tetrodotoxin, apamin, naloxone or an anti-galanin serum. Vasoactive intestinal polypeptide produced a concentration-dependent tetrodotoxin-resistant relaxation which was shifted rightward in the presence of anti-vasoactive intestinal polypeptide serum. The anti-vasoactive intestinal polypeptide serum reduced the response to capsaicin and application of capsaicin prevented the ability of anti-vasoactive intestinal polypeptide serum to block exogenous vasoactive intestinal polypeptide. Capsaicin (1 microM) evoked a significant release of vasoactive intestinal polypeptide-like immunoreactivity from the superfused muscle but not mucosa of the human colon. A significant vasoactive intestinal polypeptide-like immunoreactivity release was also observed in response to KCl (80 mM). KCl but not capsaicin evoked a significant release of neurokinin A-like immunoreactivity from colonic muscle and mucosa. No significant release of either substance P-, neuropeptide Y-, galanin- or calcitonin gene-related peptide-like immunoreactivity was detected in response to capsaicin or KCl although detectable levels of each peptide were evident in tissue extracts.(ABSTRACT TRUNCATED AT 250 WORDS)

Apamin↗
PubMed1990

The contractile effect of tachykinins on human prostatic urethra: involvement of NK-2 receptors.

The contractile response to natural tachykinins [substance P (SP), neurokinin A (NKA), arginin-neurokinin B (ArgNKB)] and to synthetic peptide [Pro9]SP sulfone, [beta Ala8]NKA(4-10) and [MePhe7]NKB, were investigated in the isolated smooth muscle from the human prostatic urethra. Natural tachykinins evoked concentration-related responses with the following order of potency: NKA----NKB--------SP. Among selective agonists [beta Ala8]NKA(4-10) produced concentration-related contractions, while [Pro9]SP sulfone and [MePhe7]NKB were inactive. These data indicate the presence of NK-2 receptors in the smooth muscle of the human prostatic urethra.

Aged↗
PubMed1990

Effect of thiorphan on the response of guinea-pig isolated urinary bladder to exogenous and endogenous tachykinins.

Thiorphan, a well known inhibitor of 'enkephalinase' (endopeptidase 24.11) potentiated and prolonged the contractile response to substance P (SP) and neurokinin A (NKA) on strips of the guinea-pig isolated urinary bladder and this effect was evident both in presence and absence of the mucosal layer. Thiorphan also enhanced and prolonged the capsaicin-induced contraction in strips from the bladder dome which is thought to be mediated by release of endogenous tachykinins. Exposure to capsaicin produced simultaneous release of SP- and tachykinin-like immunoreactivity both in presence and absence of mucosa. This effect of capsaicin was potentiated by thiorphan. Endopeptidase 24.11 activity was detected in the guinea-pig urinary bladder, being more concentrated in the mucosal than the muscular layer. These findings indicate that endopeptidase 24.11 terminates the activity of tachykinins in the guinea-pig urinary bladder and modulates the intensity of the biological response produced after their release from peripheral endings of sensory nerves.

Animals↗
PubMed1990

Tachykinin receptors in the circular muscle of the guinea-pig ileum.

1. We have studied the mechanical response of circular strips of the guinea-pig ileum to tachykinins and characterized the receptors involved by means of receptor-selective agonists. 2. The strips responded to both substance P (SP) and neurokinin A (NKA), as well as to [Pro9]-SP sulphone (selective NK1-receptor agonist), [beta Ala8]-NKA(4-10) (selective NK2-receptor agonist) and [MePhe7]-neurokinin B (selective NK3-receptor agonist). The ED50s of the various peptides (calculated as the concentration of agonist which produced 50% of the response to 10 microM carbachol) were similar, in the range of 40-200 nM, i.e. no clearcut rank order of potency was evident. 3. The response to a submaximal (10 nM) concentration of SP or NKA was unaffected in the presence of peptidase inhibitors (thiorphan, captopril and bestatin, 1 microM each). 4. The response to the NK1-agonist was totally atropine-resistant, but was reduced (about 30% inhibition) by tetrodotoxin. The response to the NK3-receptor agonist was halved by atropine and abolished by tetrodotoxin. The response to the NK2-agonist was unaffected by either atropine or tetrodotoxin. 5. The response to the selective NK2-agonist was unchanged after desensitization of NK1- or NK3-receptors. 6. The response to the NK2-selective agonist was strongly inhibited by [Tyr5, D-Trp6,8,9, Arg10]-NKA(4-10) (MEN 10,207) a selective NK2-receptor antagonist which did not modify the response to the NK1-selective agonist. 7. Our findings indicate that all the three known types of tachykinin receptors mediate the contractile response of the circular muscle of the guinea-pig ileum to peptides of this family. The response to activation of NK3-receptors is totally neurogenic and partially mediated by endogenous acetylcholine, the response to activation of NK1-receptors is partly neurogenic and largely myogenic and the response to activation of NK2-receptors is totally myogenic.

Animals↗
PubMed1990

Competitive antagonists discriminate between NK2 tachykinin receptor subtypes.

1. We have compared the ability of various tachykinins and selective tachykinin receptor agonists to induce contraction of the endothelium-denuded rabbit pulmonary artery (RPA) and hamster trachea (HT) and have estimated the affinity of some newly developed NK2 selective antagonists in the same tissues. 2. In confirmation of previous findings, experiments with the agonists indicated that NK2 receptors are the main if not the sole mediators of the response to tachykinins in both RPA and HT. No evidence for significant degradation of neurokinin A (NKA) was found in either tissue when experiments were repeated in the presence of a mixture of peptidase inhibitors (thiorphan, captopril and bestatin, 1 microM each). 3. The peptide antagonists tested were: Peptide I = [Tyr5, D-Trp6,8,9, Arg10]-NKA(4-10); Peptide II = [Tyr5, D-Trp6,8,9, Arg10]-NKA(3-10); Peptide III = Ac-Leu-Asp-Gln-Trp-Phe-Gly-NH2. The three peptides produced a concentration-dependent rightward shift of the concentration-response curve to NKA in both RPA and HT with no significant depression of the maximal response attainable. The slopes of the Schild plots were not significantly different from unity, indicating a competitive antagonism. Peptides I and II were about 100 times more potent in the RPA than in the HT, while Peptide III was about 100 times more potent in the HT than RPA. 4. The pA2 values obtained in these two tissues with the three antagonists were not significantly different when tested in the absence or presence of peptidase inhibitors, or when a selective NK2 receptor agonist, [beta Ala8]-NKA(4-10) was used instead of NKA. Similar pA2 values were obtained after 15 or 90min of incubation with the antagonists. Peptides I, II and III had no inhibitory effect on contractions produced by noradrenaline in the RPA or by carbachol in the HT. 5. Peptides I, II and III showed weak or no antagonistic activity toward the vasodilatator effect of substance P in the dog carotid artery (NK, receptor-mediated) or toward the contractile effect of neurokinin B in the rat portal vein (NK3 receptor-mediated). 6. These results provide pharmacological evidence for heterogeneity of NK2 receptors in the RPA and HT. The NK2 receptors present in these tissues are not discriminated by natural tachykinins or selective agonists, but are recognized with very different affinity by NK2 receptor antagonists.

Amino Acid Sequence↗
PubMed1990

Pharmacodynamic profile of isbufylline, a new antibronchospastic xanthine devoid of central excitatory actions.

1,3-Dimethyl-7-isobutylxanthine (isbufylline, TE/06; CAS 90162-60-0) is a newly synthetized xanthine derivative. This compound exhibits remarkable antibronchospastic properties both in in vitro and in vivo (after oral or intravenous administration) experimental models. Isbufylline is significantly more effective than theophylline in antagonizing bronchospasms elicited by spasmogens (capsaicin, arachidonic acid, PAF and antigen) which mainly act by a local release of biologically active substances proposed to be involved in the pathogenesis of asthma. Isbufylline, unlike theophylline, possesses little or no CNS excitatory properties. This reduced neuroexcitatory action is probably related to the poor affinity of isbufylline, as compared to theophylline, to A1 purinoceptor. Indeed, isbufylline is ineffective in antagonizing 2Cl-adenosine-induced EEG synchronization. In normotensive and hypertensive rats oral administration of isbufylline resulted in small and transient positive chronotropic and hypotensive response, markedly lower than those elicited by theophylline or enprofylline. Finally isbufylline exhibits phosphodiesterase inhibitory properties, although at concentration 50-100 times higher than those exerting spasmolytic effects in isolated bronchial tissues. As a whole the pharmacodynamic profile of isbufylline is promising and, in the clinical setting, this compound might exert enhanced antiasthma effects coupled to a low incidence of central and cardiovascular adverse effects.

1-Methyl-3-isobutylxanthine↗
PubMed1989

The activity of peptides of the endothelin family in various mammalian smooth muscle preparations.

The activity of natural endothelins such as ET-1, ET-2, ET-3 and of sarafotoxin S6b (SRFTX) as compared to that of the C-terminal hexapeptide ET-(16-21) was investigated in several smooth muscle preparations in the presence of indomethacin, captopril, bestatin and thiorphan. In some tissues (rat thoracic aorta, guinea-pig ileum, human urinary bladder, renal pelvis or renal artery), ET-(16-21) had little if any agonist activity. In other preparations (guinea-pig bronchus, rat vas deferens, rabbit pulmonary artery) ET-(16-21) was a full agonist. The amidated form of ET-(16-21) was either inactive or less potent than ET-(16-21). These findings provide evidence that at least two receptors exist for peptides of the ET family; these receptors were termed ETA and ETB. ET-(16-21) is a full agonist at ETB receptors while being inactive or weakly active at ETA receptors. The free acid of tryptophan in position 21 plays a key role in the activity of these peptides at ETB receptors.

Animals↗
PubMed1989

AF-DX 116 differentiates between prejunctional muscarine receptors located on noradrenergic and cholinergic nerves.

Prejunctional affinity constants of the cardioselective muscarine receptor antagonist AF-DX 116 (11-[(2-[(diethyl-amino)methyl]-1-piperidinyl)acetyl]-5,11-dihydro-6 H-pyrido [2,3-b] [1,4] benzodiazepine-6-one) were determined for muscarine autoreceptors on cholinergic nerves of the guinea-pig ileum and for heteroreceptors on noradrenergic nerves of the rat heart and guinea-pig iris. AF-DX 116 antagonized with low affinity the muscarinic inhibition induced by arecaidine propargyl ester of the stimulation-evoked [3H]acetylcholine overflow (pA2 6.74) from the guinea-pig ileum. In contrast, AF-DX 116 was more potent in antagonizing the methacholine-induced inhibition of the stimulation-evoked [3H]noradrenaline overflow from rat heart (pA2 7.29) or guinea-pig iris (pA2 7.57). The data confirm previously reported differences between prejunctional muscarine heteroreceptors in the rat heart which belong to the cardiac subtype (M2 alpha or M2) and autoreceptors in the guinea-pig ileum that cannot be distinguished from the ileal subtype (M2 beta) or M3).

Acetylcholine↗
PubMed1989

Role of muscarinic receptor subtypes in the regulation of migrating myoelectric complex in the dog.

The role played by muscarinic receptor subtypes in the regulation of the migrating myoelectric complex was investigated in 7 dogs chronically implanted with bipolar electrodes along the small intestine. Pirenzepine (3-300 micrograms/kg i.v.) and atropine (1-30 micrograms/kg i.v.) were used as selective and unselective antagonist, respectively. Atropine (30 micrograms/kg) significantly delayed the onset of the next complex. On the contrary, pirenzepine displayed a biphasic action: low doses (less than 100 micrograms/kg) shortened the cycle period, whereas at 300 micrograms/kg the drug behaved like atropine. Pirenzepine affected the cycle period in the low-dose range by reducing the length of phase I. Both atropine and pirenzepine impaired the migration of the ongoing complex, and significantly reduced the migration velocity of the following one. These findings suggest that the initiation of the migrating myoelectric complex in the dog is under an inhibitory influence mediated by the M1 muscarinic receptor subtype; on the other hand, M2 receptor activation is needed for the onset of the activity front. Finally, both receptor subtypes determine the normal migration of phase III.

Animals↗
PubMed1989

Multiple sources of calcium for contraction of the human urinary bladder muscle.

1. KCl, carbachol, neurokinin A and endothelin produced concentration-dependent contractions of mucosa-free muscle strips from the dome of the human urinary bladder. The maximal response to carbachol or neurokinin A exceeded that to KCl, while the maximal response to endothelin approached that to KCl. 2. Nifedipine (1 microM) abolished the response to KCl, reduced the response to carbachol or neurokinin A but had no effect on the response to endothelin. Bay K 8644 (1 microM) markedly potentiated the response to KCl but had little or no effect on the response produced by the other stimulants. 3. Superfusion of the strips with a nominally calcium (Ca)-free medium containing EDTA (1 mM) for 30 min markedly reduced the response to carbachol, neurokinin A and endothelin, although a small response was still evident at high concentrations. Likewise, after a prolonged (60 min) superfusion of the strips with a high K (80 mM) Ca-free medium plus EDTA (1 mM) these three agonists still produced a small contractile response. 4. The nifedipine (1 microM) resistant response to carbachol, neurokinin A or endothelin was markedly depressed by LaCl3 (1 mM). In contrast, the nifedipine-(1 microM) resistant response to carbachol was not modified by NiCl2 (0.1 mM) or omega-conotoxin (0.1 microM). 5. Caffeine produced divergent effects depending upon the temperature of incubation: a relaxation at 37 degrees C and a concentration-dependent (2.5-20 mM) contraction at 25 degrees C. The latter was markedly inhibited by procaine (3 mM) but unaffected by nifedipine (1 microM). 6. After a prolonged (60 min) superfusion with a high K, Ca-free medium containing EDTA the response to carbachol (100 microM) was abolished by previous exposure to procaine (3 mM). Conversely, the response to endothelin (1 microM) was unaffected by procaine. The response to endothelin in these experimental conditions was also resistant to LaCl3 (1 mM). 7. These findings indicate that multiple sources of Ca are mobilized for contraction of the human bladder muscle by different stimulants. Dihydropyridine- and voltage-sensitive Ca channels provide the major if not the sole source of Ca for the response to KCl, play some role in the response to muscarinic (carbachol) or NK-2 tachykinin receptor stimulation but are not involved in the response to endothelin. Carbachol, neurokinin A and endothelin all mobilize a Ca pool (either extracellular or located at membrane level) which is LaCl3-sensitive but nifedipine-resistant. Neither T- nor N-type channels appear to be involved in the response to carbachol. In addition, these agents mobilize a tightly bound Ca pool independently from membrane depolarization. This latter pool is probably a procaine-sensitive intracellular source of activator Ca mobilized by caffeine and carbachol. The failure of procaine to prevent the response to endothelin in high K, Ca-free medium raises the possibility that this peptide mobilizes an intracellular source of activator Ca, distinct from the caffeine- and carbachol-sensitive pool.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1989

Octylonium bromide interacts competitively with the PAF receptor.

To clarify the nature of the interaction of octylonium bromide with the PAF receptor, saturation studies of 3H-PAF binding were made in the presence of increasing concentrations of the radioligand (from 0.06 to 7.4 nM) and of octylonium bromide (1 X 10(-8), 5 X 10(-8) and 1 X 10(-7) M) or of a potent PAF antagonist L 652,731 (2.5 X 10(-7) M), or in the absence of competing drugs. Saturation binding data were plotted according to the non-linear fitting analysis and to Scatchard transformation. Both mathematical models indicated that the presence of added drugs decreased the affinity of the complex 3H-PAF/PAF receptors, leaving unaffected the maximum number of PAF binding sites. Receptor parameters in the absence of competitors were: KD = 1.2 nM, Bmax = 950 fmoles 3H-PAF bound/10(8) platelets. Octylonium bromide increased, in a concentration-dependent manner, KD values from 1.5 to 2.1 nM, while Bmax ranged from 910 to 980 fmoles 3H-PAF specifically bound/10(8) platelets. Likewise, L 652,731 did not influence Bmax (980 fmoles) but increased KD (1.9 nM). The binding behaviour of octylonium bromide and L 652,731 indicates that the two compounds inhibit competitively the binding of 3H-PAF to its receptors.

Animals↗
PubMed1988

Aversive conditioning of homozygous and heterozygous D.I. Brattleboro rats in the light-dark box.

Active and passive avoidance, and conditioned freezing acquisition and retention were studied in HODI and HEDI Brattleboro rats. All animals were from the same source and of the same age and sex. The light-dark box test was employed. 0.6 and 2.0 mA footshocks were administered for the same number (7) of daily trials. Extinction time-course was followed for seven consecutive daily trials. Passive avoidance: the conditioned response was acquired and retained equally well by all Ss and for both shock intensities. Active avoidance: for 0.6 mA shocks HODI Ss acquired and retained the response significantly better than HEDI Ss; for 2.0 mA shocks the response was acquired equally by both groups of Ss, and retained significantly better by HODI Ss. Freezing: in general, HODI Ss exhibited less freezing then HEDI Ss. The diverse conditioned behavior of HODI and HEDI Ss in this paradigm, which allows the contemporaneous investigation of several aversive responses, does not support the hypothesis that vasopressin deficiency impairs learning and memory in the rat.

Animals↗