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A Giachetti

Publications and source records attributed to A Giachetti.

At least 55 records · Page 3Linked to original sources
PubMed1992

Heterogeneity of tachykinin NK-2 receptors in rabbit, guinea-pig and human smooth muscles.

Recent evidence indicates that the tachykinin NK-2 receptor is heterogenous (subtypes/species variants) and the existence of NK-2A (or 'non-classical') and NK-2B (or 'classical') forms of the NK-2 receptor in mammalian tissues has been proposed. In this study we have compared the affinities of 7 linear octa- and heptapeptide derivatives of neurokinin A (4-10) and that of two cyclic hexapeptides endowed with selective NK-2 receptor antagonist properties in 5 mammalian smooth muscle preparations previously characterized as expressing the NK-2A receptor subtype (rabbit pulmonary artery and bronchus, guinea-pig bronchus, human ileum and colon) and 2 preparations previously characterized as expressing the NK-2B receptor subtype (rat vas deferens and hamster trachea). The results of this comparative study reinforce the concept of two broad categories of preparations expressing pharmacologically distinguishable forms of the tachykinin NK-2 receptor and suggest the possibility of a further heterogeneity within the previously defined NK-2A receptor subtype.

Amino Acid Sequence↗
PubMed1992

Effect of mequitamium iodide (LG 30435) on airway microvascular leakage in the guinea-pig.

Intravenous administration of mequitamium iodide (LG 30435) prevented the increase of tracheobronchial vascular permeability induced either by antigen challenge or by exogenous histamine in the guinea-pig, while it was ineffective against PAF, serotonin or capsaicin. These findings indicate that mequitamium iodide selectively interferes with the effect of histamine on airway microvascular leakage, mediated by histamine H1 receptors, and is more potent than diphenhydramine, mequitazine or astemizole. Histamine receptor antagonism is likely to be major determinant of the antiallergic activity of the compound, although additional mechanisms may be involved.

Animals↗
PubMed1992

Microvascular leakage induced by substance P in rat urinary bladder: involvement of cyclo-oxygenase metabolites of arachidonic acid.

1. Intravenous administration of substance P (SP) or of the NK1 selective agonist [beta-Ala4, Sar9, Met (O2)11] SP-(4-11) increased vascular permeability in the urinary bladder of urethane-anaesthetized rats, providing evidence for an NK1 receptor-mediated inflammatory response. 2. BW 755C, a dual inhibitor of arachidonate cyclo-oxygenase and lipoxygenase, significantly reduced the plasma extravasation induced by SP, but did not modify the effect of [beta-Ala4, Sar9, Met (O2)11] SP-(4-11). 3. SP-induced microvascular leakage was also inhibited by systemic pretreatment with indomethacin or with the prostaglandin receptor antagonist SC-19220, while it was unaffected by the selective 5-lipoxygenase inhibitor BW A4C or the leukotriene antagonist FPL 55712. 4. Pretreatment of rats with the mast cell degranulating agent compound 48/80 significantly attenuated the inflammatory effect of SP. Indomethacin administration to 48/80-pretreated animals failed to produce further inhibition. 5. These findings indicate that intravascular SP promotes plasma exudation in rat urinary bladder through an NK1-mediated effect on venular permeability and the release of cyclo-oxygenase metabolites of arachidonic acid. The latter effect largely derives from the interaction of the neuropeptide with mast cells.

Animals↗
PubMed1992

Tachykinin receptors in the guinea-pig renal pelvis: activation by exogenous and endogenous tachykinins.

1. The contractile response to substance P, neurokinin A, selective agonists for the NK1, NK2 and NK3 tachykinin receptors and the activity of receptor-selective antagonists has been investigated in circular muscle strips of the guinea-pig isolated renal pelvis in the presence of indomethacin (3 microM). 2. Neurokinin A was the most potent agonist tested, being about 32 times more potent than substance P. The action of both substance P and neurokinin A was enhanced by peptidase inhibitors (bestatin, captopril and thiorphan, 1 microM each). The selective NK2 receptor agonist [beta Ala8] neurokinin A (4-10), was slightly less potent and effective than neurokinin A itself. The selective NK1 receptor agonist [Sar9] substance P sulphone was effective at low (nM) concentrations but its maximal effect did not exceed 30% of maximal response to substance P or neurokinin A. The NK3-selective agonist [MePhe7] neurokinin B was effective only at high (microM) concentrations. 3. The pseudopeptide derivative of neurokinin A(4-10), MDL 28,564, displayed a clear-cut agonist character, although it was less potent than neurokinin A. 4. The responses to roughly equieffective (25-35% of maximal response) concentrations of [beta Ala8] neurokinin A (4-10), MDL 28,564 and [MePhe7] neurokinin B were antagonized to a similar extent by MEN 10,376 (3 microM), a selective NK2 tachykinin receptor antagonist, while the response to [Sar9] substance P sulphone was unchanged. 5. The response to [Sar9] substance P sulphone was inhibited by the NK1 receptor-selective antagonist, GR 82,334 (3 microM) while the response to [beta Ala8] neurokinin A (4-10) was unchanged. 6. The selective NK2 receptor antagonists MEN 10,376, L 659,877 and R 396 antagonized competitively the response to [PAla8] neurokinin A (4-10) with the following rank order of potency (pA2 values in parentheses): MEN 10,376 (7.41)>L 659,877 (7.15)>R 396 (6.43). MEN 10,376 and L 659,877 also competitively antagonized the response to neurokinin A, although with lower potency as compared to the selective NK2 receptor agonist.7. MEN 10,376, L 659,877 and R 396 reduced in a concentration-dependent manner the contractile response produced by electrical field stimulation (1 Hz, 100 V, 0.25 ms pulse width, trains of 10 s). The rank order of potency of NK2 receptor antagonists in blocking the response to electrical stimulation (MEN 10,376> L 659,877> R 396) closely mimicked their potency in antagonizing exogenous tachykinins.8. The inhibitory effect of MEN 10,376 toward responses produced by electrical field stimulation was significantly reduced when tested in the presence of peptidase inhibitors, which increased significantly the response to nerve stimulation.9. GR 82,334 (3 pM) did not significantly affect the response to nerve stimulation in untreated preparations and slightly reduced it in the presence of peptidase inhibitors.10. We conclude that both NK, and NK2 receptors mediate the contractile effect of tachykinins in the circular muscle of the guinea-pig renal pelvis and that the response ascribable to NK2 receptor stimulation is larger than that ascribed to NK, receptor stimulation. The NK2 receptor in the guinea-pig renal pelvis belongs to the same subtype previously identified in the rabbit pulmonary artery. NK2 receptors play a dominant role in the physiological response determined by the release of endogenous tachykinins and a contribution of NKI receptors becomes evident after inhibition of peptide degradation.

Amino Acid Sequence↗
PubMed1992

Pharmacology of idrapril: a new class of angiotensin converting enzyme inhibitors.

Idrapril is the prototype of a new chemical class of angiotensin converting enzyme (ACE) inhibitors, the hydroxamic non-amino acid derivatives. Idrapril strongly inhibited rat and human plasma ACE and rabbit lung ACE (IC50: 7-12 nM) as well as the pressor response induced by angiotensin I in anesthetized rats (ED50: 63 nmol/kg i.v.). Idrapril (0.04-23 mumol/kg i.v.) lowered the blood pressure dose dependently, up to 20-35%, in different models of hypertension (sodium-depleted spontaneously hypertensive rat, two-kidney-one-clip renal hypertensive rat, and aortic-coarctated rat), its profile being similar to that of captopril in terms of potency and efficacy. Idrapril and captopril reduced the blood pressure and potentiated substance P-induced bronchoconstriction in the guinea pig to the same extent, suggesting a similar degree of ACE inhibition in the circulation. However, idrapril potentiated capsaicin-induced bronchoconstriction (a model that has been related to the liability of ACE inhibitors to produce cough in patients) less effectively than captopril. We conclude that effective ACE inhibition in vitro and in vivo can be obtained with this novel class of compounds.

Angiotensin I↗
PubMed1991

NK2 tachykinin receptors and contraction of circular muscle of the human colon: characterization of the NK2 receptor subtype.

The contractile effect of substance P, neurokinin A, receptor selective agonists for tachykinin receptors and NK2 tachykinin receptor antagonists was investigated in mucosa-free circular strips of the human isolated colon. Neurokinin A and substance P produced concentration-dependent contractions which approached 80-90% of the maximal response to carbachol. Neurokinin A was about 370 times more potent than substance P. The action of neurokinin A and substance P was not modified by peptidase inhibitors (bestatin, captopril and thiorphan, 1 microM each). The NK2 receptor selective agonist, [beta-Ala8]neurokinin A-(4-10) closely mimicked the response to neurokinin A while NK1 and NK3 receptor selective agonists were active only at microM concentrations. The pseudopeptide, MDL 28,564, which is one of the most selective NK2 ligands available, behaved as a full agonist. Responses to [beta-Ala8]neurokinin A were antagonized by NK2 receptor selective antagonists, with the rank order of potency MEN 10,376 greater than L 659,877 much greater than R 396. These data indicate that NK2 tachykinin receptors play a dominant role in determining the contraction of the circular muscle of the human colon to peptides of this family. The NK2 receptor subtype responsible for this effect belongs to the same subtype (NK2A) previously identified in the rabbit pulmonary artery and guinea-pig bronchi.

Aged↗
PubMed1991

The behavior of the homozygous and heterozygous sub-types of rats which are genetically-selected for diabetes insipidus: a comparison with Long Evans and Wistar stocks.

Several aspects of spontaneous and conditioned behavior (food and water intake, locomotion and emotionality, passive and active avoidance acquisition and retention) of standard (albino and pigmented) rats, and rats heterozygous (HEDI) and homozygous (HODI) for diabetes insipidus, are reviewed. As would be expected, HODI rats have been repeatedly found to consume far more fluid than either HEDI or control rats. Pigmented rats appear to be more active than albinos. HODI rats exhibit less marked emotional responses than do control rats, among which the pigmented ones exhibit the highest emotionality. Light aversion is more evident in albino than in pigmented rats. No differences are found among HEDI, HODI and normal Long Evans rats. It is quite difficult to provide a clear-cut statement concerning inter-strain differences in passive avoidance behavior, possibly because of the variety of techniques employed. In any case, HODI rats do not perform worse than normal controls do. In one-way active avoidance paradigms, pigmented rats perform better than albinos, and the performance of HODI rats does not differ from that of controls. In two-way avoidance paradigms, albinos appear to outperform pigmented rats. Once again, there are no obvious differences between HODI and control animals. In addition to indicating that HODI rats may actually be less emotional than the other groups of rats reviewed here, the studies described once again fail to confirm the previously alleged functions of vasopressin in memory consolidation.

Animals↗
PubMed1991

Intracerebroventricular administration of endothelins: effects on the supraspinal micturition reflex and blood pressure in the anaesthetized rat.

Intracerebroventricular (i.c.v.) administration of endothelin-1 (ET-1, 10 and 100 pmol/rat) or endothelin-3 (ET-3, 100 pmol/rat) inhibited the supraspinal micturition reflex (SMR) in urethane-anesthetized rats. Guanethidine pretreatment, vagotomy or forced ventilation did not modify the effect of i.c.v. ET-1 on the SMR. Intravenous (i.v.) administration of ET-1 (350 pmol/rat) also blocked the SMR with a delay of about 8 min. Guanethidine pretreatment revealed a stimulatory effect of i.v. ET-1 on the frequency of the SMR and the late inhibition was also reduced. In the isolated rat urinary bladder ET-1, ET-3 and ET-(16-21) induced a dose-related contraction and a small enhancement of the neurogenic contraction caused by electrical field stimulation. Inhibition of bladder motility by i.c.v. administration of ET-1 or ET-3 was paralleled by an increase in blood pressure. Both ET-1 and ET-3, at the same doses which evoked these autonomic effects, also killed some animals. The ET-1-induced increase in blood pressure was not prevented by guanethidine pretreatment or by spinal cord transection. Guanethidine pretreatment also did not modify the pressor response induced by i.v. ET-1. Bilateral cervical vagotomy enhanced the pressor response to i.c.v. ET-1. Forced ventilation prevented the death of some animals following i.c.v. administration of ET-1.

Animals↗
PubMed1991

Effects of nucleus basolateralis amygdalae neurotoxic lesions on aversive conditioning in the rat.

After bilateral stereotaxic administration of ibotenic acid on the n. basolateralis amygdalae, male adult rats were tested in the light-dark box apparatus to measure the time-course of the acquisition and retention of passive and active avoidance responses. The results show that after the lesions both passive avoidance and active avoidance acquisition were impaired. Passive avoidance responses were retained quite well, while active avoidance responses disappeared quickly. Conditioned freezing was almost completely absent. Thus it appears that the n. basolateralis plays a facilitatory role in all the conditioned responses which were investigated.

Amygdala↗
PubMed1991

Effects of nucleus basolateralis amygdalae neurotoxic lesions on some spontaneous activities in the rat.

Drinking, feeding, locomotion and exploratory activity of male Wistar rats were assessed after bilateral stereotaxic administration of ibotenic acid in the nucleus basolateralis amygdalae. Feeding, drinking and locomotion were measured in an activity cage, while exploratory activity was determined in a multiple Y-maze. In the 24-hour cycle, lesioned animals exhibited unvaried feeding, decreased drinking and increased locomotion. Exploration was also increased. The results show that this nucleus is not involved in quantitative feeding control, while it does exert a significant facilitatory influence on drinking. It also exerts an inhibitory influence on exploration and on locomotion.

Amygdala↗
PubMed1991

Simultaneous recording of vesical and urethral pressure in urethane-anesthetized rats: effect of neuromuscular blocking agents on the activity of the external urethral sphincter.

In urethane-anesthetized rats we made a disconnection of the urinary bladder from the urethra and performed a simultaneous recording of the vesical and external urethral sphincter (EUS) pressures. Throughout the collecting phase, the EUS pressure was higher than that recorded into the bladder. Gallamine (10 mg/kg i.v.) or d-tubocurarine (100 micrograms/kg i.v.), did not alter the value of intraurethral pressure. When a reflex bladder contraction occurred in response to filling (expulsion phase) the intravesical pressure exceeded the urethral pressure and at the top of the vesical contraction a series of rapid intraluminal pressure high frequency oscillations (IPHFO) were recorded at the urethral recording site, which were abolished by neuromuscular blocking agents as well as after acute sectioning of pudendal nerves. IPHFO was still present in rats in which the periurethral muscles (pelvic floor), have been precedently dissected. To get further information about the physiological consequence of the EUS functional impairment induced by neuromuscular blocking agents, we used the non-stop transvesical cystometrogram. In these conditions, blockade of the EUS did not produce passive urine dripping during the filling phase, but absence of the rhythmic striated urethral activity during the vesical expulsion phase produced a significant increase of the residual volume from 35% (control) to 75%. We present an original pharmacological method in a species whose small dimensions create technical problems for recording pressure signals from the lower urinary tract. Moreover, we have gained information on the origin of the IPHFOs and about the role of the EUS during the collecting and the expulsion phase of the voiding cycle in urethane anesthetized rats.

Animals↗
PubMed1991

Evidence for the existence of a urethro-urethral excitatory reflex in urethane anesthetized rats: involvement of peripheral ganglionic structures.

In urethane-anesthetized rats urethral distension with saline at the level of the external urethral sphincter elicited a series of slow phasic contractions with an amplitude between two and 18 mm. Hg. Contractions having an amplitude lower than four mm Hg were unaffected by i.v. or topical hexamethonium (HEX) or by topical tetrodotoxin (TTX). HEX or TTX transiently abolished or reduced the distension-evoked contractions having an amplitude between four and 18 mm. Hg. Administration of d-tubocurarine (d-Tc), atropine, bilateral section of pudendal nerves, spinalization (T12-S1) or bilateral removal of the major pelvic ganglia did not modify the distension-induced rhythmic urethral activity. In rats desensitized to capsaicin (four days before), both amplitude and frequency of urethral contractions did not differ from control value. In rats pretreated with atropine, administration of HEX still inhibited the distension-induced urethral contractions. Intravenous dimethylphenylpiperazinium (DMPP) triggered a rapid phasic contraction with an amplitude ranging between 15 and 25 mm. Hg. This effect was inhibited by previous administration of HEX. In accordance with histochemical studies showing spherical ganglionic cell bodies between the outermost striated muscle layer and the smooth muscular coat, present data indicate that distension of the external urethral sphincter reflexly activates urethral contractions, possibly through a local mechanism.

Anesthesia↗
PubMed1991

Facilitation of reflex micturition by intravesical administration of [beta Ala8]-neurokinin A (4-10), a selective NK-2 tachykinin receptor agonist.

We have determined the ability of [beta Ala8]-NKA(4-10), a selective agonist for NK-2 tachykinin receptors to stimulate micturition in anesthetized rats and guinea-pigs. In both species, the intravesical instillation of the peptide at microM concentrations reduced bladder capacity and residual volume, indicating a facilitatory effect on reflex micturition. At these concentrations, no plasma extravasation was produced as determined by the Evans blue content of the organ. In experiments on the isolated rat or guinea-pig bladder strips, the NK-2 receptor agonist induced powerful contractions. In a in vitro model of the guinea-pig whole bladder the intravesical instillation of the NK-2 agonist facilitated the occurrence of rhythmic contractile activity. It is concluded from these studies that intravenous administration of [beta Ala8]-NKA(4-10) exerts a facilitatory effect on the micturition reflex, presumably involving the ability of the NK-2 receptor agonist to cross the urothelium and stimulate smooth muscle contraction.

Administration, Intravesical↗
PubMed1991

Effect of synthetic tachykinin analogues on airway microvascular leakage in rats and guinea-pigs: evidence for the involvement of NK-1 receptors.

1. The NK-1 selective agonists [beta-Ala4, Sar9]SP-(4-11) sulphone and [pGlu6, Pro9]SP-(6-11) dose-dependently increased vascular permeability in various segments of rat and guinea-pig tracheo-bronchial region, while the NK-2 ([Nle10]NKA-(4-10) and [beta-Ala8]NKA-(4-10)) or NK-3 ([MePhe7]NKB and [MePhe7]NKB-(4-10)) selective agonists were inactive. These findings provide evidence that the inflammatory response of the airway to intravenous tachykinins is exclusively mediated by the NK-1 receptor subtype. 2. Plasma protein extravasation induced by capsaicin was more intense in the caudal segments of the rat airways and paralleled the tissue concentration of substance P-like and calcitonin gene-related peptide-like immunoreactivity. The response to capsaicin was greatly reduced in rats pretreated with high dose of the toxin (655 mumol kg-1 s.c., 3 weeks before) and was smallest in the airway regions where the depletion of neuropeptides had been more severe. 3. The depletion of transmitters from capsaicin-sensitive nerves did not affect the inflammatory response of the airway to serotonin (500 nmol kg-1 i.v.), while increased responsiveness to a threshold dose (0.37 nmol kg-1 i.v.) of [beta-Ala4, Sar9]SP-(4-11) sulphone was observed. This finding gives preliminary evidence that, after depletion of transmitters from capsaicin-sensitive nerves, upregulation of NK-1 receptors may develop in rat trachea.

Animals↗
PubMed1991

Further evidence for the existence of NK2 tachykinin receptor subtypes.

1. We have evaluated the biological activity of a number of neurokinin A (4-10), (NKA (4-10)) analogues in the endothelium-deprived rabbit isolated pulmonary artery (RPA) and hamster isolated trachea (HT), two tissues rich in different NK2 receptor subtypes. 2. MDL 28,564, a pseudopeptide selective for NK2 receptor sites, behaved as a full agonist in the RPA, while in the HT it competitively antagonized NKA or [beta Ala8]-NKA (4-10) contractile effects. 3. The peculiar behaviour of MDL 28,564 in the RPA and HT may be explained neither by a difference in receptor reserve between the two organs (the reserve being three times greater in RPA than in the HT) nor by a different affinity for the two receptor subtypes (identical dissociation constants, pKA or pKB, calculated in the RPA and in the HT). On the other hand, MDL 28,564 displayed a very different intrinsic efficacy for the two receptor subtypes. 4. The novel peptides MEN 10,295 ([Trp7, beta Ala8]-NKA-(4-10)) and MEN 10,296 ([Tyr5, Trp7, beta Ala8]-NKA-(4-10] behaved as weaker agonists than MDL 28,564 in the RPA, but retained appreciable agonist activity also in the HT. 5. The novel peptides: MEN 10,282 ([Tyr5, D-Trp6,8, Trp9, Arg10]-NKA-(4-10], MEN 10,449 ([diI-Try5, D-Trp6,8,9, Arg10]-NKA-(4-10] and the cyclic hexapeptide L 659,877 (cyclo [Leu-Met-Gln-Trp-Phe-Gly]) behaved as competitive antagonists against NKA contractile effects both in the RPA and HT. MEN 10,282 and MEN 10,449 were unable to distinguish between the NK2 receptor subtypes, having almost the same affinity in the two organs. On the other hand L 659,877 was about 15 times more potent in the HT than in the RPA. 6. These results provide further evidence for NK2 receptors heterogeneity and are useful in outlining pharmacological features of the two subtypes present in the RPA and HT.

Amino Acid Sequence↗