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Biomedical subjects

A Giachetti

Publications and source records attributed to A Giachetti.

At least 37 records · Page 2Linked to original sources
PubMed1994

Influence of lipophilicity on the biological activity of cyclic pseudopeptide NK-2 receptor antagonists.

A series of cyclic pseudopeptides of the formula cyclo(Leu psi[CH2NH]Xaa-Gln-Trp-Phe-beta Ala), where Xaa represents the residue of an alpha-amino acid, has been synthesized in order to establish the role of the Xaa side chain for tachykinin NK-2 receptor antagonist activity. Syntheses have been carried out in solid phase with either Fmoc or Boc strategy. The antagonist potency on NK-2 receptors in the hamster isolated trachea (HT) and the rabbit isolated pulmonary artery (RPA) bioassays increases with Xaa lipophilicity; cyclo(Leu psi[CH2NH]Cha-Gln-Trp-Phe-beta Ala) and cyclo(Leu psi[CH2NH]Asp(NHBzl)-Gln-Trp-Phe-beta Ala) resulted in being the two most active antagonists (pA2 = 9.06 and 9.26 on HT, respectively). A significant linear correlation was found between pA2 values determined in HT and RPA bioassays and capacity factors measured in reversed phase HPLC. The comparison between the biological activities of cyclic hexapeptides containing or not containing the aminomethylene moiety proved the crucial role of the pseudopeptide bond for determining high antagonist potency at the NK-2 receptor.

Alkylation↗
PubMed1994

Comparison of tachykinin NK1 and NK2 receptors in the circular muscle of the guinea-pig ileum and proximal colon.

1. The aim of this study was the pharmacological characterization of tachykinin NK1 and NK2 receptors mediating contraction in the circular muscle of the guinea-pig ileum and proximal colon. The action of substance P (SP), neurokinin A (NKA) and of the synthetic agonists [Sar9]SP sulphone, [Glp6,Pro9]SP(6-11) (septide) and [beta Ala8]NKA(4-10) was investigated. The affinities of various peptide and nonpeptide antagonists for the NK1 and NK2 receptor was estimated by use of receptor selective agonists. 2. The natural agonists, SP and NKA, produced concentration-dependent contraction in both preparations. EC50 values were 100 pM and 5 nM for SP, 1.2 nM and 19 nM for NKA in the ileum and colon, respectively. The action of SP and NKA was not significantly modified by peptidase inhibitors (bestatin, captopril and thiorphan, 1 microM each). 3. Synthetic NK1 and NK2 receptor agonists produced concentration-dependent contraction of the circular muscle of the ileum and proximal colon. EC50 values were 83 pM, 36 pM and 10 nM in the ileum, 8 nM, 0.7 nM and 12 nM in the colon for [Sar9]SP sulphone, septide and [beta Ala8]NKA-(4-10), respectively. The pseudopeptide derivative of NKA(4-10), MDL 28,564 behaved as a full or near-to-full agonist in both preparations, its EC50s being 474 nM and 55 nM in the ileum and colon, respectively. 4. Nifedipine (1 microM) abolished the response to septide and [Sar9]SP sulphone in the ileum and produced a rightward shift and large depression of the response in the colon. The response to [beta Ala8]NKA(4-10) was abolished in the ileum and largely unaffected in the colon. 5. The NK1 receptor antagonists, (+/-)-CP 96,34, FK 888 and GR 82,334 competitively antagonized the response to septide and [Sar9]SP sulphone in both preparations without affecting that to [beta Ala8]NKA(4-10). In general, the NK1 receptor antagonists were significantly more potent toward septide than [Sar9]SP sulphone in both preparations. 6. The NK2 receptor antagonists, GR 94,800 and SR 48,968 selectively antagonized the response to [beta Ala8]NKA(4-10) without affecting that to [Sar9]SP sulphone or septide in the ileum and colon. SR 48,968 produced noncompetitive antagonism of the response to the NK2 receptor agonist in the ileum and competitive antagonism in the colon. 7. MEN 10,376 and the cyclic pseudopeptide MEN 10,573 antagonized in a competitive manner the response to [beta Ala8]NKA(4-10) in the ileum and colon. While MEN 10,573 was equipotent in both preparations, MEN 10,376 was significantly more potent in the colon than in the ileum. MEN 10,376was also effective against septide in both preparations, without affecting the response to [Sar9] SP sulphone. MEN 10,573 antagonized the response to [Sar9]SP sulphone and septide in both preparations,pKB values against septide being intermediate, and significantly different from, those measured against[Beta Ala 8]NKA(4-10) and [Sa9]lSP sulphone.8. These findings show that tachykinin NK1 and NK2 receptors mediate contraction of the circular muscle of the guinea-pig ileum and colon. In both preparations NK1 receptor antagonists display higher apparent affinity when tested against septide than [Sar9]SP sulphone. These findings are compatible with the proposed existence of NK1 receptor subtypes in guinea-pig, although alternative explanations (e.g.agonist binding to different epitopes of the same receptor protein) cannot be excluded at present.Furthermore, an intraspecies heterogeneity of the NK2 receptor in the circular muscle of the guinea-pig ileum and colon is suggested.

Animals↗
PubMed1994

Characterization of the tachykinin NK2 receptor in the human bronchus: influence of amastatin-sensitive metabolic pathways.

1. The aim of this study was to characterize the tachykinin NK2 receptor subtype mediating the spasmogenic response in the human isolated bronchus. The motor response to neurokinin A (NKA) and the selective NK2 agonist [beta Ala8]NKA(4-10), as well as the antagonistic effects of cyclic (L659,877) and linear (MEN 10376) peptide NK2 antagonists were assessed in the presence or absence of amastatin (an inhibitor of aminopeptidases A and M). 2. NKA was more potent than [beta Ala8]NKA(4-10) in eliciting bronchoconstriction (pD2 being 7,43 and 6,87 respectively). In the presence of amastatin (1 microM), the estimated affinity of [beta Ala8]NKA(4-10), but not that of NKA, was significantly increased to yield a pD2 of 7,44. 3. L659,877 and MEN 10376 inhibited [beta Ala8]NKA(4-10)-induced contraction with similar affinities; pA2 values were 5.7 +/- 0.22 and 6.3 +/- 0.32, respectively. Amastatin (1 microM) increased the potency of MEN 10376 to 7.28 +/- 0.46, whereas that of L659,877 was unaffected. 4. In the presence of amastatin the pseudopeptide MDL 28,564 behaved as a partial agonist. 5. We conclude that the NK2 receptor subtype present in the human bronchus has properties similar to those described for the circular muscle of the human colon and thus may be classified as a 'NK2A' subtype. We show that the apparent potency of peptides, bearing N-terminal acidic residues, is influenced by an amastatin-sensitive peptidase, possibly aminopeptidase A.

Amino Acid Sequence↗
PubMed1993

MEN 10,573 and MEN 10,612, novel cyclic pseudopeptides which are potent tachykinin NK-2 receptor antagonists.

The activity and selectivity of MEN 10,573 and MEN 10,612, novel cyclic pseudopeptides which are selective tachykinin NK-2 receptor antagonists is described, as compared to that of previously characterized linear and cyclic compounds. For the NK-2 receptor, the activity of test compounds was investigated in the hamster isolated trachea (HT) and the endothelium-deprived rabbit isolated pulmonary artery (RPA), two preparations which are endowed with pharmacologically distinct forms of the NK-2 receptor. The novel cyclic pseudopeptides, MEN 10,573 and MEN 10,612 displayed very high affinity for the NK-2 receptor in the HT (pA2 8.66 and 9.06, respectively) which is higher than that observed in the RPA (pA2 7.31 and 7.41 for MEN 10,573 and MEN 10,612, respectively). The antagonism exerted by MEN 10,573 and MEN 10,612 was of competitive nature in both preparations. MEN 10,573 and MEN 10,612 also displayed competitive antagonism for NK-2 receptor-mediated responses in the rabbit bronchus (RB), rat vas deferens (RVD), circular muscle of the human colon (HUC) and ileum (HUI). In the RB, HUC and HUI, the potency of the novel cyclic pseudopeptides was comparable to that of MDL 29,913 and about 10-fold greater than that of L659,877. In the RVD however, the potency of MEN 10,573 MEN 10,612 or MDL 29,913 was similar to that of L659,877. In anaesthetized rats, i.v. injection of MEN 10,612 produced a selective and long-lasting blockade of the urinary bladder contraction produced by the i.v. injection of the NK-2 receptor selective agonist [beta Ala8]neurokinin A(4-10), without affecting the response to the NK-1 receptor selective agonist [Sar9]substance P sulfone.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1993

In vivo and in vitro pharmacology of SR 48,968, a non-peptide tachykinin NK2 receptor antagonist.

The activity of SR 48,968, a novel non-peptide antagonist of tachykinin NK2 receptors was evaluated in vitro in several bioassays for the NK2 receptor (rabbit pulmonary artery, rabbit bronchus, hamster trachea, rat vas deferens) and compared to that of the peptide antagonists, MEN 10,376, L 659,877 and MDL 29,913. SR 48,968 behaved as a potent and competitive antagonist in the four isolated preparations (pA2 values between 8.3 and 9.6 in different preparations), being more potent (about 10 times) in the rabbit pulmonary artery and rabbit bronchus than in the hamster trachea or rat vas deferens. The antagonistic profile of SR 48,968 resembled that of MEN 10,376, and contrasted with those of L 659,877 and MDL 29,913 which were distinctly more potent on the hamster trachea and rat vas deferens. In vivo, SR 48,968 (0.1 mumol/kg i.v.) blocked the contraction of rat urinary bladder stimulated by [beta Ala8]neurokinin A-(4-10) (NK2 receptor agonist) without affecting that produced by [Sar9]substance P sulfone (NK1 receptor agonist). The hypotension and salivary secretion produced by the latter agonist were not modified by SR 48,968. In contrast, (+/-)-CP 96,345 (10 mumol/kg i.v.) blocked bladder contraction, salivary secretion and hypotensive responses elicited by the NK1 receptor agonist while leaving unaffected the bladder contraction produced by the NK2 receptor agonist. SR 48,968 is a potent and competitive antagonist of the tachykinin NK2 receptor with a limited but distinct ability to discriminate between putative subtypes/species variants of the NK2 receptor. The high potency and selectivity of SR 48,968 make this novel compound an important tool for studying the distribution and function of tachykinin NK2 receptors.

Amino Acid Sequence↗
PubMed1993

Intraurethral capsaicin produces reflex activation of the striated urethral sphincter in urethane-anesthetized male rats.

The effect of intraurethral application of capsaicin on the urethral motility of urethane anesthetized rats has been investigated. The urinary bladder and the urethra were surgically disconnected, and both organs were cannulated to record variations in intraluminal pressure (cystourethrogram). Urinary bladder reflex contractions in response to intravesical infusion of saline were paralleled by activation of the external striated urethral sphincter, resulting in intraluminal pressure high frequency oscillations (IPHFO) which were recorded at the urethral level. Intraurethral capsaicin (0.2 microgram./30 microliters.), produced an immediate enhancement of the IPHFO, the amplitude of which (70 +/- 9 mm.Hg) was significantly (p < 0.01) higher as compared with that recorded before drug administration (15 +/- 3 mm.Hg). The potentiation was followed (11 of 15 rats) by a period (5 to 12 minutes) characterized by a continuous low-amplitude urethral phasic activity. Throughout this period urinary bladder motility was inhibited. A second administration of capsaicin in the same animal was ineffective, and the response was absent in rats desensitized to capsaicin (50 mg./kg., subcutaneously, 4 days before), after application of tetrodotoxin (10 micrograms.) on the pudendal nerves, or after acute (3 hours before) sectioning, as well as in rats pretreated with d-tubocurarine (d-Tc, 100 micrograms./kg. intravenously). Intraurethral injection of capsaicin (0.2 microgram./30 microliters.), performed when the urinary bladder was empty, triggered IPHFO (12 +/- 3 mm.Hg) in 5 of 6 rats. This response was unaffected by hexamethonium (20 mg./kg., intravenously) or after removal (6 hours before) of the major pelvic ganglia, while it was absent after destruction of the lumbosacral spinal cord (3 to 6 hours before), in rats acutely spinalized (T13-L1), or after sectioning of the pudendal nerves. In rats receiving intrathecal (L5-S1) capsaicin (60 micrograms., 24 hours before), the capsaicin-induced IPHFO activation was lacking. Electrical field stimulation (EFS, 0.1 Hz, 30 microseconds, 20 to 30 v) of the rat isolated external urethral sphincter (EUS), elicited d-tubocurarine and tetrodotoxin-sensitive twitch contractions, the amplitude of which was unaffected by capsaicin (1 microM.). Altogether these results suggest a physiological interaction between capsaicin-sensitive primary afferents innervating the urethra and the somatic efferent innervation to the urethral rabdosphincter. Present findings suggest the existence of a chemonociceptive urethro-urethral neural loop which, via pudendal nerves, leads to a supraspinally-mediated activation of the external urethral sphincter.

Afferent Pathways↗
PubMed1993

Characterization of the tachykinin neurokinin-2 receptor in the human urinary bladder by means of selective receptor antagonists and peptidase inhibitors.

The tachykinin (NK2) receptor-mediating contraction of the human isolated bladder to NKA was investigated by studying the affinities of eight structurally different receptor-selective antagonists (linear peptides, cyclic peptides and pseudopeptides, nonpeptide NK2 receptor antagonists). The affinities of the antagonists were compared to those measured for the same ligands at the NK2 receptors previously characterized in the rabbit pulmonary artery and hamster trachea. In the presence of a cocktail of peptidase inhibitors (bestatin captopril and thiorphan, 1 microM each) no significant correlation was found between pA2 values measured in the human bladder vs. those measured in the other two NK2 receptor-bearing preparation. In the presence of the aminopeptidase inhibitor amastatin, however, pA2 values of linear antagonists bearing an N-terminal Asp residue MEN 10,207 and MEN 10,376 were significantly enhanced and these pA2 values were used for analysis; a significant correlation was found between pA2 values measured in the human urinary bladder and rabbit pulmonary artery. The pseudopeptide analog of NKA (4-10), MDL 28,564 which also bears a N-terminal Asp residue behaved as an agonist and its action was enhanced by amastatin. We conclude that the NK2 receptor-mediating contraction of the human urinary bladder smooth muscle is similar to that previously characterized in the rabbit pulmonary artery (NK2A receptor category); in the human bladder smooth muscle an amastatin-sensitive peptidase (possibly aminopeptidase A) limits biological activity of linear peptide derivatives of NKA bearing a N-terminal Asp residue.

Adult↗
PubMed1993

Tachykinins and reflexly evoked atropine-resistant motility in the guinea pig colon in vivo.

Distension of a balloon placed in the proximal colon of anesthetized, guanethidine- and naloxone-pretreated guinea pigs elicited a series of long-lasting regular phasic pressure waves which were suppressed by hexamethonium. Activity evoked by a low degree of balloon distension was largely, but not completely, suppressed by atropine. Further balloon distension in atropine-treated animals enabled us to study the effect of tachykinin receptor antagonists on the atropine-resistant and hexamethonium-sensitive response to distension. The selective tachykinin receptor antagonists, (+/-)-CP 96,345 for the NK-1 receptor and L 659,877, MEN 10,376 and SR 48,968 for the NK-2 receptor, inhibited with varying potency the atropine-resistant response to distension. These antagonists also blocked the contraction of the guinea pig colon produced by the i.v. administration of selective NK-1 and NK-2 receptor agonists. In vitro experiments, using mucosa-free circular muscle strips from the guinea pig colon, proved the existence of functional NK-1 and NK-2 receptors in this tissue. We conclude that both NK-1 and NK-2 receptors participate in the atropine-resistant reflex contractions produced by localized balloon distension of the guinea pig colon in vivo.

Animals↗
PubMed1992

Differential effects of various xanthines on pentylenetetrazole-induced seizures in rats: an EEG and behavioural study.

The present study deals with the EEG (electroencephalogram) and behavioural effects of a subconvulsant dose (30 mg/kg i.p.) of pentylenetetrazole in freely moving rats pretreated (100 mg/kg p.o., 1 h before pentylenetetrazole) with two classic (theophylline and caffeine) and two new (enprofylline and isbufylline) xanthines. In rats treated with vehicle, pentylenetetrazole caused a slight desynchronization of the EEG, characterized by periods of 'wave discharges', and 'spike-and-wave discharge complexes'. In rats pretreated with xanthines (theophylline or caffeine) pentylenetetrazole produced a dramatic increase in ictal seizures with the appearance of continuous spikes; concomitantly animals experienced myoclonic jerks (100%) and in some cases (ca. 20%) the animals died. In contrast, in enprofylline-pretreated rats, pentylenetetrazole induced only brief periods of wave discharges and spike-and-wave discharge complexes whose duration was significantly reduced compared to that of controls, although these discharges were associated with mild epileptic behaviour. When isbufylline-pretreated rats were challenged with pentylenetetrazole, the EEG was characterized by a short run of wave discharges (whose duration was shorter than that of other groups). No enprofylline- or isbufylline-treated rats developed seizures or died. In conclusion, only xanthines with strong adenosine A1 receptor antagonism (theophylline and caffeine) markedly enhance the EEG and behavioural effects of a subconvulsive dose of pentylenetetrazole. The present experimental approach could be used to evaluate the pro-convulsive potential of new xanthine derivatives.

1-Methyl-3-isobutylxanthine↗
PubMed1992

Heterogeneity of NK-2 tachykinin receptors in hamster and rabbit smooth muscles.

The possible existence of NK-2 receptor subtypes in peripheral smooth muscle preparations from rabbit and hamster was investigated by studying the effect of neurokinin A, the selective NK-2 receptor agonist [beta Ala8] neurokinin A (4-10), the selective NK-2 tachykinin receptor antagonists, MEN 10,376, L 659,877 and R 396, and the pseudopeptide derivative of neurokinin A (4-10), MDL 28,564. All experiments were performed in the presence of peptidase inhibitors (captopril, bestatin and thiorphan, 1 microM each). Both neurokinin A and [beta Ala8] neurokinin A (4-10) produced concentration-dependent contractions of the rabbit isolated bronchus and hamster isolated stomach and colon, as well as enhancement of the nerve-mediated twitches of rabbit isolated vas deferens (pars prostatica). MEN 10,376, L 659,877 and R 396 antagonized the effect of the NK-2 receptor selective agonist in all four tissues under study, although marked differences in antagonist potency were evident for the three antagonists. Thus MEN 10,376 was distinctly more potent (about 100 times) in rabbit than in hamster preparations while L 659,877 and R 396 were more potent in hamster than rabbit preparations. MDL 28,564 showed a distinct agonist character in rabbit preparations while it was virtually inactive in hamster preparations, where it antagonized the effect of the NK-2 receptor selective agonist.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1992

Tachykinin antagonists inhibit nerve-mediated contractions in the circular muscle of the human ileum. Involvement of neurokinin-2 receptors.

The effects of some newly developed tachykinin antagonists that are selective for the neurokinin (NK)-1 (L 668,169) or the NK-2 (MEN 10,207, L 659,877 and R 396) tachykinin receptor on the cholinergic and noncholinergic contraction and on the nonadrenergic noncholinergic relaxation produced by electrical field stimulation (50 Hz) were investigated in mucosa-free circular strips of the human ileum. The strips were contracted by substance P and neurokinin A as well as by selective NK-2-receptor ligands, [beta Ala8]neurokinin A(4-10), and MDL 28,564, the latter peptide being capable of discriminating between NK-2-receptor subtypes. The selectivity of the antagonists for NK-1 or NK-2 receptors was confirmed in pharmacological experiments using substance P, neurokinin A, and [beta Ala8]neurokinin A(4-10) as stimulants. Among the NK-2-selective antagonists, MEN 10,207 displayed the highest affinity, followed by L 659,877 and R 396. The antagonists MEN 10,207 and L 659,877 inhibited the noncholinergic contraction to electrical stimulation in a concentration-dependent manner; L 668,169 and R 396 were poorly effective. Thus the potency of antagonists toward the noncholinergic response closely paralleled their rank order of potency at NK-2 receptors. The cholinergic contraction and nonadrenergic noncholinergic relaxation were not inhibited by the antagonists. Both substance P- and neurokinin A-like immunoreactivities were detected in extracts of the human ileum, and the identity of the corresponding peptides was confirmed by reverse-phase high-performance liquid chromatography. It was concluded that in addition to NK-1 receptors, the circular muscle of the human ileum also contains NK-2 receptors. Activation of the latter is chiefly responsible for the noncholinergic contraction to nerve stimulation.

Aged↗
PubMed1992

Affinity of R 396, an NK-2 tachykinin receptor antagonist, for NK-2 receptors in preparations from different species.

We have assessed the affinity of R 396 (Ac. Leu-Asp-Gln-Trp-Phe-Gly NH2) in a number of NK-2 tachykinin receptor bearing-tissues from several species. The cyclic analog of R 396, (MEN 10354) was less potent and selective than the linear hexapeptide at NK-2 tachykinin receptors subtypes in the rabbit pulmonary artery and hamster trachea. The affinity of R 396, as measured by a smooth muscle contraction assay and a radioligand binding assay, was higher (about 10 fold) for NK-2 receptors expressed in hamster tissues (urinary bladder, stomach and trachea) than in rat tissues (urinary bladder, vas deferens, colon and stomach) and a further drop in affinity was observed in bovine tissues (urinary bladder and stomach) or rabbit bronchus. The results are discussed in relation to the proposed existence of NK-2 receptor subtypes and raise the question of the existence of species-related differences as compared to the existence of true receptor subtypes.

Amino Acid Sequence↗
PubMed1992

Interaction of amyloid beta protein (25-35) with tachykinin receptors.

Amyloid beta protein (25-35) failed to significantly interact with tachykinin NK1 (rat forebrain, guinea-pig ileum) NK2 (rabbit pulmonary artery, hamster trachea) or NK-3 (guinea-pig cortex) receptors, as determined by radioligand binding and functional assays. A weak interaction (Ki 14.8 microM) was detected with NK2 receptors in rat small intestine. It appears unlikely that direct interaction with tachykinin receptors may account for the reported ability of amyloid beta protein (25-35) to affect neuronal survival.

Amino Acid Sequence↗
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↗