Spinal effects of selective NK-1 and NK-2 receptor antagonists on bladder motility in anesthetized rats.
Explore the source record for details and available documents.
2-Amino-5-phosphonovalerate↗
Biomedical subjects
S Giuliani
Publications and source records attributed to S Giuliani.
Evidence for the presence of a septide-sensitive tachykinin receptor in the circular muscle of the guinea-pig ileum.
The selective tachykinin NK1 receptor agonists, septide ([Glp6,Pro9]substance P-(6-11)) and [Sar9]substance P sulfone, both produced concentration-dependent contraction of the circular muscle of the guinea-pig ileum (EC50 values 36 and 84 pM, respectively). The potent and selective NK1 receptor antagonist (+/-)-CP 96,345 antagonized the response to septide with significantly higher affinity than it did the response to [Sar9]substance P sulfone (pA2 values 9.24 and 8.17, respectively) without modifying the response to the selective NK2 receptor agonist, [beta-Ala8]neurokinin A-(4-10). These findings indicate that the septide-sensitive receptor in the circular muscle of the guinea-pig ileum is recognized with high affinity by the NK1 receptor selective antagonist (+/-)-CP 96,345.
Animals↗
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↗
Familial idiopathic strio-pallido-dentate calcifications with late onset extrapyramidal syndrome.
A family with autosomal dominant inheritance of idiopathic strio-pallidodentate calcifications and late onset of extrapyramidal symptoms is reported. Clinical features consisted of parkinsonism in one member and postural tremor in two. Depression and dysarthria were present in all cases. All symptomatic members showed a peculiar biochemical abnormality consisting of reduced 25-OH vitamin D3 with normal levels of 1,25(OH)2 vitamin D3, suggesting an inborn error of Vitamin D metabolism. The biochemical, clinical, and genetic pattern of this family distinguishes this syndrome from the larger group of secondary familial basal ganglia calcifications.
Adult↗
Multiple inhibitory mechanisms mediate non-adrenergic non-cholinergic relaxation in the circular muscle of the guinea-pig colon.
The mechanisms responsible for nerve-mediated, non-adrenergic, non-cholinergic (NANC) relaxation in mucosa-free circular muscle strips from the proximal colon of the guinea-pig were investigated. Electrical field stimulation (EFS, 1-20 Hz, trains of 5 s duration, 100 V, 0.25 ms pulse width) in the presence of atropine (1 mumol/l) and guanethidine (3 mumol/l) evoked a triphasic motor response consisting of: (a) a primary relaxation, (b) a rebound contraction and (c) a secondary relaxation. These three responses were abolished by tetrodotoxin (1 mumol/l). B oth apamin (0.01-0.3 mumol/l), a known blocker of low conductance, calcium-activated potassium channels in smooth muscles, and L-nitro-arginine (L-NOARG) (1-100 mumol/l), a known blocker of nitric oxide (NO) synthase, increased the tone of the strips. Maximum effects on tone were observed with 0.1 mumol/l apamin (21 +/- 3% of KCl-induced contraction) and 30 mumol/l L-NOARG (26 +/- 4% of KCl response). The combined administration of 0.1 mumol/l apamin and 30 mumol/l L-NOARG produced an increase in tone (47 +/- 5% of KCl response) that was larger than that produced by either compound alone. Neither apamin (0.1 mumol/l) nor L-NOARG (30 mumol/l) affected the isoprenaline-induced relaxation. Apamin (0.1 mumol/l) depressed, but did not abolish, the primary relaxation to EFS at all frequencies without affecting the secondary relaxation.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Cyclophosphamide-induced cystitis in rats: involvement of capsaicin-sensitive primary afferents.
The involvement of capsaicin-sensitive primary afferent neurons has been investigated in a rat model of cyclophosphamide (CYP)-induced cystitis. CYP (150 mg/kg i.p., 48 h before) was administered in both vehicle- and capsaicin-(50 mg/kg s.c., 4 days before)-treated rats. Some experiments were performed 96 h after bilateral removal of pelvic ganglia (bladder denervation). CYP produced a marked detrusor hyperreflexia which was abolished by capsaicin pretreatment. CYP produced a marked increase in bladder weight and plasma protein extravasation (PPE, measured by Evans blue leakage technique): CYP-induced PPE was reduced by bladder denervation and was aggravated by capsaicin pretreatment. PPE aggravation by capsaicin was abolished by ganglionectomy. The bladder content of calcitonin gene-related peptide, was unaffected CYP. We conclude that CYP-induced decrease in bladder capacity is entirely mediated through stimulation of capsaicin-sensitive bladder afferents. At the time chosen as end point in these experiments, capsaicin-sensitive afferents exert an antiinflammatory influence on CYP-induced cystitis.
Animals↗
Evidence for a role of tachykinins as sensory transmitters in the activation of micturition reflex.
The possible involvement of tachykinin neurokinin-1 and neurokinin-2 receptors in the activation of various micturition-related reflexes was assessed by the intrathecal administration of selective neurokinin-1 or neurokinin-2 receptor antagonists at lumbosacral spinal cord level in urethane-anaesthetized rats. The effect of the glutamate N-methyl-D-aspartate receptor antagonist, 2-amino-5-phosphonovaleric acid, was also investigated for comparison. The effect of antagonists was investigated on: (i) the chemonociceptive vesicovesical reflex activated by topical application of capsaicin onto the urinary bladder; (ii) the distension-induced micturition reflex produced by transvesical filling with saline; (iii) distension-induced rhythmic bladder contractions in isovolumetric conditions (urethra-ligated rats); and (iv) the somatovesical excitatory reflex caused by noxious perineal pinching. The neurokinin-2 receptor selective antagonists MEN 10,376 and SR 48,968 were ineffective in the three models in all doses tested. Selective neurokinin-1 receptor antagonists blocked the chemonociceptive reflex produced by topical application of capsaicin with the rank order of potency (lowest effective dose in brackets): GR 82,334 (1 nmol/rat) > RP 67,580 (10 nmol/rat) > (+/-)CP 96,345 (100 nmol/rat). Unlike GR 82,334, RP 67,580 (10 nmol/rat) and (+/-)CP 96,345 (100 nmol/rat) were also effective on the distension-induced micturition reflex elicited by transvesical filling. Similarly, distension-induced rhythmic contractions were inhibited by RP 67,580 (10 nmol/rat) and (+/-)CP 96,345 (100 nmol/rat) whereas the effect of GR 82,334 was not significant. RP 68,651, the enantiomer of RP 67,580 devoid of neurokinin-1 receptor blocking activity, was inactive in both models. 2-Amino-5-phosphonovateric acid (250 nmol/rat) blocked the three types of vesicoexcitatory reflexes. Intravenous administration of (+/-)CP 96,345, RP 67,580 or 2-amino-5-phosphonovateric acid at the same doses proven effective after the intrathecal route, had no effect on distension-induced rhythmic contractions. To ascertain whether the effect of neurokinin-1 receptor antagonists or 2-amino-5-phosphonovaleric acid may be related to a blockade of tachykinins released from capsaicin-sensitive primary afferent neurons, the effect of RP 67,580 was investigated on the distension-evoked micturition reflex in capsaicin-pretreated rats. Capsaicin pretreatment (50 mg/kg, subcutaneously, four days before) increased bladder capacity. RP 67,580 was no longer effective in capsaicin-pretreated rats. In contrast, 2-amino-5-phosphonovateric acid produced a further increase in bladder capacity in capsaicin-pretreated rats. We conclude that tachykinin neurokinin-1 but not neurokinin-2 receptors are involved in the activation of vesicoexcitatory micturition-related reflexes in the rat spinal cord.(ABSTRACT TRUNCATED AT 400 WORDS)
2-Amino-5-phosphonovalerate↗
Effect of bradykinin and tachykinin receptor antagonist on xylene-induced cystitis in rats.
The effects of the bradykinin receptor selective antagonist, Hoe 140, and of the tachykinin NK-1 receptor antagonist (+/-)CP 96,345 were investigated in a rat model of chemically-induced cystitis (intravesical instillation of xylene in female rats). Intravenous injection of bradykinin (1 mumol./kg.) or substance P (3 nmol./kg.) produced plasma protein extravasation (PPE) in the rat urinary bladder. Bradykinin response was prevented by Hoe 140 (100 nmol./kg. intravenously) and unaffected by (+/-)CP 96,345 (10 mumol./kg. intravenously). Plasma protein extravasation produced by substance P was inhibited by (+/-)CP 96,345 but unchanged by Hoe 140. Catheterization required for intravesical xylene instillation into the female rat bladder produced per se an inflammatory response which was abolished by either Hoe 140 or (+/-)CP 96,345. Intravesical instillation of xylene produced a large PPE response which was reduced by about 65% by Hoe 140 or (+/-)CP 96,345. Combined administration of the two antagonists produced an additive effect on the PPE response to xylene. We conclude that both bradykinin and tachykinins are involved in the inflammatory reaction of the rat urinary bladder to catheterization and xylene irritation.
Administration, Intravesical↗
Failure of L-nitroarginine, a nitric oxide synthase inhibitor, to affect hypotension and plasma protein extravasation produced by tachykinin NK-1 receptor activation in rats.
1. We have assessed the effect of L-nitroarginine (L-NOARG), a nitric oxide (NO) synthase inhibitor, on hypotension and plasma protein extravasation produced by i.v. administration of substance P (SP) in urethane-anaesthetized rats. 2. I.v. administered SP (1 nmol kg-1) produced maximal blood pressure lowering effect which was not modified by previous administration of L-NOARG (45.6 mumol kg-1 i.v.). The hypotensive response to SP was greatly reduced by the nonpeptide SP antagonist, RP 67,580 (0.68 mumol kg-1) indicating the involvement of tachykinin NK-1 receptor. L-NOARG caused by itself a sustained increase in both systolic and diastolic blood pressure, while RP 67,580 was without effect. 3. I.v. administration of SP produced plasma protein extravasation in the trachea, ureter and urinary bladder (determined by the Evans blue leakage technique). A dose of 10 nmol kg-1 SP was necessary to produce a maximal effect, while the tachykinin NK-1 receptor selective agonist [Sar9]SP sulphone produced a similar maximal response at 3 nmol kg-1 in the various organs tested. 4. L-NOARG failed to affect plasma protein extravasation produced by either SP or [Sar9]SP sulphone while RP 67,580 inhibited the response to both agents. 5. The present findings fail to reveal a significant contribution of NO production in the hypotensive and inflammatory response to NK-1 receptor stimulation in urethane-anaesthetized rats.
Amino Acid Oxidoreductases↗
Effects of capsaicin and 5-HT3 antagonists on 5-hydroxytryptamine-evoked release of calcitonin gene-related peptide in the guinea-pig heart.
1. The effect of 5-hydroxytryptamine (5-HT) on the release of calcitonin gene-related peptide (CGRP) was studied directly in the isolated perfused heart and indirectly in the isolated left atria of guinea-pig. 2. 5-HT injection into the guinea-pig isolated and perfused heart evoked a dose-dependent (1-100 microM) release of CGRP-like immunoreactivity (LI) that was abolished by in vitro pretreatment with capsaicin and was not affected by indomethacin. 3. Chlorophenyldiguanide (CPD, 100 microM), but not 8-hydroxy-dipropylaminotetralin (8-OH-DPAT, 100 microM), sumatriptan (100 microM) or 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI, 100 microM) evoked a release of CGRP-LI. Ondansetron (10 microM) or ICS205-930 (20 microM) completely abolished the 5-HT (100 microM)-evoked CGRP-LI release. 4. In the isolated electrically driven left atria of the guinea-pig 5-HT (1-10 microM) and CPD (3-100 microM) produced a positive inotropic response, which was abolished by capsaicin pretreatment. 8-OH-DPAT (10 microM) and DOI (10 microM) were inactive. Ondansetron inhibited the response to 5-HT with a pA2 of 6.50 (CL 6.08-6.91). 5. It is concluded that 5-HT causes a release of CGRP in the whole heart and a positive inotropic response in the isolated atria of guinea-pig. Both these effects are sensitive to capsaicin pretreatment and to 5-HT3 antagonists.
Animals↗
A comparison of capsazepine and ruthenium red as capsaicin antagonists in the rat isolated urinary bladder and vas deferens.
1. The ability of capsazepine, a recently developed capsaicin receptor antagonist, to prevent the effects of capsaicin on the rat isolated urinary bladder (contraction) and vas deferens (inhibition of electrically-evoked twitches) was compared to that of ruthenium red, a dye which behaves as a functional antagonist of capsaicin. 2. In the rat bladder, capsazepine (3-30 microM) produced a concentration-dependent rightward shift of the curve to capsaicin without any significant depression of the maximal response to the agonist. By contrast, ruthenium red (10-30 microM) produced a non-competitive type of antagonism, characterized by marked depression of the maximal response attainable. Similar findings were obtained in the rat isolated vas deferens in which capsazepine (10 microM) produced a rightward shift of the curve to capsaicin while ruthenium red (3 microM) depressed the maximal response to the agonist. 3. At the concentrations used to block the effect of capsaicin, neither capsazepine nor ruthenium red affected the contractile response of the rat urinary bladder produced by either neurokinin A or electrical field stimulation or the twitch inhibition produced by rat alpha-calcitonin gene-related peptide (alpha CGRP) in the vas deferens. 4. These findings provide additional evidence that both capsazepine and ruthenium red are valuable tools for exploration of the function of capsaicin-sensitive primary afferent neurones. The antagonism of the action of capsaicin by capsazepine is entirely consistent with the proposed interaction of this substance with a vanilloid receptor located on primary afferents, while the action of ruthenium red apparently involves a more complex, non-competitive antagonism.
Animals↗
Role of magnetic resonance imaging (MRI) in detecting liver changes after gallstone extracorporeal shock wave lithotripsy (ESWL).
Recently published literature on biliary extracorporeal shock wave lithotripsy (ESWL) has shown that high-energy ESWL utilizing high kV is more effective than the low-energy ESWL and low kV used previously. Prior studies have not reported injury to the gallbladder or adjacent liver following ESWL. Our study evaluated 29 patients that were treated with high kV ESWL. Magnetic resonance imaging (MRI) was used to study the gallbladder and adjacent liver for possible injury resulting from the high-energy treatment. The patients, selected using the Dornier MPL-9000 United States protocol, underwent ESWL using 18-24 kV (average 21 kV). MRI was done both pre and post-ESWL in all 29 patients. Ten patients had a second treatment to reduce fragment size and, subsequently, had an additional MRI examination. Spin echo MRI images were obtained at the level of the gallbladder fossa using a 0.5-Tesla ESATOM RM 5000 (ESAOTE Biomedica, Genva, Italy.) superconductive unit. Both T1- and T2-weighted images were obtained. In 26 patients the hepatic parenchyma was normal post-ESWL. Two patients had a hyperintense region on T1-weighted images post-ESWL that was felt to be related to pericholecystic fat. A third patient had an abnormality detected on T2-weighted images that was thought to be due to hepatic edema or microhemorrhage. No significant changes were shown by laboratory or concurrent ultrasound examinations. Repeat MRI examinations in these three patients were normal. High-energy ESWL appears as safe as low-energy ESWL in the treatment of patients with symptomatic gallstones.
Adult↗
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↗
Evidence against a peripheral role of tachykinins in the initiation of micturition reflex in rats.
This study investigates the role of peripheral tachykinin receptors in the initiation of reflex urinary bladder contractions in urethane-anesthetized rats. Intravenous administration of the selective tachykinin neurokinin (NK)-1 receptor agonist [Sar9]substance P (SP) sulfone (0.3-30 nmol/kg) or of the selective tachykinin NK-2 receptor agonist [beta Ala8]NK-A(4-10) (0.3-100 nmol/kg) produced dose-related bladder contractions. Among NK-3 receptor agonists, senktide (1-100 nmol/kg) was not effective; [MePhe7] NK-B (3-100 nmol/kg) induced bladder contraction, but the magnitude of the response was only 20 to 25% of that produced by NK-1 or NK-2 agonists. The NK-1 receptor antagonist GR 82,334 (0.1 mumol/kg i.v.) blocked the urinary bladder contraction induced by [Sar9]SP sulfone (1 nmol/kg i.v.), but not that induced by [beta Ala8]NK-A(4-10). On the contrary, the NK-2 receptor antagonist L 659,877 (0.1-1 mumol/kg i.v.) abolished the effect of [beta Ala8] NK-A(4-10) (1 nmol/kg i.v.), but failed to affect the response to [Sar9]SP sulfone. The combined administration of GR 82,334 (0.1 mumol/kg i.v.) and L 659,877 (1 mumol/kg i.v.) blocked the tonic bladder contraction induced by topical application of capsaicin in pelvic ganglionectomized rats (efferent response of sensory nerves), but did not affect the hexamethonium-sensitive phasic reflex bladder contractions evoked by capsaicin in sham-operated rats (chemonociceptive micturition reflex). GR 82,334 (0.1 mumol/kg i.v.) or L 659,877 (1 mumol/kg i.v.), alone or in combination, did not modify cystometric parameters of the volume-evoked micturition reflex.(ABSTRACT TRUNCATED AT 250 WORDS)
Acetylcholine↗
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↗
CT findings in peripheral mononeuropathies.
Thirty-six patients with a peripheral localized nerve lesion (18 of median nerve, 7 of ulnar nerve, 2 of radial nerve, 1 of lateral cutaneous brachii nerve, 1 of sciatic nerve, 5 of peroneal nerve and 2 of tibial nerve), were evaluated by Computed Tomography (CT). We used a high resolution scanner (Siemens Somatom CR) and we performed 2mm thickness slices. Sagittal and coronal reconstructed images were obtained too. Thirty-two out of 36 patients underwent surgery. CT scan was useful in all cases in defining the relationship between nerve lesions and surrounding tissues and in planning surgical procedures. The CT evaluation of tissues densities and characteristics allowed us to define the pathologic nature of the lesions in 10 cases.
Adult↗
Calcitonin gene-related peptide in the regulation of urinary tract motility.
Explore the source record for details and available documents.
Animals↗
Cyclophosphamide cystitis in rats: involvement of capsaicin-sensitive primary afferents.
The involvement of capsaicin-sensitive primary afferent neurons in cyclophosphamide (CYP)-induced cystitis has been investigated in rats. CYP (150 mg/kg) was administered 48 h before testing in both vehicle- and capsaicin- (50 mg/kg s.c., 4 days before) treated rats. Some experiments were also performed 96 h after bilateral removal of pelvic ganglia to produce bladder denervation. CYP administration produced a marked detrusor hyperreflexia which was abolished by capsaicin pretreatment, demonstrating that it is mediated through stimulation of capsaicin-sensitive afferent neurons. CYP administration was followed by a marked increase in bladder weight and plasma protein extravasation (measured by the Evans blue leakage technique). The latter effect was largely prevented by ganglionectomy but was aggravated by capsaicin pretreatment. The effect of capsaicin was suppressed by ganglionectomy. Isolated strips of detrusor muscle from CYP-treated animals developed less tension in response to various stimuli as compared to strips from vehicle-treated animals; however, when contractile responses were expressed as percentage of an internal standard (carbachol-induced contraction) no difference was evident between the two groups. The bladder content of calcitonin gene-related peptide, used as a marker of the bladder afferent fibres that are capsaicin-sensitive in adult rats, was slightly reduced as compared to controls, but the difference can be accounted for by the increased bladder weight. We conclude that CYP-induced cystitis is not accompanied by a toxic effect on bladder nerves and that the decrease in bladder capacity is entirely mediated through stimulation of capsaicin-sensitive afferent fibres, presumably linked to the formation of the irritant metabolite of CYP, acrolein.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗