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C A Maggi

Publications and source records attributed to C A Maggi.

At least 235 records · Page 13Linked to original sources
PubMed1993

Adenosine A1 receptors mediate the presynaptic inhibition of calcitonin gene-related peptide release by adenosine in the rat spinal cord.

Electrical field stimulation evoked a reproducible outflow of calcitonin gene-related peptide-like immunoreactivity (CGRP-LI) from the dorsal half of the rat spinal cord, an effect which was abolished by prior application of capsaicin, tetrodotoxin or removal of extracellular Ca2+. Adenosine (EC50 3.2 microM) and the selective adenosine A1 receptor agonist N6-cyclohexyladenosine (EC50 8.2 nM) inhibited evoked CGRP-LI outflow, while the selective adenosine A2 receptor agonist CGS-21680 was ineffective up to 10 microM. The action of adenosine was prevented by the adenosine A1 receptor selective antagonist 8-cyclopentyl-1,3-dipropylxanthine (30 microM), which did not affect CGRP-LI release on its own.

Adenosine↗
PubMed1993

Evidence for the involvement of bradykinin in chemically-evoked cystitis in anaesthetized rats.

The effect of Hoe 140, a potent bradykinin B2 receptor antagonist, on the micturition reflex and detrusor hyperreflexia induced by chemical cystitis has been investigated in anaesthetized rats. Hoe 140 (1-100 nmol/kg i.v.) produced a dose-dependent blockade of the contraction of the rat urinary bladder induced by i.v. administration of bradykinin (100 nmol/kg) without affecting the response produced by the selective tachykinin NK-1 receptor agonist, [Sar9] substance P (SP) sulfone (1 nmol/kg i.v.). At doses which produce selective and long-lasting blockade of bradykinin receptors in the urinary bladder, Hoe 140 did not modify urodynamic parameters in normal rats. Intravesical instillation of xylene in female rats decreased bladder capacity and increased micturition frequency. These effects also occurred in rats pretreated with capsaicin as adults. Hoe 140 did not modify xylene-induced cystitis. Intraperitoneal administration of cyclophosphamide (150 mg/kg, 48 h before) decreased bladder capacity and increased micturition frequency. These effects of cyclophosphamide were abolished in rats pretreated with capsaicin as adults. Hoe 140 increased bladder capacity and decreased micturition frequency in rats pretreated with cyclophosphamide. Addition of bradykinin (10 mumol/l) to the medium in the superfused rat urinary bladder preparation evoked a prompt increase in the outflow of calcitonin gene-related peptide like immunoreactivity (CGRP-LI). Hoe 140 (3 mumol/l) inhibited (by about 50%) the CGRP-LI out-flow stimulated by bradykinin. These findings demonstrate the participation of bradykinin, through B2 receptors, in the genesis of detrusor hyperreflexia during cyclophosphamide-induced cystitis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

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↗
PubMed1993

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↗
PubMed1993

Calcitonin gene-related peptide (CGRP)1 receptor mediates vasodilation in the rat isolated and perfused kidney.

The vasodilator activity of rat(r) alpha and beta calcitonin gene-related peptide (CGRP) as compared to the structurally related peptide, rAmylin, [Cys(ACM)2,7]human (h)CGRP and salmon calcitonin, was investigated in the rat isolated and perfused kidney which vascular tone was increased by 3 microM noradrenaline. The order of potency in producing vasodilation was alpha CGRP > beta CGRP >> rAmylin. [Cys(ACM)2,7]hCGRP and salmon calcitonin were ineffective. The activity of alpha and beta forms of rCGRP and rAmylin was antagonized by hCGRP (8-37), a CGRP1 receptor antagonist, at a concentration which did not affect acetylcholine-induced vasodilation. These results indicate the involvement of CGRP1 receptor in the CGRP-induced vasodilation in the rat kidney.

Animals↗
PubMed1993

Substance P increases cyclic GMP levels on coronary postcapillary venular endothelial cells.

The vasodilating effect of substance P (SP) at the microvascular level is endothelium-dependent. In the present study we evaluated whether SP activates nitric oxide (NO) production by venular endothelial cell. We evaluated NO activation by measuring cyclic GMP levels in cultured endothelial cells isolated from coronary postcapillary venules of bovine origin (CVEC). Our results indicate that 5 min exposure of CVEC to 10 nM SP doubled basal cyclic GMP levels. Cell treatment with the NO synthase inhibitor L-NMMA reduced the basal levels of cyclic GMP and abolished the effect of SP but did not modify the increase in cyclic GMP in response to exogenous NO. These data indicate that a) microvascular endothelium responds in an autocrine fashion to NO with increased cyclic GMP levels, b) SP activates cyclic GMP pathway through NO production.

Animals↗
PubMed1993

Effect of selective tachykinin receptor antagonists on the growth of human skin fibroblasts.

The effect of synthetic selective tachykinin receptor antagonists was studied on the growth of cultured human skin fibroblasts (HF). Selective antagonists for the NK1 receptor ([D-Pro4, D-Trp7,9,Phe11]-SP(4-11), GR71251 and L 668,169) and the NK2 receptor (L 659,877) were tested against Substance P (SP), against the selective NK1 receptor agonist [beta-Ala4,Sar9, Met(O2)11]-SP(4-11) and against basic Fibroblast Growth Factor (bFGF). All the selective NK1 receptor antagonists, tested at the concentration of 10(-5)M, induced a significant displacement to the right of the dose-response curves induced by SP and by the selective NK1 receptor agonist. The selective NK2 receptor antagonist did not modify the proliferative response to the tachykinins used. The growth promoting effect of bFGF was not modified by any of the tachykinin antagonists tested. These results indicate that the newly developed receptor-selective tachykinin antagonists appear to be a useful tool to assess the biological effects of tachykinin in vitro on cultured isolated cells.

Cell Division↗
PubMed1993

Studies on the mechanism of the contractile action of rat calcitonin gene-related peptide and of capsaicin on the guinea-pig ileum: effect of hCGRP (8-37) and CGRP tachyphylaxis.

Both the neuropeptide calcitonin gene-related peptide (CGRP) and the sensory stimulant drug capsaicin exert excitatory as well as inhibitory actions in the guinea-pig ileum. It has been known that their excitatory effects are due to activation of myenteric neurons. In the present study it has been established that a fairly high concentration (3 microM) of the CGRP antagonist human alpha CGRP (8-37) [hCGRP (8-37)], which has been known to reverse the inhibitory effects of rCGRP, failed to inhibit longitudinal contractions of ileal longitudinal muscle-myenteric plexus strips due to rat (r) CGRP. Instead, a slight enhancement of the contractions was observed, probably due to the inhibition of the relaxant effect. Tachyphylaxis to rCGRP was able to markedly reduce the contractile action of rCGRP but did not influence contractions due to capsaicin (1 microM). It is concluded that myenteric neuronal excitation due to rCGRP involves receptors not sensitive to hCGRP (8-37). Moreover, neuronal excitation by capsaicin does not seem to involve a CGRP-like mediator.

Acetylcholine↗
PubMed1993

Relative contribution of sympathetic and sensory nerves to thermal nociception and tissue trophism in rats.

Neonatal injection of 6-hydroxydopamine (420 mg/kg s.c.) lowered thermal nociceptive threshold (hot plate and tail immersion tests) and increased levels of substance P-like immunoreactivity in the skin (paws, tail, area of vibrissae) of Wistar rats. Chemical ablation of primary afferents, induced in either neonatal or adult rats by systemic administration of capsaicin, increased thermal nociceptive threshold (hot plate), irrespective of 6-hydroxydopamine pretreatment, and reduced substance P-like immunoreactivity in the hind-paw skin of either control or sympathectomized rats. Capsaicin pretreatment of neonatal but not adult rats produced antinociceptive effect in the tail-immersion test and completely reversed the hyperalgesic effect of sympathectomy, without affecting levels of substance P-like immunoreactivity in the tail skin. These findings indicate that sympathetic nerves and different subsets of capsaicin-sensitive primary afferents are involved in the processing of thermal nociceptive input. Corneal and cutaneous lesions were induced by neonatal sensory denervation with capsaicin. Sympathectomy afforded protection against the development of corneal pathology, while it did not affect the occurrence of cutaneous lesions. It appears that a balance in the neuronal activity between sympathetic neurons and trigeminal sensory neurons is critical for maintaining the normal trophism of the cornea, and that sensory neuropeptides play a key role in the maintenance of normal trophism of the skin.

Aging↗
PubMed1993

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↗
PubMed1993

The role of neurokinin and N-methyl-D-aspartate receptors in synaptic transmission from capsaicin-sensitive primary afferents in the rat spinal cord in vitro.

The rat spinal cord with connected dorsal root ganglia was used to study neurokinin and N-methyl-D-aspartate receptors involved in the sensory synaptic transmission of dorsal horn cells. Selective C-fibre excitation was produced by capsaicin (200-500 nM) administered to the dorsal root ganglions. Sixty-nine per cent of dorsal horn cells responded with a postsynaptic depolarization and enhanced synaptic activity, recorded via intracellular electrodes, to capsaicin-activated primary afferent input. Dorsal horn neurons activated by the capsaicin-evoked input were also excited by a 1-min perfusion of the neurokinin-1 receptor agonists substance P methyl ester or GR73 632 and by the neurokinin-2 agonist neurokinin-A. These cells were also depolarized by N-methyl-D-aspartate. Responses to substance P methyl ester and GR73 632 were selectively reduced by the neurokinin-1 receptor antagonist CP96,345, and responses to neurokinin-A were completely blocked by the neurokinin-2 receptor antagonist MEN10 376. The depolarization evoked by N-methyl-D-aspartate was not altered by either of the antagonists, but was completely blocked by the selective N-methyl-D-aspartate receptor antagonist (-)-2-amino-5-phosphonovaleric acid. Capsaicin-evoked responses in the dorsal horn were inhibited by MEN10,376 (63 +/- 13% inhibition) but no significant change was observed with CP96,345. The N-methyl-D-aspartate receptor antagonist (-)-2-amino-5-phosphonovaleric acid consistently inhibited the capsaicin-induced response by 76 +/- 14%. Combination of (-)-2-amino-5-phosphonovaleric acid and MEN10,376 produced an almost complete abolition of the capsaicin-evoked depolarization.(ABSTRACT TRUNCATED AT 250 WORDS)

2-Amino-5-phosphonovalerate↗
PubMed1993

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↗
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

Relief of pain following intravesical capsaicin in patients with hypersensitive disorders of the lower urinary tract.

We have extended our earlier observations on pain relief produced by intravesical instillation of capsaicin (10 microM in saline) in patients with hypersensitive disorders of the lower urinary tract. Patients in group A (n = 15) received intravesical capsaicin on days 0, 14 and 28: on each occasion the drug produced a warm or burning sensation, reduction in bladder capacity and a delayed, transient improvement or disappearance of symptoms. Patients in group B (n = 5) received intravesical capsaicin (10 microM at cystometry) 3 times on day 0. The initial sensation of warmth was experienced on each occasion, indicating that no significant desensitisation has been produced by the first instillation. Clinical improvement similar to that found in group A was observed. Three patients (group C) received warm saline (42 degrees C) at cystometry. This produced a pricking sensation, no change at cystometry and no subjective clinical improvement. Apart from the initial sensation of warmth, no patient in group A or B experienced side effects, either local or systemic. These findings confirm that intravesical instillation of capsaicin has a beneficial effect on patients with hypersensitive bladder disorders. Counter-irritation rather than desensitisation of primary afferents could be a possible mechanism of action. Further studies are needed to establish whether the intravesical administration of capsaicin or capsaicin-like agents represents a new form of treatment for relief of bladder pain.

Administration, Intravesical↗
PubMed1993

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↗
PubMed1993

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↗
PubMed1993

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↗