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At least 19 recordsLinked to original sources
PubMed2004

Electrodynamic smooth muscle sphincter: development and biomechanical evaluation of a novel porcine artificial smooth muscle sphincter in a new in vitro stoma simulator.

AIM: Many authors have suggested that the activity of the enteric inhibitory nerves is important in regulating normal gastrointestinal motility and inducing smooth muscle relaxation. Hitherto, no experimental or clinical models exist that transfer these physiological aspects to creating an autologous artificial sphincter for the treatment of major incontinence. Therefore, this study was performed to determine the contractile and relaxant capacity of gastrointestinal muscle types and to investigate the efficiency of a novel smooth muscle sphincter, based on the non-adrenergic, non-cholinergic (NANC) receptive relaxation under electrical field stimulation (EFS). METHODS: For the first step, the isometric tension from isolated circular porcine fundus and colon muscle strips was recorded during pharmacological stimulation (TTX, L-NNA and atropine) and EFS. As a result, a continent electrodynamic smooth muscle sphincter (ESMS) was created by wrapping a fundus muscle flap around an isolated segment of porcine distal colon. The EFS of the free nerve fibers of the flap was realized using a circular platinum wire electrode. Parameters such as threshold of continence, intra/preluminal pressure and fluid passage were analyzed in a newly designed in vitro stoma simulator. RESULTS: Electrical field stimulation produced a maximal and voltage-dependent fundus relaxation to --12.4 mN/mm(2) (frequency of 40 Hz, pulse duration, train duration and voltage of 5 ms, 1 s and 60 mA respectively), which were abolished by N-nitro-L -arginine (L-NNA; 10(-4) M) in a dose-dependent manner, confirming that relaxant responses were mediated by NANC nerves. The results of eight ESMS showed that circular electrical stimulation of the muscle flap caused muscle relaxation with a concomitant and effective reduction in the occlusion pressure. CONCLUSION: The NANC-induced relaxation mechanism of porcine fundus preparations could be transferred to an efficient smooth muscle sphincter with a high threshold of continence and electrically controlled defecation.

Anal Canal↗
PubMed1996

Effect of prostaglandins on cultured porcine iris sphincter muscle cells.

Porcine iris sphincter muscle strips contracted in response to carbachol. The tissue contraction was inhibited by prostaglandin (PG) E2 but not by PGF2 alpha. In order to investigate the effect of PGs on the iris cells, the porcine sphincter muscle cells were grown in culture to a confluence and characterized. Using the secondary culture of cells, the effect of PGs on carbachol-induced cell contraction was investigated. Both PGE2 and PGF2 alpha at 100 microM blocked cell contraction completely. The concentration required to inhibit 50% of the maximum contraction in 15 minutes was 10(-6) M for PGE2 and 10(-6)-10(-7) M for PGF2 alpha. Using PGE2 receptor subtype agonists (EP2 agonist, 11-deoxy-16, 16 dimethyl PGE2 and EP3 agonist, sulprostone), PGE2 receptor involved in the inhibition of carbachol-induced contraction was identified to be of the EP2 subtype. In support of this characterization, the addition of PGE2 to cultured porcine sphincter muscle cells increased intracellular cAMP level. The discrepancy in PGF2 alpha effect on carbachol-induced sphincter muscle contraction between iris tissue strips and cultured cells suggests that nonmuscular cells may be involved in the modulation of the PGF2 alpha effect on sphincter muscle cells in vivo.

Animals↗
PubMed1985

Neurogenic mechanisms in control of the rabbit iris sphincter muscle.

The iris sphincter muscle is supplied with cholinergic, adrenergic and substance P-containing nerve fibers, all with a possible role in the control of pupil size. The functional significance of the various nervous components in the rabbit iris sphincter muscle was examined in vitro and in vivo. The contractile response to electrical stimulation is composed of several contractions, occurring along different time scales. Single pulse stimulation produced an atropine-sensitive twitch. Pulse train stimulation revealed two successive atropine-sensitive twitches followed by a slow, long-lasting contraction, sensitive to Spantide, an antagonist of tachykinins such as substance P. A guanethidine- and phentolamine-sensitive contractile response to pulse train stimulation could be demonstrated in the presence of both atropine and Spantide. Only the Spantide-sensitive response could be completely exhausted by prolonged electrical stimulation. In vivo, neither the adrenergic nor the substance P-containing nerve fibres appeared to contribute to the miotic response to light since Spantide and guanethidine were without effect. This response was inhibited by atropine only.

Animals↗
PubMed1993

[Morphological investigation of external sphincter muscle of the male posterior urethra].

For investigation of function of the male posterior urethra, morphological study was performed in terms of the muscle architecture including sphincter muscle of the posterior urethra. The muscle localization was demonstrated by microdissection in eight male cadavers. Histological examination was also employed with HE staining and immunohistochemical method to detect the nature of these muscles. At the dorsal side, the muscle fibers of the deep trigone were located from the inter-ureteral ridge beyond the bladder neck to the vermontanum surrounding the posterior urethra. They were regarded as the internal urethral sphincter muscles. At the ventral side, the muscle fibers were also found just outside the ventral prostate running from the base to the apex of the prostate. Then, they were circularly located around the membranous urethra. These saddle shaped muscles were proved to be striated muscle by the immunohistochemical examination using anti-Desmin and anti-Myoglobin antibody. Therefore, the external urethral sphincter muscle would consist of the pelvic floor muscles and the urethral sphincter muscles.

Aged↗
PubMed1997

Different responsiveness to nitric oxide-cyclic guanosine monophosphate pathway in cholinergic and tachykinergic contractions of the rabbit iris sphincter muscle.

PURPOSE: In the rabbit iris sphincter muscle, sodium nitroprusside (SNP), a nitric oxide (NO) donor, inhibits cholinergic contraction but does not affect tachykinergic contraction in vitro. The objectives of the current study were to clarify the mechanism for the different responsiveness to NO in cholinergic and tachykinergic muscular contractions, and to examine whether the mechanism for NO-induced inhibition of cholinergic muscular contraction is operative in vivo. METHODS: Iris sphincter muscle was dissected from the rabbit eye pretreated with or without endotoxin (lipopolysaccharide, LPS) in vivo. Cyclic guanosine monophosphate (cGMP) content in the iris sphincter muscle was determined by radioimmunoassay. The motor activity of the ring-shaped iris sphincter muscle was measured isometrically. Sodium nitroprusside, carboxy-2-phenyl-4,4,5,5,-tetramethyl-imidazoline-1-oxyl-3-oxide (C-PTIO, a scavenger of NO radicals), and 8-bromo cGMP (a permeable cGMP analogue) were administered between the first and second administrations of carbachol and neurokinin A, both of which had caused sustained contraction in the iris sphincter muscle. RESULTS: Sodium nitroprusside inhibited the contraction of the iris sphincter muscle caused by carbachol but had no effect on the contraction caused by neurokinin A. Application of C-PTIO significantly reduced SNP-induced cGMP accumulation in the muscle, as well as the SNP-induced inhibition of muscular contraction caused by carbachol. Neither carbachol nor neurokinin A influenced SNP-induced cGMP accumulation in the muscle. Induction of 8-bromo-cGMP significantly diminished the muscular contraction caused by carbachol but not that caused by neurokinin A. In vivo pretreatment of the eye with LPS increased, in a time-dependent manner, the cGMP accumulation in the iris sphincter muscle, which was significantly inhibited by pretreatment of NG-nitro-L-arginine methyl ester (an inhibitor of NO synthesis) in vivo. CONCLUSIONS: These results demonstrate that in rabbits the increase in cGMP accumulation induced by NO in the iris sphincter muscle is involved in the cholinergic contraction but not in the tachykinergic contraction, suggesting that different sensitivities to cGMP are essential for the different responsiveness to NO. Furthermore, the results of this study showed that the NO-cGMP pathway is operative in vivo and regulates iris sphincter muscle tone, at least when the eyes are infected with bacteria.

Animals↗
PubMed1996

Nitric oxide-sensitive and -insensitive contractions of the isolated rabbit iris sphincter muscle.

PURPOSE: The rabbit iris sphincter muscle is innervated by cholinergic and tachykinergic nerves that regulate its tone. To clarify the involvement of nitric oxide (NO) in the postsynaptic regulation of the rabbit iris sphincter muscle tone, the authors examined the effects of NO-related agents on the cholinergic contraction induced by carbamylcholine (carbachol) and the tachykinergic contraction induced by neurokinin A. METHODS: The motor activity of the ring-shaped rabbit iris sphincter muscle was measured isometrically. Sodium nitroprusside (SNP, a NO donor) was administered between the first and second administrations of carbachol and neurokinin A, each of which induced sustained contraction. The effects of carboxy-2-phenyl-4,4,5,5,-tetramethyl-imidazoline-l-oxyl-3-oxide (carboxy-PTIO, a scavenger of NO radicals), NG-monomethyl-L-arginine (L-NAME, an inhibitor of NO formation from L-arginine), and methylene blue (an inhibitor of soluble guanylate cyclase) on contractions induced by carbachol and neurokinin A also were studied. Cyclic guanosine monophosphate (GMP) content in the muscle was determined by radioimmunoassay. RESULTS: Sodium nitroprusside inhibited carbachol-induced contractions of the iris sphincter muscle in a concentration-dependent manner but had no effect on neurokinin A-induced muscle contractions. Carboxy-PTIO and methylene blue significantly diminished the inhibitory effect of SNP on carbachol-induced contractions. L-NAME had no effect on contractions induced by either carbachol or neurokinin A. Sodium nitroprusside alone increased cyclic GMP accumulation in a concentration-dependent manner. CONCLUSIONS: This study showed that SNP inhibited cholinergic contractions mainly through a cyclic GMP-dependent mechanism but did not affect the tachykinergic contractions, indicating that cholinergic contraction is NO sensitive, whereas tachykinergic contraction is NO insensitive. These findings suggest that in rabbits, the cholinergic and tachykinergic responses have distinct features for the fine adjustment of the iris sphincter muscle tone.

Animals↗
PubMed2000

Morphometric study of the sphincter of oddi (hepatopancreatic) and configuration of the submucosal portion of the sphincteric muscle mass.

The sphincter of Oddi (SO) hepatopancreatic sphincter from 114 Japanese adults, especially the sphincteric muscle mass lying in the duodenal mucosal layer (the submucosal portion of the SO: SMSO), was measured macroscopically under a binocular microscope. The SMSO was classified into two types according to shape. The horizontal type (95/114) usually displayed a rod-like shape (6.0 mm at average diameter at the root) directed toward the anus and was situated on the duodenal muscle wall with the papillary orifice at or near the tip (anal side) of the SMSO. The horizontal type SMSO followed the underlying muscle wall widely ranging from 5.0 mm to 17.9 mm length (9.8 mm at average) and was attached to the wall by the loose connective tissue along the entire length. In the horizontal type, the extramural portion (the portion penetrating and outside of duodenal muscle of the SO) of the SO was very small. The vertical type (19/114) erected on the muscle wall vertically into the lumen of the duodenum. The average length and average maximum diameter of the vertical type were 6.0 mm and 6.2 mm, respectively. The extramural portion of the SO was thicker and tighter in the vertical type, which suggested that endoscopic sphincterotomy might preserve the length of the SO longer than endoscopic papillary balloon dilation (EPBD). Of the individuals in our study, 18% (19/114) had SO diameters <5 mm, a finding that may have implications for selection of balloon size in EPBD.

Aged↗
PubMed1992

Local generation and action of angiotensin II in dog iris sphincter muscle.

Existence of the renin-angiotensin system was pharmacologically investigated in the dog isolated iris sphincter muscle. The sphincter muscle contracted in response to tetradecapeptide, a synthetic renin substrate, angiotensin (ANG) I and ANG II dose-dependently. The contractions induced by these peptides were suppressed by treatment with saralasin, indomethacin and aspirin. Contractile responses to tetradecapeptide and ANG I were also reduced by KRI-1314, a renin inhibitor, and captopril, respectively. ANG II stimulated the release of prostaglandin (PG) F2 alpha from the sphincter muscle. Angiotensin-converting enzyme activity was measurable in the sphincter muscle. Miosis was observed by intracameral injection of ANG I and ANG II into the anterior chamber. These results strongly suggest that angiotensin generating enzymes function in the sphincter muscle and ANG II produced by these enzymes contracts the sphincter muscle via the formation of PG (s), possibly PG F2 alpha.

Angiotensin I↗
PubMed1982

Influence of contractility of papillary sphincter muscle on penetrability of the papillary duct in the bovine quarter after machine milking.

It has been suggested that machine milking causes the papillary sphincter muscle (teat sphincter muscle) to relax or to stretch and therefore increases the probability of successful penetration of the papillary duct (streak canal) by microorganisms. To determine the potential for contractile tension of the papillary sphincter muscle to influence penetrability of the papillary duct, selected quarters of individual cows were treated to cause the sphincter muscles to contract at 10 minutes after milking. All quarters were then subjected to a penetrability assay. To cause the papillary sphincter muscles to contract, 1 quarter was dipped into ice water and a 2nd quarter was squeezed twice at the papillary tip. Ice water increases base-line contractile tension and squeezing induces 1 or more rhythmic contractions of the teat sphincter muscle. To measure penetrability, Escherichia coli endotoxin (1 microgram in 2.5 microliters of distilled water; type O128; B12) was inserted 3 mm into all quarters. A 3rd teat was then squeezed at its tip. The 4th teat served as a control. This procedure was repeated for 5 days or until individual quarters responded in terms of a precipitous increase in the Wisconsin mastitis test score. Of a total of 345 observations, chi 2 analysis indicated that the proportion of responsive quarters was the same for each of the 4 treatment groups. Overall, it would seem that the contractile state of the teat sphincter muscle after milking does not significantly affect penetrability of the papillary duct, at least in terms of a solute, such as endotoxin. However, in a subset of animals, pretreating teats to increase contractile tension actually enhanced penetrability.

Animals↗
PubMed1985

[Functional architecture of smooth muscle sphincters: longitudinal and circular muscles, encircling the anal canal in cats and dogs].

The short-lasting 'burst' activity was recorded from decerebrate, unanesthetized cats and dogs, by means of a single, bipolar needle electrode, originally aimed at recording of 'slow spikes' of internal anal sphincters. The recording of the 'burst' was more accessible in cats than in dogs, although the same macro-electrode, of which diameter was 0.3 mm, has been used throughout. There was no such species difference of accessibility for recording of 'slow spikes' of internal sphincters. Histological examinations indicated that the difference of accessibility may be due to relative thinness of muscular tissue in the cat. Some of the bursts were seen simultaneously on the background of continuous 'slow spikes', however, the most of the bursts appeared in reciprocal manner with those 'slow spikes', namely, the bursts were elicited by rectal distension, while the 'slow spikes' of internal sphincters were wholly inhibited by the same distension. The participation of bursts to the anal canal pressure was little in fact, though the longitudinal length of anal canal was invariably shortened, whenever the repetitive bursts occurred either spontaneously or in response. It is concluded that the 'burst' activity is generated by longitudinal muscles of anal sphincters. The observation suggests further that cell-to-cell electrical communication does not operate between longitudinal and circular muscles in this portion, instead, that neural mechanism regulates dominantly for co-ordination of those muscles encircling the anal canal.

Anal Canal↗
PubMed1993

The effect of serotonin on the rabbit isolated iris sphincter muscle.

The rabbit isolated iris sphincter muscle maintained in an isotonic state is unaffected by applied serotonin (5-hydroxytryptamine or 5-HT) whereas carbachol causes the muscle to contract. Serotonin does, however, produce a relaxation of the contracted muscle in a dose-dependent manner. This effect is also induced by the 5-HT receptor agonists 8-OH-DPAT (8-hydroxy-2-[di-n-propyl-amino] tetralin, RU 24969 (5-methoxy-3-[1,2,3,6, tetrahydro-4-pyridinyl]-1-indole) and ipsapirone, suggesting the involvement of 5-HT1A receptors. This view is supported by the finding that metergoline, methysergide and propranolol all counteracted the effect produced by serotonin. While 5-HT3 receptors are not involved in the described process, a minor involvement of 5-HT2 receptors cannot be excluded as methysergide partially counteracted the serotonin response. These data provide evidence that serotonin receptors, in particular the 5-HT1A subtype, may be associated with the iris sphincter muscle and suggest their involvement in the regulation of pupil size.

Animals↗
PubMedDate not supplied

Comparative study of sensitive and vegetative innervation of external and internal anal sphincter muscles in different mammals.

Proprioceptive innervation of the external anal sphincter muscle and the organization of the vegetative and sensitive nerve components of the internal and sphincter muscle have been studied in different mammals. The findings of typical muscle spindles in the external anal sphincter muscle were constant in the pig, frequent in the goat and cow, rare in the sheep and horse and absent in the roe and rabbit. In the pig, muscle spindles were observed in the entire extension of the muscle, while in the sheep, goat, cow and horse, the receptors were found only in the cranial portion of the muscle. In all the species studied, the internal anal sphincter muscle had numerous ganglion cells, isolated or grouped, and rare Pacinian, Pacinian-like, and Golgi-Mazzoni corpuscles. Their functional role has been hypothesized.

Anal Canal↗
PubMed1981

Noncholinergic, nonadrenergic contraction and substance P in rabbit iris sphincter muscle.

In the rabbit iris sphincter muscle, electrical transmural stimulation produced fast and slow components of contraction which were markedly attenuated by tetrodotoxin. The fast component was augmented by physostigmine and was abolished by atropine, while the slow component was little affected. Adrenergic and ganglionic blocking agents did not inhibit the slow component. Therefore, the fast component is probably cholinergic, while the slow one is noncholinergic, nonadrenergic in nature. Capsaicin did produce a considerable contractile response, but there was a gradual decline with repetitive application and a tachyphylaxis occurred. Under such conditions the slow but not the fast component was abolished. Substance P and acetylcholine produced the largest contraction, while ATP, histamine, serotonin and noradrenaline produced little or no response. In cold stored preparations, the responses to electrical transmural stimulation and capsaicin were either markedly attenuated or abolished, whereas substance P and acetylcholine produced considerable contractions. Baclofen and theophylline did not inhibit the slow response to electrical transmural stimulation or the response to substance P and capsaicin. Thus, electrical transmural stimulation produces cholinergic and noncholinergic, non-adrenergic contractions in the rabbit iris sphincter muscle and the latter response is considered to be mediated by substance P or a related peptide released from the neural component.

Acetylcholine↗
PubMed2005

Relaxant effect of adrenomedullin on bovine isolated iris sphincter muscle under resting conditions.

1. The mechanisms involved in the fine adjustment of iris sphincter muscle tone are largely unknown. The aim of the present study was to clarify the effects of adrenomedullin on the resting tension of the bovine isolated iris sphincter muscle. 2. The motor activity of the bovine isolated iris sphincter muscle was measured isometrically. The effects of adrenomedullin on resting tension were analysed in the presence of indomethacin. The presence of adrenomedullin mRNA in the preparation was determined by reverse transcription-polymerase chain reaction. Immunolabelling for adrenomedullin was also performed. 3. Adrenomedullin significantly decreased the resting tension of the muscle. The relaxant effect of adrenomedullin was significantly inhibited by adrenomedullin (22-52), a putative antagonist for the adrenomedullin receptor, or calcitonin gene-related peptide (CGRP) (8-37), a putative antagonist for the CGRP1 receptor. The relaxant effect was almost completely blocked by a combination of adrenomedullin (22-52) and CGRP (8-37). 4. The relaxant effect of adrenomedullin was also significantly diminished by 2',5'-dideoxyadenosine, an inhibitor of adenylate cyclase, N(G)-nitro-L-arginine, an inhibitor of nitric oxide synthesis, or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, an inhibitor of soluble guanylate cyclase. 5. Reverse transcription-polymerase chain reaction analysis showed that adrenomedullin mRNA was expressed in the muscle strip. Immunopositive staining for adrenomedullin was detected in blood vessel cells and in the iris sphincter muscle cells. 6. These results suggest that adrenomedullin may be an autocrine and paracrine regulator of the resting tension of the iris sphincter muscle. Its biological effects may be due to the direct involvement of adrenomedullin receptors and also to the stimulation of CGRP1 receptors. The stimulation of these receptors by the peptide leads to the activation of adenylate cyclase and soluble guanylate cyclase and subsequent relaxation of the muscle strip.

Adrenomedullin↗
PubMed1998

Pharmacological characterization of muscarinic receptors in rabbit isolated iris sphincter muscle and urinary bladder smooth muscle.

1. The pharmacological characteristics of muscarinic receptors in the rabbit iris sphincter muscle were studied and compared to M3 receptors in rabbit urinary bladder smooth muscle. 2. (+/-)-Cis-dioxolane induced concentration-dependent contractions of the iris sphincter muscle (pEC50 = 6.41+/-0.10, Emax = 181+/-17 mg, n = 38) and urinary bladder smooth muscle (pEC50 = 6.97+/-0.04, Emax = 4.28+/-0.25 g, n = 54). These contractions were competitively antagonized by a range of muscarinic receptor antagonists (pK(B) values are given for the iris sphincter muscle and the bladder smooth muscle, respectively): atropine (9.30+/-0.07 and 9.40+/-0.04), AQ-RA 741 (6.35+/-0.04 and 6.88+/-0.03), darifenacin (9.56+/-0.05 and 9.12+/-0.05), methoctramine (5.75+/-0.07 and 5.81+/-0.06), oxybutynin (8.10+/-0.09 and 8.59+/-0.06), pirenzepine (6.79+/-0.05 and 6.89+/-0.04), secoverine (7.54+/-0.05 and 7.66+/-0.05), p-F-HHSiD (7.55+/-0.09 and 7.50+/-0.05) and zamifenacin (8.69+/-0.10 and 8.36+/-0.06). A significant correlation between the pK(B) values in the bladder and the pK(B) values in the iris was obtained. 3. In both tissues, the pK(B) values correlated most favorably with pKi values for these compounds at human recombinant muscarinic m3 receptors. A reasonable correlation was also noted at human recombinant muscarinic m5 receptors given the poor discriminative ability of ligands between m3 and m5 receptors. 4. Overall, the data from this study suggest that the muscarinic receptors mediating contraction of the rabbit iris sphincter muscle and urinary bladder smooth muscle are similar and equate most closely with the pharmacologically-defined muscarinic M3 receptor.

Animals↗
PubMed2003

Fetal surgery for repair of myelomeningocele allows normal development of anal sphincter muscles in sheep.

One major problem for patients with myelomeningocele (MMC) is fecal incontinence. To prevent this problem, fetal surgery for repair of MMC has been recently undertaken. The strategy behind this surgery is to allow normal development of anal sphincter muscles. The purpose of this study was to determine whether fetal surgery for repair of MMC allows normal development of anal sphincter muscles. Myelomeningocele was surgically created in fetal sheep at 75 days of gestation. At 100 days of gestation, fetal surgery for repair of the MMC lesion was performed. Three repair methods were used: standard neurosurgical repair (4 fetal sheep), covering the MMC lesion with Alloderm (2 fetal sheep), and covering the MMC lesion with Gore-Tex (2 fetal sheep). After the sheep were delivered (140 days of gestation), external and internal anal sphincter muscles were analyzed histopathologically. In control fetal sheep (not repaired) anal sphincter muscles did not develop normally. In contrast, in fetal sheep that underwent repair of the MMC, the external and internal anal sphincter muscles developed normally. Histopathologically, in the external sphincter muscles, muscle fibers were dense. In the internal sphincter muscles, endomysial spaces were small, myofibrils were numerous, and fascicular units were larger than those in unrepaired fetal sheep. There was no difference in muscle development for the repair methods. Fetal surgery for repair of MMC allows normal development of anal sphincter muscles.

Anal Canal↗
PubMed1985

Anorectal incontinence and rectal prolapse: differential assessment of the innervation to puborectalis and external anal sphincter muscles.

The innervation of the puborectalis and external anal sphincter muscles was studied in 32 patients with idiopathic (neurogenic) faecal incontinence, 12 of whom also had complete rectal prolapse, using transcutaneous spinal stimulation, transrectal pudendal nerve stimulation, single fibre EMG, anorectal manometry, and measurement of perineal descent. Fourteen normal subjects served as controls. Significant increases in the spinal motor latencies from L1 to the puborectalis and external anal sphincter muscles were shown in all 32 incontinent patients (p less than 0.01). The single fibre (EMG) fibre density was increased in the puborectalis muscle in 60% and in the external anal sphincter in 75% of patients. An increased pudendal nerve terminal motor latency was found in 68% of patients; 69% had an abnormal degree of perineal descent and all had reduced anal canal contraction pressures. These data show that the different innervations of the puborectalis and external anal sphincter muscles are both damaged in patients with anorectal incontinence.

Adult↗
PubMed1997

Characterization of NK3 receptors in rabbit isolated iris sphincter muscle.

1. Tachykinin NK3 receptors were characterized in the rabbit isolated iris sphincter muscle by use of autoradiography and in vitro functional studies. 2. [125I]-[MePhe7]-neurokinin B (NKB) (1nM), a selective NK3 receptor agonist, specifically labelled a population of NK3 receptors that were uniformly distributed throughout the rabbit iris sphincter muscle. This labelling was inhibited by unlabelled [MePhe7]-NKB (1 microM) but not by the NK1 receptor antagonist CP 99994 (1 microM). 3. In the presence of CP 99994 (1 microM), the selective NK3 receptor agonists senktide (n = 14) and [Pro7]-NKB (n = 4), and the natural preferred ligand for the NK3 receptor, NKB (n = 8), were potent contractile agents in the rabbit iris sphincter muscle. They all produced monophasic concentration-effect curves with pD2 values of 9.53 +/- 0.08, 8.56 +/- 0.09 and 9.75 +/- 0.09, and nH values of 0.93 +/- 0.03, 1.53 +/- 0.17 and 0.76 +/- 0.06, respectively. [MePhe7]-NKB (n = 12) was also a potent agonist, but produced shallow concentration-effect curves which appeared biphasic (nH = 0.45 +/- 0.04). 4. Contractile responses to senktide were surmountably antagonized in a concentration-dependent manner by the selective non-peptide NK3 receptor antagonist, SR 142801 (3-30 nM; pA2 = 8.9; slope = 0.99) and the non-peptide NK2/NK3 receptor antagonist, SR 48968 (3-30 microM; pA2 = 6.1; slope = 1.5). These pA2 values were consistent with functional rabbit NK3 receptors more closely resembling guinea-pig and human NK3 receptors, than rat NK3 receptors. SR 142801 (10-100 nM) and SR 48968 (3 and 30 microM) inhibited responses to low (< or = 1 nM) but not higher (> 1 nM) concentrations of [MePhe7]-NKB, and concentration-effect curves to [MePhe7]-NKb became steeper and monophasic in the presence of either antagonist. 5. SR 142801 (3-30 nM) and SR 48968 (3-30 microM) also surmountably antagonized concentration-effect curves to [Pro7]-NKB and NKB, although results were more difficult to interpret, since the relationship between log concentration-ratios and the concentration of antagonist used did not adhere to the Schild equation. However, analysis of data with the lowest concentration of SR 142801 (3 nM) tested against NKB, and SR 48968 (3 microM) tested against [Pro7]-NKB and NKB, yielded apparent pA2 estimates of 9.3, 6.8 and 6.4, respectively, consistent with blockade of NK3 receptors. 6. SR 142801 (100 nM) had no effect on contractions induced by transmural nerve stimulation (2 Hz, 0.3 ms, 20 V for 30 s), whereas CP 99994 (1 microM) abolished these responses. 7. Phenoxybenzamine pretreatment (20 microM, 10 min) markedly reduced maximum responses to [MePhe7]-NKB (from 101 +/- 6.2% to 38 +/- 9.5% reference contraction, n = 4) and induced a marked (10 fold) rightward shift in the concentration-effect curve. The residual responses to [MePhe7]-NKB after phenoxybenzamine pretreatment were unaffected by 1 microM CP 99994 (maximum response = 41 +/- 9.4%, n = 4). 8. These results demonstrate autoradiographically and functionally, the presence of NK3 receptors in rabbit iris sphincter muscle that mediate contractile responses to NK3 receptor agonists, but not to sensory trigeminal nerve simulation. The present data with senktide and selective NK3 receptor antagonists suggest that functional rabbit NK3 receptors more closely resemble human and guinea-pig NK3 receptors than rat NK3 receptors. However, the pharmacological profiles of [MePhe7]-NKB, SR 142801 and SR 48968 suggest the presence of an 'atypical' NK3 receptor or a heterogeneous population of NK3 receptors in this tissue.

Adrenergic alpha-Antagonists↗