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C A Maggi

Publications and source records attributed to C A Maggi.

At least 181 records · Page 10Linked to original sources
PubMed1995

Pharmacological analysis of the local and reflex responses to bradykinin on rat urinary bladder motility in vivo.

1. The topical application of bradykinin (BK) (0.05-5000 pmol/rat) onto the serosal surface of the urinary bladder in urethane-anaesthetized rats, evoked low amplitude tonic contractions (not exceeding 25 mmHg) or high amplitude (about 50 mmHg), phasic reflex contractions (chemoceptive micturition reflex) which were abolished by bilateral ablation of the pelvic ganglia. In ganglionectomized rats, BK induced only a local, tonic-type contraction. 2. Systemic capsaicin pretreatment (164 mumol kg-1, 4 days before) reduced the incidence of chemoceptive reflex induced by BK (500 pmol/rat) but had no effect on the magnitude of the tonic-type contraction elicited by BK in ganglionectomized rats. Indomethacin (11 mumol kg-1, 20 min before) reduced the incidence but not the amplitude of the reflex contractions induced by topical application of BK (500 pmol/rat). In ganglionectomized rats, indomethacin (11 mumol kg-1, 20 min before) decreased the amplitude of the tonic contraction evoked by BK. Indomethacin did not affect the chemoceptive reflex induced by topical application of capsaicin (15 nmol/rat) onto the bladder. 3. Intrathecal administration of the tachykinin NK1 receptor antagonists, RP 67,580 (10 nmol/rat) or SR 140,333 (10 nmol/rat), abolished the chemoceptive reflex induced by BK without modifying the magnitude of the tonic contraction. SR 140,333 (10 nmol/rat) also abolished the occurrence of the chemoceptive reflex induced by capsaicin. 4. Intravenous administration of the B2 receptor antagonist, Hoe 140 (35 nmol kg-1, 10 min before) abolished the reflex and local effects induced by BK on bladder motility but failed to modify the chemoceptive reflex induced by topical application of capsaicin (15 nmol/rat). 5. Intrathecal administration of Hoe 140 (10 nmol/rat) reduced the incidence of the chemoceptive reflex induced by BK but had no effect on the amplitude of the local motor response. Likewise, Hoe 140(10 nmol/rat, i.t.) reduced the incidence of reflex bladder contractions induced by topical application of capsaicin (15 nmol/rat) without affecting the magnitude of the tonic-type contraction.6. These findings indicate that BK stimulates motility through B2 receptors in the rat urinary bladder.BK activates the reflex response by stimulating capsaicin-sensitive afferent nerves with a contribution from prostanoids. At the spinal cord level, tachykinin NK1 and BK B2 receptors could also be involved in the chemoceptive reflex induced by BK or capsaicin.

Adrenergic beta-Antagonists↗
PubMed1995

Calcitonin gene related peptide as inhibitory neurotransmitter in the ureter.

A dense plexus of calcitonin gene related peptide (CGRP) containing nerve fibres is present in the mammalian ureter, from which CGRP is released by depolarizing stimuli, including chemical normally present in the urine. CGRP exerts a profound, receptor-mediated, inhibitory effect on the evoked motility of the ureter by suppressing latent pacemakers in the smooth muscle. This effect is largely glibenclamide sensitive, indicating the activation of potassium (K) channels in its genesis. Electrical stimulation of intramural nerves in the guinea-pig ureter produces a transient membrane hyperpolarization, which is blocked by glibenclamide or by capsaicin pretreatment, enhanced in a low-K medium, and inhibited by a CGRP receptor antagonist. Thus endogenous CGRP acts as a neurotransmitter K channel opener in the ureter. The refractory period of the guinea-pig ureter is markedly and similarly reduced by capsaicin pretreatment or administration of a CGRP receptor antagonist, indicating that endogenous CGRP can modulate the maximal frequency of ureteral peristalsis. Using a three-chamber organ bath that enabled the separate perfusion of the renal, middle, and bladder regions of the organ, evidence was obtained that CGRP blocks propagation of impulses along the ureter through a glibenclamide-sensitive mechanism. These findings indicate a role of CGRP in the local regulation of ureteral motility and peristalsis.

Animals↗
PubMed1995

Proliferation and migration of endothelial cells is promoted by endothelins via activation of ETB receptors.

The growth and migration of endothelial cells are the prerequisites for vascular remodeling. The effects of endothelin (ET)-1 and -3 (ET-1, ET-3) on the proliferation and migration of endothelial cells isolated from bovine adrenal capillaries (BACE) and human umbilical veins (HUVEC) have been investigated. Cell proliferation (measured as DNA synthesis and as total cell number) and migration were significantly increased by ET-1 and ET-3. Dose-dependent proliferation was produced by ET-1 and ET-3 in both cell lines, with maximal effects at 0.1 nM concentration. ET-1 and ET-3 also stimulated BACE and HUVEC mobilization in a dose-dependent manner. The maximal responses were obtained at 10 nM concentration in both BACE and HUVEC. The full agonist for the ETB receptor, ET-(16--21), was able to reproduce the effects of ET on proliferation and migration of both cell lines. Modification of ET-(16--21) at Leu17 and Ile19 and amidation of the COOH-terminal were accompanied by loss of activity. The ETB-receptor antagonist IRL-1038 blocked the migration induced by ET-3 and ET-(16--21), whereas the ETA-receptor antagonist BQ-123 was not effective. We conclude that ETs, by favoring endothelial cell growth and mobilization, can contribute to neovascularization through an autocrine mechanism that requires ETB-receptor activation.

Adrenal Glands↗
PubMed1995

Vesical-renal reflex: diuresis and natriuresis activated by intravesical capsaicin.

In the last years the role of capsaicin sensitive innervation, in the activation of the micturition reflex, has been reported in many papers. In our experience, upon the intravesical administration of capsaicin in humans, we noticed an increase of diuresis. No interaction is known about the sensory innervation of the bladder and renal function, so we studied the possibility of the existence of a vesical-renal reflex arc. Twenty-one patients (9 men and 12 women) were randomised to receive intravesical infusion of saline solution containing 10 microM capsaicin. Urine output, glomerular renal filtrate (GRF) and effective plasma renal flow (EPRF), measured by Technetium-99m diethylenetetramine-penta-acetic acid (DTPA) renal scintigraphy, were recorded over twenty minutes before and after the intravesical administration of capsaicin. Urine density, [Na+] and [K+] concentration, and prostaglandin E2 excretion were also determined before and after intravesical administration of capsaicin or vehicle. Installation of saline solution containing 10 microM capsaicin produced a significant increase of mean urine output, an increase of GRF, of EPRF and of [Na+] and [K+] urine concentration. An increase, not statistically significant, was observed of PgE2 excretion. None of the patients treated with vehicle showed any modification of parameters examined. The present findings demonstrate a hitherto unrecognized effect: increased diuresis following selective chemical stimulation of bladder efferents with capsaicin. The renal diuretic response to intravesical capsaicin represents a working hypothesis about the possible involvement of a vesical-renal reflex arc organized at spinal or supraspinal level.

Administration, Intravesical↗
PubMed1995

Substance P stimulates and inhibits intestinal peristalsis via distinct receptors.

The tachykinins substance P (SP) and neurokinin A participate in the neural control of intestinal peristalsis. This study aimed at elucidating the types of tachykinin receptors involved in SP's ability first to stimulate and then to inhibit propulsive activity. Peristalsis in the guinea pig isolated ileum was triggered by fluid-induced distension of the intestinal wall. Unlike SP, the neurokinin (NK)-1 receptor-selective agonist SP methyl ester (1-100 nM) failed to facilitate peristalsis but caused a delayed inhibition of peristaltic activity. In contrast, the NK-2 receptor-selective agonist [beta-Ala8]-NKA-(4-10) (BANKA, 1-100 nM) stimulated, but did not inhibit, peristalsis. The NK-3 receptor-selective agonist succinyl-[Asp6,N-MePhe8]-substance P-(6-11) (SENKTIDE, 0.1-10 nM) was most potent in facilitating propulsive activity, and only with 10 nM SENKTIDE was a delayed inhibition of peristalsis seen. The receptors responsible for the tachykinin-evoked stimulation and inhibition of peristaltic activity were further characterized by use of the NK-1 receptor-selective antagonist (+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine (CP-99,994, 300 nM) and the NK-2 selective antagonist (-)-N-methyl-N[4-acetylamino-4-phenyl-piperidino-2 (3,4 dichlorophenyl)butyl]-benzamide (SR-48,968, 100 nM). CP-99,994 antagonized the inhibitory effects of SP (100 nM) and SP methyl ester (100 nM) on peristalsis but did not alter the facilitation of propulsive motility brought about by SP or BANKA (100 nM). Conversely, SR-48,968 (100 nM) suppressed the ability of SP and BANKA to stimulate persitaltic activity but did not attenuate the inhibitory motor effects of SP and SP methyl ester.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Activity of cyclic pseudopeptide antagonists at peripheral tachykinin receptors.

The cyclic pseudopeptides MEN 10,548, MEN 10,581, MEN 10,619, MEN 10,677, MEN 10,777 and MEN 10,867 were studied at tachykinin neurokinin (NK)1, NK2 and NK3 receptors on several in vitro bioassays. All compounds were potent and competitive antagonists at tachykinin NK1 and NK2 receptors of the guinea-pig ileum, rabbit pulmonary artery and hamster trachea, showing the highest affinity for the hamster NK2 receptor (e.g., MEN 10,677: pKB = 9.3). By contrast, none showed affinity for NK3 receptors of the rat portal vein, up to 3 microM. In the guinea-pig isolated bronchus, the pseudopeptide compounds competitively antagonized the NK2 receptor-selective agonist [beta Ala8]-NKA (4-10) with potencies comparable to those shown at the rabbit NK2 receptor. In addition, the pseudopeptides were from 3.5-fold (MEN 10,677) to 16-fold (MEN 10548) more potent antagonists against septide than against [Sar9]SP sulfone, two agonists reportedly selective for two distinct sites/subtypes of the NK1 receptor. In binding experiments at human IM9 cells, the pseudopeptide compounds displaced [3H]substance P from human NK1 receptor, showing similar affinities to those displayed at the NK1 receptor in the guinea-pig ileum or bronchus against substance P methylester or septide, as agonists, respectively. This new class of pseudopeptide antagonists, by showing a comparable and high affinity at both tachykinin NK1 and NK2 receptors, might be proposed for treatment/prevention of airway diseases in which endogenous tachykinins play a role by activation of both receptors.

Amino Acid Sequence↗
PubMed1994

Different mechanism of tachykinin NK2 receptor blockade by SR 48968 and MEN 10,627 in the guinea-pig isolated gallbladder and colon.

The mechanism of action of the tachykinin NK2 receptor antagonists, SR 48968 ((S)-N-methyl-N[4-acetylamino-4-phenyl-piperidino)-2-(3,4- dichlorophenyl)butyl]benzamide) and MEN 10,627 (cyclo[(Met-Asp-Trp-Phe-Dap-Leu) cyclo (2 beta-5 beta)]), was compared in the guinea-pig isolated gallbladder and circular muscle of proximal colon by using neurokinin A and [beta Ala8]neurokinin A-(4-10) as agonists. The experiments performed with colon were in the presence of the tachykinin NK1 receptor-selective antagonist, (+/-)-CP-96,345 ([2-(diphenylmethyl)-N-[(2-methoxyphenyl)-methyl]-1- azabicyclo[2,2,2]octan-3-amine]). SR 48968 caused an insurmountable antagonism of tachykinin NK2 receptor-mediated contraction in both preparations; its blockade was essentially irreversible, since it was not reversed by washout (up to 2 h) and was increased by prolonging the incubation from 15 to 120 min. In contrast, MEN 10,627 produced simple competitive antagonism, which was time-independent and fully reversible in both preparations. In both preparations, the simultaneous administration of SR 48968 and MEN 10,627 produced an intermediate antagonism of the responses to the agonists, as compared to the antagonism produced by each antagonist alone. The present results are discussed in the light of the reported interaction of SR 48968 with tachykinin NK2 receptors at a recognition epitope distinct from that of agonist(s).

Amino Acid Sequence↗
PubMed1994

Tachykinin NK3 receptor mediates NANC hyperpolarization and relaxation via nitric oxide release in the circular muscle of the guinea-pig colon.

In the presence of atropine (1 microM), guanethidine (3 microM) and of the tachykinin NK1 (SR 140,333 0.1 microM) and NK2 (GR 94,800 3 microM) receptor antagonists, the application of the tachykinin NK3 receptor selective agonist senktide, or that of neurokinin B, produced concentration-dependent sustained nonadrenergic noncholinergic (NANC) relaxation of mucosa-free circular muscle strips from the guinea-pig proximal colon. The maximal relaxant responses to senktide and neurokinin B were similar, approaching about 70% of the relaxation to 1 microM isoprenaline. Senktide (EC50 0.16 nM) was about 64-fold more potent than neurokinin B (EC50 10.3 nM). When tested in the presence of peptidase inhibitors (thiorphan 1 microM, captopril 1 microM and amastatin 10 microM), neurokinin B (EC50 0.24 nM) was equipotent to senktide (EC50 0.19 nM). At 1 nM, substance P and neurokinin A were ineffective in producing a NANC relaxation of the colon. At 1 microM substance P, neurokinin A and neurokinin B produced a NANC relaxation, which averaged 23, 40 and 79% of the maximal response to isoprenaline, respectively. In the presence of peptidase inhibitors, 1 nM substance P and neurokinin A produced threshold relaxant responses and, at 1 microM, the three natural tachykinins were equieffective (66 +/- 8, 72 +/- 5 and 75 +/- 5% of the relaxation to isoprenaline for substance P, neurokinin A and neurokinin B, respectively). The relaxant response to 1 nM senktide (producing about 70-80% of its maximal effect) was totally abolished by 1 microM tetrodotoxin and largely (> 90%) inhibited by 100 microM L-nitroarginine (L-NOARG). The inhibition by L-NOARG was partially reversed by L-arginine (3 mM) but not D-arginine. Apamin (1 microM) produced a slight (about 20%) inhibition of the response to senktide. The peptide blocker of N-type calcium channels, omega-conotoxin (0.1 microM) was ineffective. In sucrose gap electrophysiological experiments, superfusion with senktide (0.1 microM for 10 s) produced a slowly developing and prolonged hyperpolarization of the membrane and relaxation. Both effects were inhibited by L-NOARG while apamin had no effect. These findings indicate that a neuronal NK3 receptor mediates NANC hyperpolarization and relaxation of the circular muscle of the guinea-pig proximal colon, principally through the release of NO. NO generation/release in response to NK3 receptor stimulation does not require calcium influx through N-type calcium channels.

Animals↗
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

Involvement of spinal tachykinin NK1 and NK2 receptors in detrusor hyperreflexia during chemical cystitis in anaesthetized rats.

The intraperitoneal administration of cyclophosphamide (150 mg/kg, 48 h before cystometry) induced detrusor hyperreflexia in urethane-anaesthetized rats. Intrathecal administration of the selective tachykinin NK1 receptor antagonist, GR 82,334 ([D-Pro9(spiro-gamma-lactam)Leu10,Trp11]physalaemin-(1-11)) (1 nmol/rat i.t.) had no significant effect on micturition in normal rats but increased the volume threshold In cyclophosphamide-treated rats. Another tachykinin NK1 receptor antagonist, RP 67,580 ((3aR,7aR)-7,7-diphenyl-2-[1-imino-2(2-methoxyphenyl)ethyl]+ ++perhydroisoindol -4-one) (10 nmol/rat i.t.) increased the volume threshold to a similar extent in both vehicle- and cyclophosphamide-treated animals. The tachykinin NK2 receptor antagonist, SR 48,968 (S7-N-methyl-N[4-(acetylamino-4-phenylpiperidino)-2-(3,4- dichlorophenyl)butyl]benzamide hydrochloride (10 nmol/rat i.t.) did not modify micturition parameters in normal rats but antagonized bladder hyperreflexia in cyclophosphamide-treated animals; SR 48,968 restored the volume threshold for the micturition reflex to values close to control values. SR 48,965 (R7-N-methyl-N[4-(acetylamino-4-phenylpiperidino)-2-(3,4- dichlorophenyl)butyl]benzamide hydrochloride) (10 nmol/rat i.t.), the enantiomer of SR 48,968 devoid of affinity for tachykinin NK2 receptors, was inactive. 2-Amino-5-phosphonovaleric acid (25 and 250 nmol/rat i.t.), a selective antagonist of NMDA receptors, augmented the volume threshold both in controls and in rats with detrusor hyperreflexia; after administration of this antagonist, however, the volume threshold in cyclophosphamide-treated animals was still lower than in controls. Intravenous administration of SR 48,968, RP 67,580, or the combined administration of SR 48,968 and RP 67,580 had no effect on cystometry variables either in rats with detrusor hyperreflexia or in controls.(ABSTRACT TRUNCATED AT 250 WORDS)

2-Amino-5-phosphonovalerate↗
PubMed1994

Tachykinin NK1 and NK2 receptors mediate atropine-resistant ileal circular muscle contractions evoked by capsaicin.

The atropine-resistant contractile action of the sensory stimulant drug capsaicin was examined on guinea-pig ileum circular muscle in vitro, with special regard to the involvement of endogenous tachykinins acting through tachykinin NK1 and NK2 receptors. A protocol, using ruthenium red was developed for overcoming desensitization to capsaicin so that two reproducible responses to this drug were obtained. Capsaicin (10(-6) M) caused tonic and phasic contractions of the tissue. This effect was significantly inhibited by the tachykinin NK1 receptor blocking drug FK 888 (N2-[(4R)-4-hydroxy-1-(1-methyl-1H-indol-3-yl)carbonyl-L-proly]-N- methyl-N-phenylmethyl-3-(-2-naphthyl)-L-alaninamide) or the tachykinin NK2 receptor inhibitor GR 94,800 (PhCO-Ala-Ala-D.Trp-Phe-D.Pro-Pro-NleNH2) (10(-6) M each) and was practically abolished by the combined administration of the two tachykinin receptor blockers. Likewise, the neuronal Na+ channel inhibitor tetrodotoxin abolished the response to capsaicin. It is concluded that the contractile effect of capsaicin in the circular muscle is predominantly mediated by tachykinin release and both subtypes of tachykinin receptor (NK1 and NK2) play an important role in this process. The source of tachykinins, however, is probably intrinsic neurons of the myenteric plexus, indirectly activated by capsaicin-sensitive nerves, as shown by the sensitivity of the response to tetrodotoxin.

Amino Acid Sequence↗
PubMed1994

A thiorphan-sensitive mechanism regulates the action of both exogenous and endogenous calcitonin gene-related peptide (CGRP) in the guinea-pig ureter.

The aim of this study was to assess the existence of mechanisms regulating the intensity and duration of action of calcitonin gene-related peptide (CGRP), the main candidate inhibitory transmitter released from capsaicin-sensitive afferents in the guinea-pig ureter. In a first series of experiments, performed in capsaicin-pretreated ureters, exogenously administered human alpha CGRP (h alpha CGRP) produced inhibition of contractions of the guinea-pig isolated ureter evoked by direct electrical stimulation of smooth muscle. The intensity and duration of the inhibitory effect of h alpha CGRP were potentiated by the inhibitor of neutral endopeptidase, thiorphan, while captopril and bestatin were without effect. In a second series of experiments, background motility of the guinea-pig ureter was evoked by administration of endothelin-1 (ET-1): electrical stimulation of intramural nerves produced a transient suppression of the ET-1-evoked contractions, ascribable to release of endogenous CGRP. Thiorphan enhanced the inhibitory effect produced by endogenous CGRP, while bestatin and captopril were without effect. These findings demonstrate that a thiorphan-sensitive mechanism, presumably neutral endopeptidase, regulates the intensity and duration of the inhibitory activity of both exogenous and endogenous CGRP in the guinea-pig ureter. The existence of a mechanisms for inactivation of the released peptide is consistent with the proposed role of CGRP as inhibitory neurotransmitter in this preparation.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1994

Different Ca2+ influx pathways mediate tachykinin receptor-induced contraction in circular muscle of guinea-pig colon.

We used an electrophysiological approach (single sucrose gap) to compare the mechanism of action of selective tachykinin NK1 and NK2 receptor agonists ([Sar9]substance P sulfone and [beta ala8]neurokinin A-(4-10), respectively) in producing contraction of the circular muscle of the guinea-pig proximal colon. [Sar9]Substance P sulfone produced a marked depolarization, action potentials and increase in membrane conductance. On the other hand, [beta Ala8]neurokinin A-(4-10) produced less depolarization of the cell membrane and did not change membrane resistance. Nifedipine (1 microM) greatly reduced (80% inhibition) the contraction due to [Sar9]substance P sulfone while that due to [beta Ala8]neurokinin A-(4-10) was slightly affected (13% inhibition). Action potentials induced by either agonist were suppressed by nifedipine, while depolarization was reduced only to a minor extent. When tested in a Ca(2+)-free medium, the contraction produced by either agonist was greatly reduced (84-89%) as compared to the control. In organ bath experiments [Sar9]substance P sulfone and [beta Ala8]neurokinin A-(4-10) produced concentration-dependent contraction of the circular muscle of the colon (EC50 8 and 12 nM, respectively). Nifedipine (1 microM) markedly suppressed the response to [Sar9]substance P sulfone while that to [beta Ala8]neurokinin A-(4-10) was only slightly depressed. These findings demonstrate that NK1 receptor-mediated contraction is strictly linked to membrane depolarization and action potentials generation through nifedipine-sensitive Ca2+ channels (electromechanical coupling) while the NK2 receptor-mediated contraction is substantially unrelated to depolarization and, while being largely dependent upon extracellular Ca2+, is nifedipine-resistant, possibly linked to the opening of non-selective (Ca(2+)-permeable) receptor-gated cation channels (pharmacomechanical coupling).

Action Potentials↗
PubMed1994

Modulation of calcitonin gene-related peptide release evoked by bradykinin and electrical field stimulation in guinea-pig atria.

Electrical field stimulation (EFS) and bradykinin (BK) are able to activate capsaicin-sensitive sensory neurons of guinea-pig atria in a omega-conotoxin (CTX)-sensitive and Ruthenium Red (RR)-insensitive manner. The aim of this work was to study EFS and BK-induced release of calcitonin gene-related peptide (CGRP) from guinea-pig atria and in particular the action of morphine and neuropeptide Y (NPY) on this release. EFS-induced CGRP release was frequency-dependent and tetrodotoxin (TTX)-sensitive, while BK-evoked CGRP release was TTX-insensitive. On the other hand, CGRP outflow induced by either EFS or BK was similarly reduced in the presence of morphine and NPY. It is therefore hypothesized that NPY and opioids exert their inhibitory action by acting on the very terminal region of the nerve fibre. Moreover, our results show that dermorphine but not dynorphin reduced BK-evoked CGRP release, suggesting that mu opioid receptors are responsible for morphine action. Studying the action of peptide YY and NPY(16-36) on BK-evoked CGRP release, we demonstrated that both had similar inhibitory effects, supporting the presence of Y2 receptors on the nerve terminal region.

Animals↗
PubMed1994

Differential effects of selective tachykinin NK2 receptor antagonists in rat spinal cord.

The effects of intrathecally (i.t.) injected selective tachykinin NK2 receptor antagonists, MEN 10,207, MEN 10,376 and R396, on the spinal effect of neurokinin A were studied in decerebrate, spinalized, unanesthetized rats. I.t. neurokinin A (7 pmol) briefly facilitated the flexor reflex, an effect that was dose dependently inhibited by pretreatment with MEN 10,207 and MEN 10,376 with similar and high potency. I.t. R396 itself caused strong facilitation of the flexor reflect. At lower doses, the effect of i.t. neurokinin A was potentiated by R396. R396 only exhibited moderate antagonism of neurokinin A-induced reflex facilitation even at very high doses. It has been proposed that the tachykinin NK2 receptor may be further classified into two subtypes, NK2A and NK2B, with MEN 10,207 and MEN 10,376 having high affinity for the former and R396 for the latter. Our results suggested that the tachykinin NK2 receptor in rat spinal cord which mediates the excitatory effect of neurokinin A may belong to the NK2A subpopulation of receptors.

Amino Acid Sequence↗
PubMed1994

Structural comparison of NK2 receptor agonists and antagonists.

The conformational space of two NK2 receptor agonists and a new potent antagonist has been sampled by the simulated annealing technique. Low-energy conformers were obtained, which were compared with respect to their key residues, namely phenylalanine, leucine and methionine. The hypothesis is that they share part of the binding site on the receptor.

Amino Acid Sequence↗
PubMed1994

Effect of Bay K 8644 and ryanodine on the refractory period, action potential and mechanical response of the guinea-pig ureter to electrical stimulation.

We have investigated the effect of the dihydropyridine calcium channel agonist, Bay K 8644, and of the plant alkaloid blocker of calcium-induced calcium release (CICR) from the sarcoplasmic reticulum, ryanodine, on the refractory period, action potential and mechanical response of the guinea-pig isolated ureter to electrical stimulation. All experiments were performed in ureters pre-exposed to 10 microM capsaicin to eliminate the inhibitory influence exerted by local release of sensory neuropeptides on ureteral excitability and contraction. In organ bath experiments, electrical field stimulation with parameters which produce direct excitation of ureteral smooth muscle (train of pulses at 10 Hz, 5 ms pulse width, 60 V for 1 s) produced tetrodotoxin- (1 microM) resistant phasic contractions. The response to EFS was abolished by nifedipine (1 nM-3 microM) and was enhanced by Bay K 8644 (1 nM-3 microM). In the presence of Bay K 8644 (1 microM), nifedipine (30 microM) abolished the evoked contractions. Ryanodine (10-100 microM) had no significant effect on the amplitude of evoked contraction. The response of the guinea-pig ureter to direct electrical stimulation of smooth muscle is characterized by a refractory period: at least 40 s interstimulus interval was required to produce a second response in all preparations tested. Bay K 8644 (1 microM) markedly reduced the refractory period of the ureter and a similar effect was observed with ryanodine (100 microM). To further analyze the effect of Bay K 8644 and ryanodine on the refractory period, the response of the ureter was investigated over a 10 s period of stimulation (other parameters as above). In control ureters, continuous stimulation for 10 s produced only one phasic contraction just after the beginning of the train of stimuli. In the presence of Bay K 8644 or ryanodine, more than one phasic contraction developed during a 10 s stimulation, i.e. the refractory period became shorter than the train duration. When both Bay K 8644 and ryanodine were tested on the same preparations, an additive excitatory effect was observed on the mechanical response to electrical stimulation. A slight elevation of KCl concentration (5-10 mM) reduced the refractory period of the ureter as observed with ryanodine or Bay K 8644. Application of KCl (80 mM) produced a biphasic contractile response of the ureter: a series of phasic contractions occurred first, which were then replaced by a slowly developing tonic response. Bay K 8644 (1 microM) enhanced both components of the response to KCl. Ryanodine (10 and 100 microM) markedly prolonged the duration of phasic contractions evoked by KCl and, at 100 microM, slightly (about 25%) reduced the amplitude of tonic contraction.(ABSTRACT TRUNCATED AT 400 WORDS)

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗