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Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The effects of acetylcholine and substance P on the efflux of 86Rb+ and 42K+ from rat aorta and pig coronary artery, respectively, were compared with those of the K+ channel opening agent, cromakalim. 2. In rat aorta preloaded with 86Rb+ and/or 42K+, acetylcholine produced transient, concentration-dependent increases in the efflux rate coefficients of these tracers (maximum approximately 35%). These effects were abolished by endothelial cell removal. 3. Donor/acceptor experiments with rat aorta suggested that at least some of the efflux of 86Rb+ seen in the presence of acetylcholine was not derived from the endothelium, but came from the smooth muscle itself. 4. Acetylcholine (10 microM)-induced 86Rb+ efflux was reduced by tetraethylammonium (TEA, 10 mM) to 33% and ouabain (300 microM) to 54% of control. Preincubation with Ba2+ (100 microM) did not significantly inhibit acetylcholine-induced efflux. 5. Acetylcholine-induced 42K+/86Rb+ efflux was unaffected by preincubation with glibenclamide (10 microM). In contrast, the 42K+/86Rb+ efflux induced by cromakalim was inhibited by glibenclamide (50 nM) by 50%. 6. Acetylcholine (0.3-10 microM)-induced inhibition of phenylephrine (1 microM)-induced tone was abolished by endothelial cell removal but unaffected by glibenclamide. Cromakalim-induced relaxations were endothelium-independent and were inhibited by glibenclamide in a concentration-dependent manner. 7. LG-monomethyl L-arginine (L-NMMA, 250 microM) produced a significant (37 +/- 14%) inhibition of acetylcholine-induced 86Rb+ efflux whereas DG-monomethyl L-arginine was without effect. In the tissue bath L-NMMA inhibited relaxations produced by acetylcholine (0.3-10 microM), but was without effect on responses to cromakalim. 8. In the pig coronary artery, substance P induced an endothelium-dependent efflux of 86Rb+ and 42K+, which was unaffected by preincubation with glibenclamide (10 microM) or L-NMMA (250 microM). 9. The present study shows that acetylcholine and substance P each open K(+)-channels in arterial smooth muscle. However, the insensitivity of the stimulated 86Rb/42K+ efflux to inhibition by glibenclamide suggests that the K(+)-channel opened by these agents is different from the K(+)-channel opened by cromakalim. In addition, the inability of L-NMMA to inhibit fully the acetylcholine- and substance P-stimulated 86Rb+ efflux suggests that in rat aorta and pig coronary artery the endothelium-derived hyperpolarizing factor(s) (EDHF) is different from endothelium-derived relaxing factor (EDRF).
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PMID:Differences in the K(+)-channels opened by cromakalim, acetylcholine and substance P in rat aorta and porcine coronary artery. 128 96

1. The regulation of Ca2(+)-activated K+ channels by the agonist substance P in freshly dissociated smooth muscle cells from the rabbit longitudinal colonic muscle was characterized using the patch clamp technique. 2. In the cell-attached recording mode, when pipette and bath solutions contained equal [K+] (126 mM), the Ca2(+)-activated K+ channels showed a linear current-voltage relationship (between -50 mV and 50 mV) with a slope conductance of 210 +/- 35 pS (n = 12). Reversal potential measurements indicated that the channel was highly selective for K+ over Na+ (PK/PNa = 110). 3. Channels were activated by depolarizing membrane voltages and cytosolic Ca2+, and in inside-out patches channel activation depended sigmoidally on voltage and [Ca2+]. The potential for half-activation at a cytosolic [Ca2+] of 5 x 10(-6) M was 0 mV. A tenfold increase in cytosolic Ca2+ resulted in a 60 mV shift of the sigmoidal voltage activation curve to more negative potentials. 4. Threshold concentrations of substance P (10(-12) M), which did not result in cell contraction, caused a prolonged activation of K+ channels. The K+ channels were observed to open in clusters: simultaneous opening of multiple channels was interrupted by complete, prolonged channel closure. 5. Lowering bath [Ca2+] to submicromolar concentrations abolished the effect of substance P. The activation of K+ channels by substance P (10(-12) M) was also inhibited by the dihydropyridine nifedipine (10(-6) M), a blocker of L-type Ca2+ channels. 6. In the whole-cell recording mode, with the pipette solution containing 126 mM-KCl, 0.77 mM-EGTA and 1 mM-ATP, depolarization from a holding potential of -70 mV elicited outward currents which increased to steady-state values. These were K+ currents as they were blocked by TEA (tetraethylammonium, 30 mM) and Ba2+ (1 mM) and were abolished when pipette K+ was replaced by Cs+. 7. The depolarization-activated outward current was not affected by lowering extracellular [Ca2+] or by the Ca2+ channel antagonists Cd2+ (200 microM), nifedipine (10(-6)-10(-5) M) or verapamil (10(-6) M). The current was greatly reduced when the EGTA concentration in the pipette solution was increased from 0.77 to 10 mM. 8. When the pipette solution contained CsCl, membrane depolarization activated inward currents. The peak inward current was identified as current through L-type Ca2+ channels based on its voltage- and time-dependent kinetics, and its modulation by dihydropyridines.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The activation of calcium and calcium-activated potassium channels in mammalian colonic smooth muscle by substance P. 169 Dec 93

The effect of substance P (SP) on the contractile responses produced by periarterial (mesenteric) nerve stimulation was studied in the rat isolated ileum. Periarterial nerve stimulation at 1-50 Hz, with 10 V (maximum) and 0.2 msec pulse duration, for 15-20 sec, produced frequency-dependent contractions in the rat ileum. In the presence of guanethidine (10 microM) and 6-hydroxydopamine (1 microM), to block noradrenergic responses, periarterial nerve stimulation at 1-20 Hz still produced small contractions which were reduced by atropine (1 microM) and morphine (1 microM). In the presence of atropine, morphine, guanethidine and 6-hydroxydopamine, the contraction produced by periarterial nerve stimulation was readily abolished by tetrodotoxin (1 microM), capsaicin (3.3 microM) and an SP-antagonist (SPA1, 10 microM). SP in low concentrations (0.01-1.0 microM) potentiated the contractions produced by periarterial nerve stimulation at 1-2 Hz by 20-30%. High concentrations of SP (1.0-10.0 microM) reduced the contractile response by 40-50%. Indomethacin (2.8 microM) amd mepyramine (1 microM) had no effect on these responses. When the mesenteric nerve supply to the gut was cut, periarterial nerve stimulation produced no contraction in the rat ileum. However, SP in low concentrations, still produced small contractions which were abolished by an SP-antagonist but not by tetrodotoxin. SP in low concentrations, slightly increased the contractions produced by ACh (0.5-50 microM) or TEA (2.4-12 mM). High concentrations of SP significantly reduced the ACh and TEA-induced contractions in the rat ileum.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Possible involvement of substance P in the contraction produced by periarterial nerve stimulation in the rat ileum. 241 Apr 25

The effects of several polypeptides, e.g. angiotensin II, substance P, oxytocin and vasopressin, on the isolated frog gastrocnemius, chick biventer cervicis and rat hemodiaphragm preparations were studied using electrophysiological and neurochemical techniques. The effects of angiotensin II, substance P, oxytocin and vasopressin on neuromuscular transmission and muscle contraction were investigated by studying the following parameters: the directly and indirectly-elicited twitch and tetanic contractions, nerve compound action potential, uptake of 3H-methylcholine into nerve-muscle preparations, the contractures produced by depolarizing drugs, e.g. ACh or TEA. The results showed that angiotensin II (10(-10)-10(-6) M) and substance P (10(-7)-10(-6) M) enhanced neuromuscular transmission and muscle contraction by increasing the amplitudes of the indirectly-elicited twitch and tetanic contractions. Oxytocin and vasopressin (1-100 mU/ml-1) both depressed neuromuscular transmission by reducing the contractile and electrical response in the frog, chick and rat skeletal muscle. It was concluded that, like their effects on ganglionic transmission, the peptides can modify neuromuscular transmission. The mechanism by which these peptides produce their effects may be dependent on external calcium concentration. These peptides may affect both pre- and postjunctional mechanisms; prejunctionally by increasing/decreasing the release of ACh, and postjunctionally by affecting the sensitivity of the postjunctional membrane to depolarizing drugs and/or producing a contracture in the skeletal muscle.
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PMID:Actions of polypeptides at the neuromuscular junction. 241 8

1. The nature of the non-cholinergic, non-adrenergic (non-ch., non-adr.) excitatory and inhibitory transmission in the longitudinal and circular muscle layers of the guinea-pig ileum was investigated, and the effects of various agents on the junction potentials were observed using the micro-electrode method.2. In longitudinal muscle cells, ATP (3 x 10(-5)-10(-4) M) and adenosine (10(-5)-10(-4) M) depolarized the membrane, decreased the input resistance, increased the spike activity and abolished the generation of cholinergic excitatory junction potentials (e.j.p.s).3. In the presence of atropine (10(-6) M) with guanethidine (10(-5) M), field stimulation evoked three different types of the response (non-ch., non-adr. e.j.p.s, i.j.p.s (inhibitory junction potentials) or both) from cells of the longitudinal muscle layers, and only one type of the response (non-ch., non-adr. i.j.p.s) from cells of the circular muscle layer. In the following experiments atropine and guanethidine were present in the bathing fluid for at least 20 min.4. In some longitudinal muscle cells (non-ch., non-adr. i.j.p. type), ATP (5 x 10(-6)-10(-3) M) and adenosine (10(-5)-3 x 10(-5) M) depolarized the membrane, while in other cells (non-ch., non-adr. e.j.p. type), ATP (10(-5)-10(-4) M) and adenosine (10(-5)-3 x 10(-5) M) hyperpolarized the membrane and further increases in the concentration of ATP (10(-3) M) resulted in a depolarization of the membrane.5. Apamin (10(-7)-3 x 10(-6) M) inhibited the generation of non-ch., non-adr. i.j.p.s in both longitudinal and circular muscle cells, while this agent had no effect on the non-ch., non-adr. e.j.p.s. As a consequence, in some cells of the longitudinal muscle layer (non-ch., non-adr. e.j.p. and i.j.p. type) the amplitude of e.j.p.s was enhanced in the presence of apamin. TEA (5 x 10(-3)-1.5 x 10(-2) M) suppressed the after-hyperpolarization of the spike and i.j.p.s recorded from both muscle layers, whereas the duration and amplitudes of cholinergic and non-ch., non-adr. e.j.p.s were enhanced.6. Vasoactive intestinal polypeptide (VIP; 10(-8)-10(-7) M) had no effect on the membrane potential and junction potentials of longitudinal and circular muscle layers.7. Substance P (SP; 10(-8)-10(-7) M) depolarized the membrane of cells of the longitudinal layer (non-ch., non-adr. e.j.p. type), while this agent had no effect on cells of longitudinal (non-ch., non-adr. i.j.p. type) and circular muscle layers. SP suppressed the generation of non-ch., non-adr. e.j.p.s but had no effect on i.j.p.s. Generation of non-ch., non-adr. e.j.p.s was not restored under conditions of repolarization of the membrane to the resting level by application of inward current.8. Bradykinin (BK; 10(-8)-10(-5) M) hyperpolarized the membrane and suppressed the generation of i.j.p.s in the cells of longitudinal (non-ch., non-adr. i.j.p. type) and circular muscle layers. However, when the membrane potential was displaced to the control level by outward current in the presence of BK, field stimulation evoked the i.j.p. In cells of non-ch., non-adr. e.j.p. type of the longitudinal muscle layer, BK depolarized the membrane, increased the spike activity, generated slow waves and blocked the generation of non-ch., non-adr. e.j.p.s. Displacement of the membrane potential to the control level by inward current did not restore the non-ch., non-adr. e.j.p.s.9. These results suggest that in the guinea-pig ileum ATP and adenosine probably do not contribute to the generation of non-ch., non-adr. e.j.p.s and i.j.p.s, as transmitter substances. The actions of other possible candidates such as SP and BK, are discussed.
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PMID:The nature of non-cholinergic, non-adrenergic transmission in longitudinal and circular muscles of the guinea-pig ileum. 629 75

1. Intracellular recordings were made in intact and in acutely dissociated vagal afferent neurones (nodose ganglion cells) of the ferret to investigate the effects of substance P(SP). 2. In current-clamp recordings, SP (100 nM) applied by superfusion hyperpolarized the membrane potential (7 +/- 0.7 mV; mean +/- S.E.M.; n = 105) and decreased the input resistance in 80% of the neurones. With voltage-clamp recording, SP produced an outward current of 3 +/- 0.2 nA (n = 10). 3. The SP current was concentration dependent with an estimated EC50 of 68 nM. The SP-induced hyperpolarization or current was mimicked by the tachykinin receptor NK1 agonist Ac-[Arg6, Sar9, Met(O2)11]SP(6-11) (ASM-SP; 100 nM; n = 10) and blocked by the NK1 antagonist CP-96,345 (10 nM; n = 6), but not by the NK2 antagonist SR48968 (100 nM; n = 4). No measurable change in membrane potential or input resistance was observed with application of either [beta-Ala8]neurokinin A or senktide, selective NK2 and NK3 receptor agonists, respectively (100 nM; n = 3 for each agonist). 4. The reversal potential (Erev) for the SP outward current was -85 +/- 2.5 mV (n = 4). The Erev for the SP response shifted in a Nernstian manner with changes in extracellular potassium concentration. Alterations in extracellular sodium or chloride concentrations had no significant effect on the Erev for the SP response (n = 3 for each ion). 5. Nominally Ca(2+)-free external solution abolished the SP response. Removal of magnesium from the extracellular solution had no effect on the response. 6. Caesium (100 microM), barium (1 mM), tetraethylammonium (TEA; 5 mM), apamin (10 nM) and 4-aminopyridine (4-AP; 4 mM) each completely prevented the SP response (n > or = 3 for each). 7. These results indicate that SP, via an NK1 receptor, can induce a Ca(2+)-dependent outward potassium current which hyperpolarizes the resting membrane potential of vagal afferent somata.
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PMID:Substance P hyperpolarizes vagal sensory neurones of the ferret. 873 1

Intracellular recordings were performed on isolated rat DRG neurons to investigate the changes in the membrane potential in response to substance P and the involved ionic mechanisms. The resting membrane potential examined was -58.9 +/- 8.2 mV (X +/- SE) (n = 81). The conduction velocities estimated were: 20.4 +/- 4.8 m/s (X +/- SE) ranging from 14.1 to 28.7 m/s (47/60) in type A(alpha beta) cell, 9.8 +/- 5.2 m/s (X +/- SE) ranging from 1.2 to 13.7 m/s (13/60 in type A(delta) and type C cell. In majority of the neurons bath application of SP (10(-7) - 3 x 10(-4) mol/L) induced marked membrane potential depolarization (56/60). The membrane conductance increased 24.6% in average from control value of 2.72 x 10(-8) S during SP-induced depolarization (n = 3). The reversal potential was between +40 - %50 mV (n = 3). When NaCl in BSS was substituted with choline chloride or containing TTX (10(-5) mol/L), the amplitude of SP-induced depolarization attenuated markedly but not incompletion eventually. When high (20 mmol/L) and low (0 mmol/L) Ca2+ BSS was used, the amplitude of SP-induced depolarization increased and decreased respectively. However, when BSS containing 10(-4) mol/L Cd2+ or 10(-2) mol/L TEA was used SP-induced depolarization was reduced. The above results indicate that SP-induced depolarization involves a rather multiple changes in ionic conductance.
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PMID:[Effect of substance P on the somatic membrane of rat DRG neurons]. 875 84

Neurons in the superior vagal (jugular) ganglion relay afferent information from thoracic visceral organs and may be important in inflammatory processes due to the peripheral release of bioactive neuropeptides such as substance P. We characterized the excitable properties and underlying voltage-gated Na+ (INa) and K+ (IKv) currents in acutely dissociated guinea pig jugular ganglion neurons with microelectrode and whole-cell patch-clamp recording techniques. Current clamp recordings revealed a resting potential of approx. -55 mV and input resistance of approx. 100 M ohms. Brief depolarizing steps evoked an overshooting action potential (approx. 2 ms duration), fast (< 20 ms duration) afterhyperpolarization (AHPF) sequence in all neurons, followed by a slow (> 1 s) Cd(2+)-sensitive afterhyperpolarization (AHPS) in 45% of the neurons. The AHPS was implicated in limiting repetitive action potential firing during maintained depolarizing steps. The action potential in 15/17 neurons, and a major component of the whole cell INa in 13/13 neurons were insensitive to TTX (1-10 microM), indicating that jugular neurons express predominantly a TTX-resistant type of INa. Cd2+ (200 microM) did not affect action potential repolarization, while tetraethylammonium (TEA; 10 mM) in the presence of Cd2+ markedly prolonged action potential repolarization, and blocked the AHPF in 11/11 neurons. This suggested that the action potential repolarization and the AHPF are mediated by IKv, with little contribution by Ca(2+)-dependent IK (IK(Ca)). Whole cell IKv activated rapidly (tau < 1.5 ms), and inactivated variably over a time period of seconds. IKv activation and inactivation voltage dependencies and TEA sensitivity were compatible with its availability during the action potential and AHPF. Only 1/26 neurons exhibited current with the rapid inactivation kinetics and voltage-dependencies characteristic of classic IA-type current. These results highlight differences in the properties of jugular neurons (e.g., deficiency of rapid IA, and lack of a TTX-sensitive subpopulation), relative to those known for other visceral and somatic afferents, and thus provide a basis for further functional studies.
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PMID:Excitable properties and underlying Na+ and K+ currents in neurons from the guinea-pig jugular ganglion. 878 83

The aim of this study was to examine the activity of SCA40, a novel charybdotoxin-sensitive potassium channel opener, against a variety of spasmogens or against electrical field stimulation in guinea pig isolated main bronchi and in human isolated bronchi; the effects of SCA40 were compared with those of cromakalim. Like cromakalim, SCA40 reduced the contractility of guinea pig and human isolated bronchi precontracted with acetylcholine 10(-6) M or neurokinin A 10(-6) M, SCA40 being more efficient and more potent than cromakalim. Moreover, on guinea pig isolated main bronchi, SCA40 can exert a preventive effect on contractions induced by acetylcholine, neurokinin A or capsaicin, that is, it shifts to the right the concentration-effect curves of these substances, whereas cromakalim has no such effect. The effects of cromakalim were antagonized by glibenclamide 10(-5) M, whereas the effects of SCA40 were inhibited by tetraethylammonium (TEA 10(-2) M) and charybdotoxin (3 x 10(-8) M), but this inhibitory effect of TEA was reversed by nifedipine (10(-6) M). Electrical field stimulation of guinea pig isolated main bronchi induced two successive contractile responses. Both contractions were significantly reduced by SCA40 (10(-6) and 10(-5) M) and cromakalim (10(-5) M). Since cromakalim was unable to inhibit the effects of acetylcholine or neurokinin A, it might be suggested that for this latter compound the inhibition seems to take place prejunctionally and to affect the release of neuromediators produced by electrical field stimulation. In contrast, in the case of SCA40, a postjunctional effect seems to be likely, owing to its preventive effects, although a prejunctional effect cannot be excluded. Finally, on guinea pig isolated main bronchi, SCA40 (10(-8)-10(-6) M) did not potentiate the relaxant effect of isoprenaline or sodium nitroprusside, suggesting a lack of functional manifestation of inhibition of phosphodiesterase for these concentrations. In conclusion, these results demonstrate that SCA40 is a potent and efficient relaxant of guinea pig and human airway smooth muscle, and is able to inhibit, in the guinea pig isolated main bronchi, the contractions induced by electrical field stimulation. It has an effect on TEA-sensitive K+ channels, but this effect is probably not involved in its relaxant effect which does not also rest on an inhibitory effect of phosphodiesterase.
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PMID:Effects of SCA40 on human bronchi and on guinea pig main bronchi in vitro. Comparison with cromakalim. 887 Nov 36

1. The aim of this study was a pharmacological characterization of the multiple NANC inhibitory transmission systems producing relaxation of the circular muscle of guinea-pig proximal colon. In the presence of atropine (1 microM), guanethidine (3 microM) and of the tachykinin NK1 and NK2 receptor antagonists, SR 140333 (0.3 microM) and MEN 10627 (1 microM), respectively, electrical field stimulation (EFS) produced a frequency-dependent (0.1-3 Hz) relaxation. During a cumulative frequency-response curve, the maximal relaxant effect was produced at 3 Hz and approached the maximal relaxation to 1 microM isoprenaline. In the presence of both apamin (0.3 microM) and L-nitroarginine (L-NOARG, 100 microM), EFS failed to evoke relaxation up to 1 Hz; at 1-10 Hz, a slowly developing relaxation ensured which approached 50% of the Emax to isoprenaline. The EFS-evoked NANC relaxation, either in the presence or absence of apamin and L-NOARG, was unaffected by in vitro capsaicin pretreatment (10 microM for 15 min). 2. Three protocols of EFS were developed for further pharmacological analysis: (a) EFS at 1 Hz for 5 s in the presence of L-NOARG, producing a transient fast apamin-sensitive relaxation; (b) EFS at 1 Hz for 5 s in the presence of apamin, producing a transient fast L-NOARG-sensitive relaxation; and (c) EFS at 10 Hz for 5 s in the presence of both apamin and L-NOARG, producing a transient but slowly developing and more sustained relaxation. 3. The neutral endopeptidase inhibitor, thiorphan (1-10 microM), enhanced and prolonged the apamin- and L-NOARG-resistant NANC relaxation produced by EFS at 10 Hz, without affecting that evoked at 1 Hz in the presence of apamin or L-NOARG. The angiotensin converting enzyme inhibitor, captopril (1-10 microM) was without effect. 4. The cAMP analogue inhibitor of protein kinase A, Rp-cAMPs (100-300 microM) significantly reduced and shortened the NANC relaxation produced by 10 Hz EFS in the presence of L-NOARG without affecting that produced by 1 Hz EFS in the presence of apamin or L-NOARG. 5. The inhibitor of sarcoplasmic reticulum Ca-ATPase, cyclopiazonic acid (CPA, 3-10 microM for 60 min) abolished the 1 Hz EFS-induced relaxation in the presence of L-NOARG, and greatly inhibited that produced by 10 Hz EFS in the presence of both apamin and L-NOARG. The relaxation produced by 1 Hz EFS in the presence of apamin was inhibited by about 32% at 10 microM only. 6. Nifedipine (1 microM) did not affect the EFS-induced NANC relaxations. In the presence of nifedipine, tetraethylammonium (TEA, 1 mM) enhanced the 1 Hz EFS-induced relaxation in the presence of L-NOARG (158% of control) and that produced by 10 Hz EFS in the presence of apamin and L-NOARG (215% of control) while that evoked by 1 Hz EFS in the presence of apamin was slightly affected (109% of control). 7. In the presence of atropine, guanethidine, SR 140333 and MEN 10627, bath application of human vasoactive intestinal polypeptide (VIP, 0.1 nM-10 nM) produced a concentration-dependent, slowly developing relaxation of colonic strips. The relaxation to VIP was unaffected by apamin (0.3 microM), L-NOARG (100 microM), nifedipine (1 microM) or nifedipine plus TEA (1 mM); it was inhibited by CPA (10 microM) and Rp-cAMPs (100 microM) and was potentiated by thiorphan (10 microM). 8. The putative VIP receptor antagonist, VIP(10-28) (10 microM) did not affect the VIP-induced relaxation nor the NANC relaxation to 10 Hz EFS in the presence of apamin and L-NOARG. 9. The present findings provide evidence that three distinct NANC inhibitory mechanisms mediate relaxation of the circular muscle of the guinea-pig proximal colon. The first system provides a fast relaxation in response to low frequency of stimulation and may involve the action of a transmitter(s) (possibly ATP) which mobilizes intracellular Ca2+ from sarcoplasmic reticulum leading to the activation of apamin-sensitive K+ channels. The second system likewise provides a fast relaxation of the colon in
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PMID:Characterization of the apamin- and L-nitroarginine-resistant NANC inhibitory transmission to the circular muscle of guinea-pig colon. 888 60


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