Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Dual-excitation microfluorometry (Fura-2 as indicator) was employed to monitor directly changes in the cytosolic calcium concentration [( Ca2+]i) in single cells. We investigated and compared the effects of stimulation of AR42J rat pancreatic acinar cells by two peptide agonists, substance P and bombesin. 2. Substance P (10(-7) M) and bombesin (10(-8) M) each gave rise to a marked, but transient, elevation in [Ca2+]i. The calcium signals evoked by the two peptides were qualitatively and quantitatively very similar. However, in the absence of extracellular Ca2+ the response to substance P, but not bombesin, was abolished. These results suggest that substance P induces calcium influx across the cell surface membrane but does not release calcium from internal stores. Bombesin in marked contrast releases calcium from intracellular stores in the absence of any detectable calcium influx. 3. Depolarization by high-K+ extracellular solutions evoked a marked, but transient, rise in [Ca2+]i. This elevation in [Ca2+]i was strictly dependent upon the presence of Ca2+ in extracellular media. 4. Nifedipine (5 x 10(-6) M), an antagonist of L-type voltage-dependent Ca2+ channels, blocked the elevations in [Ca2+]i induced by either substance P or high-K+ solutions, but not that evoked by application of bombesin. 5. Patch-clamp, single-channel current recordings from cell-attached patches of membrane confirmed the presence of voltage-dependent calcium channels in the surface membranes of AR42J cells. Whole-cell current recordings demonstrated voltage-dependent inward Ca2+ (Ba2+) currents which were increased in amplitude by substance P and blocked by nifedipine. 6. The protein kinase C (PKC) activators, the phorbol diester, phorbol 1,2-myristate 13-acetate (PMA, 10(-7) M), and cell-permeable diacylglycerol analogues, 1-oleoyl-2-acetyl-sn-glycerol (OAG, 2.5 x 10(-6) M) and sn-2-dioctanoyl glycerol (DiC8, 2.5 x 10(-6) M), mimicked the effect of substance P, but not bombesin, in elevating [Ca2+]i in a manner that was blocked by removal of extracellular Ca2+ or application of nifedipine. 7. The PKC inhibitor, polymyxin B (2.5 x 10(-6) M), applied 2 min prior to stimulation blocked the effects of substance P and PKC activators, but not bombesin, in elevating [Ca2+]i. 8. The calcium signals evoked by substance P and bombesin are achieved by activation of different molecular mechanisms. Substance P, the evidence suggests, activates PKC which in turn stimulates calcium influx by opening voltage-dependent Ca2+ channels in the cell surface membranes.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Substance P and bombesin elevate cytosolic Ca2+ by different molecular mechanisms in a rat pancreatic acinar cell line. 170 Jan 6

1. Single pulse electrical field stimulation (EFS) produces a biphasic response of muscle strips of the rat isolated urinary bladder consisting of an early and a late contraction which were atropine-resistant and atropine-sensitive, respectively. Repeated application of desensitizing doses of the P2 purinoceptor agonist, alpha, beta-methylene ATP (mATP) inhibited the early response while leaving unaffected the late component. 2. Omega conotoxin (CTX, 0.1 microM) inhibited both the early and the late response either in control conditions or after enhancement by physostigmine (0.1 microM). The effect of CTX was, in both cases, more pronounced on the late than the early response to EFS. CTX (0.1 microM) failed to affect contraction produced by ATP or acetylcholine at concentrations (0.3 mM and 0.5 microM) which produced a response similar to that to EFS. 3. The effect of physostigmine was more intense for the late than the early response and was abolished by atropine. In the presence of CTX, physostigmine enhanced both the early and the late components of the mechanical response to EFS. 4. Nifedipine (0.1-1 microM) reduced to a similar extent both the early and late responses. Bay K 8644 (1 microM) produced a marked enhancement of the response to EFS, which, however, did not have a distinct late peak. In the presence of Bay K 8644, either atropine (3 microM) or tetrodotoxin (1 microM) had minor inhibitory effects indicating the myogenic origin of the response. 5. Neurokinin A (0.1-1 nM) enhanced both the early and late responses to EFS without affecting the contraction produced by exogenous acetylcholine or ATP. A consistent potentiation was evident also in the presence of CTX and for the early response, in the presence of atropine. Clonidine (3 microM) inhibited the response to EFS either in the absence or the presence of physostigmine. The inhibitory effect of clonidine, shown previously to depend upon activation of prejunctional alpha 2-adrenoceptors, was still observed in presence of CTX or atropine. 6. It is concluded that CTX-sensitive voltage dependent calcium channels play a more important role in determining the cholinergic rather than the non-cholinergic, putatively purinergic, component of the biphasic response of the rat bladder to single pulse EFS. The action of CTX is likely to be exerted on N-type rather than L-type (dihydropyridine-sensitive) calcium channels. Prejunctional modulation (enhancement by neurokinin A, inhibition by clonidine) occurs even in the presence of CTX-sensitive channels blockade.
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PMID:Omega conotoxin and prejunctional modulation of the biphasic response of the rat isolated urinary bladder to single pulse electrical field stimulation. 172 Oct 69

A long-term culture system of dissociated rat dorsal root (DRG) and trigeminal ganglion cells with high cell density has been developed. Two to 3 weeks after plating, the cultures consist of a nearly pure population of sensory neurons, which can be kept for more than 2 months in culture. Cultured neurons synthesize and release the tachykinins substance P (SP) and substance K (SK, neurokinin A) with a time course similar to that observed in vivo. High-pressure liquid chromatography (HPLC) analysis of peptides extracted from neuronal cultures and synthetic tachykinins revealed identical retention characteristics. Northern blot analysis of mRNAs from cultured cells with a specific tachykinin-probe demonstrated that the preprotachykinin-gene is expressed in preparations of both DRG and trigeminal ganglia cells. Depolarizing stimuli such as high potassium (47 mM) evoked a peptide release from cultured neurons in a strictly Ca(++)-dependent manner. Capsaicin, a compound known to stimulate nociceptive sensory neurons, dose-dependently released tachykinins in concentrations as low as 10(-9) M. Only total absence of Ca++ ions from the incubation medium abolished the capsaicin-induced peptide release. Nifedipine, a blocker of voltage-dependent L-type Ca++ channels, completely blocked the potassium-induced release of SP but did not reduce the capsaicin-evoked release. Mediator substances of pain and inflammation, such as bradykinin, serotonin, and histamine, triggered the release of tachykinins from sensory neurons in vitro. These results clearly demonstrate that the neurons characterized express properties similar to those of sensory neurons in vivo and provide model systems for detailed studies of the biosynthesis and release of neuropeptides as well as the participation of sensory neurons in pain and inflammatory reactions.
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PMID:Biosynthesis and release of tachykinins from rat sensory neurons in culture. 179 53

Clonidine, noradrenaline and adrenaline (in the presence of propranolol), but not phenylephrine and methoxamine, stimulated an increase in the oxygen consumption of these slices that was blocked by yohimbine but not by prazosin. The stimulation was inhibited by ouabain and required the presence of Ca2+ in the incubation medium. The calcium ionophore A 23187 stimulated oxygen consumption in the tissue slices and enhanced the respiratory effect of clonidine. Atropine and (D-Pro2, D-Trp7.9)-substance P failed to block the respiratory response to clonidine in concentrations that inhibited the respiratory effects of carbachol and substance P, respectively. Release of acetylcholine from the unstimulated gland slices was reduced by clonidine or Ca2+ omission. Yohimbine prevented the clonidine effect and stimulated acetylcholine resting release. Nifedipine did not affect either the release of acetylcholine or the clonidine-induced reduction of acetylcholine release but blocked the oxygen uptake due to clonidine or to release acetylcholine.
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PMID:Differentiation of alpha adrenoceptors mediating increase of oxygen consumption in rat submandibular salivary gland slices. 217 72

From 20 women undergoing hysterectomy, strip preparations were isolated from the outer, longitudinal and the inner, circular smooth muscle layer of the ampullary-isthmic junction (AIJ), together with small arterial segments dissected as ring preparations from the root of the mesosalpinx. The specimens were mounted in organ baths and isometric tension was recorded. In addition, tissue concentrations of substance P (SP) in the ampulla, AIJ and utero-tubal junction were determined by radioimmunoassay. Tissue concentrations of SP expressed as pmol X g tissue-1 (wet weight, +/- SE) amounted to 3.09 +/- 1.40 in the utero-tubal junction, 1.08 +/- 0.299 in the AIJ and 0.742 +/- 0.299 in the ampulla. In strips of circular muscle, SP at concentrations of 10(-7) -3 X 10(-6) mol X l-1 elicited a combined phasic and tonic response and in longitudinal muscle a mainly tonic contraction was produced. In both tissues, contractions elicited by SP were rapidly abolished in calcium-free medium. Nifedipine abolished the phasic contraction elicited in circular muscle by SP while the tonic response was resistant. The contraction in longitudinal muscle was reduced by 20-30%. Vasoactive intestinal polypeptide (VIP) decreased tension in preparations contracted by SP, prostaglandin F2 alpha and K+-depolarization (124 mmol X l(-1). In unstimulated oviductal arterial preparations, SP had no effect, while the peptide induced a transient relaxation of noradrenaline contracted preparations, and slightly decreased tension of K+-depolarized vessels. The results suggest that SP may be involved in the control of motility of the human AIJ.
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PMID:Concentrations and contractile effects of substance P in the human ampullary-isthmic junction. 240 45

The effects of the dihydropyridine calcium channel entry blockers nifedipine and nilvadipine on colonic contractions were determined in vitro and in vivo. In circular muscle strips prepared from the canine proximal colon, cumulative concentration-response curves were generated to potassium chloride (KCl), acetylcholine (ACh) and substance P, and the effects of electrical field stimulation were determined. Responses to KCl and ACh were examined in circular muscle strips prepared from the monkey proximal and distal colon. Nifedipine (10(-8) - 10(-6) M) significantly decreased KCl-induced contractions, whereas equimolar concentrations of nilvadipine were less effective at modifying these responses. Both calcium channel entry blockers produced similar significant decreases in ACh, substance P and electrical field stimulation contractions. In anesthetized dogs, strain gauge force transducers were oriented to record proximal colonic circular muscle contractions. Colonic contractions to i.a. infusions of ACh, cholecystokinin-(26-33) and substance P were produced in a small segment of the proximal colon. Nifedipine and nilvadipine (200 micrograms/kg i.v.) significantly decreased maximal ACh contractions. Nilvadipine also decreased maximum cholecystokinin-(26-33) and substance P contractions. Both calcium channel entry blockers decreased systolic and diastolic blood pressure significantly at 100 micrograms/kg i.v. These results indicate that nifedipine and nilvadipine are equieffective at reducing colonic contractile activity to a variety of colonic stimulants and illustrate the importance of extracellular calcium in the mediation of colonic motility
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PMID:Effects of calcium channel entry blockers, nifedipine and nilvadipine, on colonic motor activity. 242 Sep 71

1. Capsaicin produced a prompt release of substance P-like immunoreactivity (SP-LI) from superfused mucosa-free muscle strips excised from the guinea-pig urinary bladder. A second application of capsaicin had no further effect, indicating desensitization. 2. Neither tetrodotoxin (1 microM) or nifedipine (10 microM) had any inhibitory effect on SP-LI release by capsaicin nor influenced the establishment of the desensitized state. Nifedipine produced per se some SP-LI release. 3. SP-LI release by capsaicin was abolished by incubation in a Calcium(Ca)-free medium containing EDTA (1.0 mM) which also afforded a partial protection toward desensitization. A lower EDTA concentration (0.1 mM) did not suppress SP-LI release by capsaicin but still inhibited desensitization. 4. When the concentration of CaCl2 in the medium was lowered to 1/10-1/100 of that present in normal Krebs solution, capsaicin still evoked a marked SP-LI release and desensitization occurred. In a nominally Ca free medium (maximal Ca concentration due to impurities was 6.7 microM) SP-LI release was still observed and desensitization was incomplete. 5. In a nominally Ca free medium, removal of Mg ions enhanced the SP-LI release induced by capsaicin and enhanced desensitization. 6. In functional studies, nifedipine greatly reduced or abolished the capsaicin- or SP-induced contraction of the rat or guinea-pig isolated bladder but did not prevent desensitization. Likewise, SP-LI depletion in the rat bladder following systemic capsaicin desensitization was not prevented by nifedipine pretreatment. On the other hand, the protective action of Ca free media (containing EDTA) was confirmed in organ bath studies (guinea-pig bladder). 7. These findings indicate that: (a) the requirements of extracellular calcium for activation of neuropeptide release from sensory nerves by capsaicin are very low; (b) both excitation of sensory fibers (SP-LI release) and desensitization are dependent upon the presence of extracellular calcium and (c) L-type voltage-sensitive Ca channels are not likely to be involved in the actions of capsaicin on sensory nerve terminals.
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PMID:The effect of calcium free medium and nifedipine on the release of substance P-like immunoreactivity and contractions induced by capsaicin in the isolated guinea-pig and rat bladder. 247 39

1. KCl, carbachol, neurokinin A and endothelin produced concentration-dependent contractions of mucosa-free muscle strips from the dome of the human urinary bladder. The maximal response to carbachol or neurokinin A exceeded that to KCl, while the maximal response to endothelin approached that to KCl. 2. Nifedipine (1 microM) abolished the response to KCl, reduced the response to carbachol or neurokinin A but had no effect on the response to endothelin. Bay K 8644 (1 microM) markedly potentiated the response to KCl but had little or no effect on the response produced by the other stimulants. 3. Superfusion of the strips with a nominally calcium (Ca)-free medium containing EDTA (1 mM) for 30 min markedly reduced the response to carbachol, neurokinin A and endothelin, although a small response was still evident at high concentrations. Likewise, after a prolonged (60 min) superfusion of the strips with a high K (80 mM) Ca-free medium plus EDTA (1 mM) these three agonists still produced a small contractile response. 4. The nifedipine (1 microM) resistant response to carbachol, neurokinin A or endothelin was markedly depressed by LaCl3 (1 mM). In contrast, the nifedipine-(1 microM) resistant response to carbachol was not modified by NiCl2 (0.1 mM) or omega-conotoxin (0.1 microM). 5. Caffeine produced divergent effects depending upon the temperature of incubation: a relaxation at 37 degrees C and a concentration-dependent (2.5-20 mM) contraction at 25 degrees C. The latter was markedly inhibited by procaine (3 mM) but unaffected by nifedipine (1 microM). 6. After a prolonged (60 min) superfusion with a high K, Ca-free medium containing EDTA the response to carbachol (100 microM) was abolished by previous exposure to procaine (3 mM). Conversely, the response to endothelin (1 microM) was unaffected by procaine. The response to endothelin in these experimental conditions was also resistant to LaCl3 (1 mM). 7. These findings indicate that multiple sources of Ca are mobilized for contraction of the human bladder muscle by different stimulants. Dihydropyridine- and voltage-sensitive Ca channels provide the major if not the sole source of Ca for the response to KCl, play some role in the response to muscarinic (carbachol) or NK-2 tachykinin receptor stimulation but are not involved in the response to endothelin. Carbachol, neurokinin A and endothelin all mobilize a Ca pool (either extracellular or located at membrane level) which is LaCl3-sensitive but nifedipine-resistant. Neither T- nor N-type channels appear to be involved in the response to carbachol. In addition, these agents mobilize a tightly bound Ca pool independently from membrane depolarization. This latter pool is probably a procaine-sensitive intracellular source of activator Ca mobilized by caffeine and carbachol. The failure of procaine to prevent the response to endothelin in high K, Ca-free medium raises the possibility that this peptide mobilizes an intracellular source of activator Ca, distinct from the caffeine- and carbachol-sensitive pool.
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PMID:Multiple sources of calcium for contraction of the human urinary bladder muscle. 248 Jan 67

Substance P released from motoneurons or primary afferent nerves innervating the gut is an excitatory noncholinergic regulator of gastrointestinal motility and has been shown to stimulate contractions in longitudinal colonic muscle. By using the patch-clamp technique on single myocytes from the longitudinal muscle of the rabbit colon, we have studied the action of the peptide on membrane conductances. In cell-attached patches, addition of the peptide to the bath activates a large conductance Ca2(+)-activated K+ channel. At peptide concentrations (10(-12) M) that did not result in cell contraction, K+ channels were activated in a synchronized, cyclical fashion. The activation did not occur in the presence of nifedipine (10(-6) M), a blocker of dihydropyridine-sensitive Ca2+ channels. The activation was also absent when the cells were depolarized in 126 mM KCl-Ringer solution. In contrast, at a concentration of the peptide (10(-7) M) that resulted in cell contraction, there was a transient activation of K+ channels, followed by a prolonged inhibition. Nifedipine (10(-6) M) did not block the K+ channel activation by this concentration of the peptide. Removal of bath Ca2+ abolished activation of the K+ channels by both the high and low concentrations of substance P. These results indicate that substance P exerts its effect via two different membrane pathways for extracellular Ca2+.
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PMID:Differential modulation of Ca2(+)-activated K+ channels by substance P. 248 80

We studied the effect of bradykinin on ciliary activity and its modulation by peptidases in cultured rabbit tracheal epithelium in vitro. Bradykinin (10(-7) M) elicited a rapid, transient increase in ciliary beat frequency (CBF) from the baseline values of 1,031 +/- 25 to 1,388 +/- 38 beats/min (mean +/- SE, p less than 0.001), followed by a decline to a steady-state value of 1,180 +/- 30 beats/min, which was still greater than the baseline CBF. This ciliostimulation was dose-dependently inhibited by the B2-receptor antagonist (D-Arg,Hyp3,Thi5.8,D-Phe7)-bradykinin but not by the B1-receptor antagonist (Des-Arg9,Leu8)-bradykinin. Nifedipine, Ca2+-free medium, indomethacin, the phospholipase A2 inhibitor mepacrine, and the methyltransferase inhibitor 3-deazaadenosine reduced the change in CBF. Involvement of tachykinins, leukotrienes, prostaglandin D2, or thromboxane A2 was ruled out because bradykinin's action was not affected by (D-Pro2,D-Trp7.9)-substance P, nordihydroguaiaretic acid, or SQ29548, an antagonist for prostaglandin D2 and thromboxane A2. Bradykinin also increased prostaglandin E2 release (p less than 0.01), an effect that was abolished by indomethacin and Ca2+ deficiency. The CBF dose-response curve for bradykinin was shifted to lower concentrations by 1 log U by the neutral endopeptidase inhibitor phosphoramidon (p less than 0.01), whereas the angiotensin-converting enzyme inhibitor captopril was without effect. These results suggest that bradykinin interacts with B2-type receptors and stimulates ciliary activity through Ca2+-dependent prostaglandin E2 release, and that neutral endopeptidase may play a role in modulating the effect of bradykinin on airway mucociliary transport.
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PMID:Effect of bradykinin on airway ciliary motility and its modulation by neutral endopeptidase. 276 79


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