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)

Marked hyperemia accompanies reperfusion after ischemia in the brain, and may account for the propensity of cerebral hemorrhage to follow embolic stroke or carotid endarterectomy, and for the morbidity that follows head injury or the ligation of large arteriovenous malformations. To evaluate the contribution of trigeminal sensory fibers to the hyperemic response, CBF was determined in 12 symmetrical brain regions, using microspheres with up to five different isotopic labels, in four groups of cats. Measurements were made at 15-min intervals for up to 2 h of reperfusion after global cerebral ischemia induced by four-vessel occlusion combined with systemic hypotension of either 10- or 20-min duration. In normal animals, hyperemia in cortical gray matter 30 min after reperfusion was significantly greater after 20 min (n = 10) than after 10 min (n = 7) of ischemia (312 ml/100 g/min versus 245 ml/100 g/min; p less than 0.01). CBF returned to preischemic levels approximately 45 min after reperfusion and was reduced to approximately 65% of basal CBF for the remaining 75 min. In cats subjected to chronic trigeminal ganglionectomy (n = 15), postocclusive hyperemia in cortical gray matter was attenuated by up to 48% on the denervated side (249 versus 150 ml/100 g/min; p less than 0.01) after 10 min of ischemia. This effect was maximal in the middle cerebral artery (MCA) territory, and was confined to regions known to receive a trigeminal innervation. In these animals, substance P (SP) levels in the MCA were reduced by 64% (p less than 0.01), and the density of nerve fibers containing calcitonin gene-related peptide (but not vasoactive intestinal polypeptide or neuropeptide Y) was decreased markedly on the lesioned side. Topical application of capsaicin (100 nM; 50 microliters) to the middle or posterior temporal branch of the MCA 10-14 days before ischemia decreased SP levels by 36%. Postocclusive hyperemia in cortical gray matter was attenuated throughout the ipsilateral hemisphere by up to 58%, but the cerebral vascular response to hypercapnia (PaCO2 = 60 mm Hg) was unimpaired. The duration of hyperemia and the severity of the delayed hypoperfusion were not influenced by trigeminalectomy, capsaicin application, or the intravenous administration of ATP. These data demonstrate the importance of neurogenic mechanisms in the development of postischemic hyperperfusion, and suggest the potential utility of strategies aimed at blocking axon reflex-like mechanisms to reduce severe cortical hyperemia.
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PMID:Chronic trigeminal ganglionectomy or topical capsaicin application to pial vessels attenuates postocclusive cortical hyperemia but does not influence postischemic hypoperfusion. 170 54

1. Experiments were performed in cats anaesthetized with pentobarbitone. Laser Doppler flowmetry was used to assess the responses of knee joint blood vessels to nerve stimulation under control conditions and in the presence of different adrenoceptor antagonists in order to establish the nature of neurotransmitters released from articular nerve fibres. 2. The posterior articular nerve (PAN) supplying the knee was stimulated at different intensities, and frequency-response curves were obtained. In fourteen animals electrical stimulation of PAN produced an initial vasoconstriction during stimulation which in eight of these was followed by a prolonged dilatation on cessation of stimulation. The constrictor response was increased as a function of frequency but was little altered with increasing intensity beyond a threshold level. 3. The constrictor response to electrical stimulation of PAN was markedly reduced by the alpha-adrenergic antagonist phentolamine (10(-5) M, the alpha 1-blocker prazosin (10(-5) M), and guanethidine (10(-5) M) which inhibits the release of noradrenaline, ATP, and neuropeptide Y from sympathetic nerve endings. 4. The constrictor response to PAN stimulation was unaffected by the alpha 2-blocker rauwolscine and the P2-purinoceptor desensitizer alpha,beta-methylene ATP. 5. The dilator response was due to activation of afferent fibres as it could also be produced by direct electrical stimulation of the L7 dorsal roots. 6. The dilator response to stimulation of PAN or the L7 dorsal root was reduced by prior intra-articular injection of 100 micrograms of the substance P antagonist D-Pro4-D-Trp7,9,10-SP4-11. 7. These results suggest that the vasoconstrictor response to electrical stimulation of PAN is most likely to be mediated via noradrenaline acting mainly upon alpha 1-adrenoceptors. As the dilator response to articular nerve stimulation is reduced by a substance P antagonist, the mediator inducing this response may be substance P or a related neurokinin.
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PMID:Alterations in cat knee joint blood flow induced by electrical stimulation of articular afferents and efferents. 170 71

1. Contractile responses and acetylcholine release evoked by nicotine in guinea-pig detrusor strips were determined by isotonic transducer and radioimmunoassay, respectively. Nicotine stimulated acetylcholine release and a contractile response in guinea-pig detrusor strips treated with the cholinesterase inhibitor, methanesulphonyl fluoride (MSF). Both actions evoked by nicotine were antagonized by the nicotinic receptor antagonist, hexamethonium but were insensitive to tetrodotoxin. 2. A sympathetic nerve blocker, guanethidine and a tachykinin antagonist, [D-Arg1, D-Pro2, D-Trp7,9, Leu11]-substance P (rpwwL-SP) partially inhibited the acetylcholine release evoked by nicotine to much the same degree. The inhibitory effects of guanethidine and rpwwL-SP on acetylcholine release were significantly greater than corresponding effects on the contraction evoked by nicotine. 3. In preparations treated with rpwwL-SP to block the tachykinin receptors, guanethidine had no effect on the response to nicotine. Conversely, after treatment with guanethidine to block release of a mediator from sympathetic nerve endings, nicotine-induced responses were not affected by rpwwL-SP. 4. Nicotine-induced contraction was reduced to 30% by the muscarinic cholinoceptor antagonist, atropine and completely abolished after desensitization of P2-purinoceptors with alpha,beta-methylene ATP in the presence of atropine. 5. A concentration-contractile response curve to neurokinin A (NKA) was shifted to the left after cholinesterase inhibition with MSF. Atropine abolished the facilitatory effect of MSF and partially inhibited contractions induced by NKA at 100 nM to 1 microM. The contractile responses to substance P methyl ester (SPOMe) and Tyr0-neurokinin B (Tyr0-NKB) were not influenced by MSF or atropine. 6. After desensitization of NK, tachykinin receptors with SPOMe or preincubation with senktide, the cholinergic component of the nicotine-induced contraction was the same as the control value (100%). 7. Our findings give further support to our previous results: nicotine stimulates acetylcholine release in a tetrodotoxin-resistant manner in guinea-pig bladder and acetylcholine release evoked by nicotine is increased by the coordinated action of sympathetic nerves and tachykinin(s). It is suggested that the tachykinin receptor subtype involved in acetylcholine release is NK,.
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PMID:Contrasting effects of tachykinins and guanethidine on the acetylcholine output stimulated by nicotine from guinea-pig bladder [corrected]. 171 27

1. The possible involvement of tachykinins (TKs) in the contraction produced by capsaicin in the rat isolated urinary bladder was addressed on the hypothesis that co-release of substance P (SP) and neurokinin A (NKA) occurs from sensory nerve terminals. 2. A low concentration of SP (30 nM) produced a rapid contraction which faded to baseline within 10 min. A low concentration of NKA (10 nM) produced a slowly developing contraction which was still evident at 10 min. Capsaicin (1 microM) produced a rapid phasic response and a tonic response (late response to capsaicin). Co-administration of SP and NKA mimicked the response to capsaicin more than each TK alone. 3. Fading of the response to SP was not caused by receptor desensitization and was partially prevented by peptidase inhibitors. 4. Spantide (3 microM) selectively antagonized the SP-induced contraction while L-659,877 (3-10 microM) or MEN 10,376 (10-30 microM) which are NK2 receptor selective antagonists selectively blocked the response to NKA. Co-administration of spantide and L-659,877 inhibited the response to both SP and NKA by an amount not greater than that produced by each antagonist alone. 5. Spantide selectively reduced the peak response to capsaicin, while leaving the late response unaffected. L-659,877 (3 microM) and MEN 10,376 (10 microM) selectively inhibited the late response to capsaicin while, at higher concentrations, also reduced the peak response to capsaicin. Co-administration of spantide and L-659,877 reduced the peak response to capsaicin more than that produced by each antagonist alone. 6. Bombesin (10 nM) produced a tonic contraction similar to that induced by NKA. The response to bombesin was not affected by spantide, L-659,877 or MEN 10,376. 7 P2. purinoceptor desensitization by repeated administration of alpha,betal-methylene ATP depressed the twitch response to electrical stimulation of postganglionic nerves but did not affect the peak or the late response to capsaicin. 8. We conclude that multiple TKs are coreleased by capsaicin in the rat bladder and mediate the capsaicin-induced contraction by activating both NKI and NK2 receptors. Endogenous TK with preferential affinity for the NK, receptor (putatively SP) are selectively involved in the peak response to capsaicin while endogenous TK with preferential affinity for the NK2 receptor (putatively NKA) are selectively involved in the late response to capsaicin and partly contribute to the peak response. These findings provide pharmacological evidence for tachykinin-mediated cotransmission in the rat urinary bladder. ATP is unlikely to be involved in the efferent function of capsaicin-sensitive sensory nerves in the rat bladder.
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PMID:Tachykinin antagonists and capsaicin-induced contraction of the rat isolated urinary bladder: evidence for tachykinin-mediated cotransmission. 171 97

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

1. Mechanical activity was recorded in isolated muscle preparations from circular and longitudinal layers of gastric fundus, corpus and antrum and from the duodenum of pigs, using conventional organ bath technique. Rectangular current pulses were applied to the muscle strips for electrical field stimulation (EFS). 2. Fundic and circular corpus preparations developed a marked spontaneous tonic activity. Vasoactive intestinal polypeptide (VIP, 10(-9)-10(-7) mol l-1) inhibited this spontaneous activity. This inhibitory effect was not affected by application of tetrodotoxin (TTX) showing its myogenic nature. 3. Pretreatment of fundic and circular corpus preparations with VIP reduced the excitatory responses to substance P, bombesin, serotonin and histamine, but it had no effect on the acetylcholine (ACh)-induced tonic and phasic activity. 4. Longitudinal duodenal preparations showed purely phasic activity which was almost insensitive to VIP. In circular duodenal preparations particularly strong spontaneous tonic contractions were observed which could be inhibited by VIP. 5. Circular duodenal preparations excised 3-5 cm postpyloric had a spontaneous tone which could reach up to 80% of the maximum contractions induced by 10(-4) mol l-1 ACh. These preparations were chosen for further pharmacological studies and for experiments with EFS. VIP was the most powerful substance for the inhibition of spontaneous tone, followed by serotonin, PGE2 and bradykinin. This type of preparation exhibited particularly strong inhibitory effects to EFS; even single stimuli could induce near maximum relaxation. The inhibition induced by EFS was unaffected by treatment with ATP, guanethidine, atropine, methysergide and apamin. TTX completely abolished the EFS-induced relaxation, showing its neurogenic nature. 6. Porcine circular duodenum is a good model for studying the transmitter system of the non-adrenergic, non-cholinergic (NANC) innervation. The results are consistent with the assumption that VIP is the transmitter in this system, although the very slow time-course of the VIP-induced inhibition in comparison with the EFS-induced inhibition is not consistent with this notion.
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PMID:Responses of porcine gastric and duodenal smooth muscle to VIP. 172 15

In inflammation, non-neuronal cells produce a variety of chemical mediators that act on nociceptive neurones. Ultimately, the discharge of these neurones is controlled by the activity of membrane ion channels. Some chemical mediators (e.g. ATP, protons, 5-hydroxytryptamine) act on receptors that are linked directly to ion channels. Other mediators (e.g. bradykinin) act indirectly through receptors linked to second messenger systems and in this way modulate the activity of ion channels and either activate or sensitize the neurones. The eicosanoids, which are produced by a variety of cell types, have important intra- and inter-cellular roles in nociception. The interactions between neurones and non-neuronal cells are likely to be complex as some types of non-neuronal cells express receptors for sensory neuropeptides (substance P). Recent studies also suggest that cytokines and growth factors can have long term effects on nociceptive neurone function.
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PMID:Chemical activation of nociceptive peripheral neurones. 172 3

In atrial preparations obtained from reserpine-pre-treated guinea-pigs, incubated in the presence of 1 microM atropine plus 1 microM CGP 20712A (a beta 1 blocking drug), a positive inotropic effect due to CGRP release from capsaicin-sensitive sensory neurons was induced by electrical field stimulation (EFS). This response was concentration-dependently reduced by noradrenaline (0.01-3 microM), neuropeptide Y (NPY, 3-300 nM) and adenosine triphosphate (ATP, 1-30 microM). On the other hand, the overflow of [3H]-noradrenaline from sympathetic nerve terminals induced by EFS in isolated atria obtained from normal untreated animals was not modified in 10 nM calcitonin gene-related peptide (CGRP). Substance P (SP) and neurokinin A (NKA), at concentrations ranging from 0.01 to 1 microM did not affect the cardiac response to field stimulation of adrenergic terminals of atrial tissue. These findings demonstrate that all the co-transmitters stored in adrenergic nerve terminals have a modulatory role on the efferent function of cardiac capsaicin-sensitive sensory neurons, while cardiac adrenergic neurotransmission is not influenced by the peptidergic transmitters released from sensory neurons.
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PMID:Modulation by adrenergic transmitters of the efferent function of capsaicin-sensitive nerves in cardiac tissue. 172 21

The effect of acrylamide intoxication on the innervation and local control of the rabbit central ear artery was investigated. There was no difference in the noradrenaline, neuropeptide Y and calcitonin gene-related peptide tissue content between control and experimental animals. There was, however, a slight reduction in catecholamine histofluorescence. Although the contractile efficiency of the rabbit central ear artery as measured by responses to potassium chloride was unchanged, nerve-mediated contractile responses were significantly attenuated in acrylamide-treated animals. Contractile responses induced by exogenous alpha,beta-methylene ATP were markedly increased after acrylamide treatment, in contrast to contractions induced by exogenous noradrenaline which were attenuated at maximal concentrations. Modulatory effects of nerve-mediated contractile responses by neuropeptide Y were unaffected by acrylamide intoxication. It therefore appears that acrylamide intoxication damages sympathetic cotransmission, perhaps with preferential action on the purinergic component. Endothelium-dependent relaxant responses to acetylcholine and substance P were attenuated in acrylamide-treated animals, whereas relaxant responses mediated by calcitonin gene-related peptide (endothelium independent) were unaffected. The question of whether the damage to the endothelial cell action is a primary effect, or a secondary consequence of sympathetic nerve damage, is discussed.
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PMID:Changes in sympathetic and endothelium-mediated responses in the rabbit central ear artery after acrylamide treatment. 175 64

The modulation of Ca2+ currents by neurotransmitters was studied in freshly dissociated rat spinal cord neurons, using the whole-cell patch-clamp technique. GABA, baclofen, adenosine, ATP, serotonin, norepinephrine, somatostatin, and dynorphin A inhibited the current through Ca2+ channels in a substantial fraction of cells, while substance P, vasoactive intestinal polypeptide, [D-ala2,d-leu5]-enkephalin, cholecystokinin-8 (sulfated), calcitonin gene-related peptide, angiotensin II, neurotensin, vasopressin, and thyrotropin-releasing hormone had no effect. In the case of baclofen, the inhibition is mediated, at least in part, by a GTP-binding protein. Suppression of Ca2+ current by neurotransmitters may represent a mechanism of presynaptic inhibition in the spinal cord.
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PMID:Neurotransmitter modulation of calcium current in rat spinal cord neurons. 196 36


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