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)

Calcitonin gene-related peptide [CGRP]--a powerful vasodilator, is a 37 amino acid peptide that is find primarily in the central and peripheral nervous system. It affects the regulation of local blood flow, smooth muscle tone and glandular secretion. It is an endocrine regulator and in the lungs it also exerts a bronchoconstricting effect. CGRP has a proliferative effect on human endothelial cells. Therefore, it is important for the formation of new vessels, example, in ischemia, inflammations, and in the healing of wounds. Plasma levels of CGRP are increase in patients with chronic cardiac failure and sepsis, indicating that CGRP may be another important peptide in chronic illness. We have therefore measured the release of this peptide and another sensory peptide [Substance P (SP)]; a vasoconstrictor peptide [Endothelin (ET)]; and a perivascular peptide [Neuropeptide Y (NPY)], within 24 hours of injury, in the plasma of patients with soft tissue injury. Neuropeptides were measure by enzyme immunoassay technique. Median: (lower quartile-upper quartile) in pmol/L CGRP level was elevated in patients [50.37: (12.4-110.9)] compared to controls [13.9: (10.9-36.96)] p<0.05; Endothelin and NPY did not vary much between groups p=NS; ET: patients [8.7: (1.7-87.1), controls 8.8: (1.7-32.9)]; NPY: Patients [11.7: (10.5-14.99), controls 11: (10.3-12.8)]. SP was increase in patients [302.3: (79.9-707.3)], than controls [5.6: (3.2-36.6)] p<0.05. Furthermore, Elastase (a decisive marker for inflammation and infectious complications), was measure (ng/L), and found to be slightly higher in patients (102: 25.5-223), than controls (91.8: 45.9-127). In summary, plasma levels of sensory peptides increased significantly, in patients with soft tissue injury, in contrast to vasocostrictor peptides that remained unchanged. These sensory peptides may yet be another group of neuromodulators playing a significant role in immune, pain, inflammatory and wound healing in soft tissue injury patients.
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PMID:Calcitonin gene-related peptide and other neuropeptides in the plasma of patients with soft tissue injury. 1050 54

Calcitonin gene-related peptide (CGRP) and substance P co-exist in capsaicin-sensitive primary sensory neurons and are released from the myocardium after activation of sensory nerve fibres as well as by ischemia in animals. This study was undertaken to try to clarify the potential involvement of immunoreactive (ir) CGRP in anginal pain and myocardial ischemia in humans. One clinical group (n = 87) and one experimental group (n = 14) were studied. The clinical group was admitted to a coronary care unit with suspected or definite acute myocardial infarction (AMI). The experimental group consisted of patients with severe angina pectoris (NYHA III-IV). This group was subjected to atrial pacing up to the appearance of angina pectoris. Mean irCGRP levels at admission for the clinical group with and without AMI showed no significant difference. Neither were any significant differences found in irCGRP concentrations between patients with pain as compared to those without pain or in the group who had had chest pain >30 min before hospital admission as compared to those with chest pain <30 min. Extraction ratios for lactate and irCGRP was calculated in the experimental group. No statistically significant covariance was found between irCGRP extraction ratio and lactate extraction ratio (r(xy) = -0.006) at the time of appearance of angina during atrial pacing. Despite the facts that CGRP may be liberated by a variety of physiological stimuli and may act as a potent vasodilator in the human vasculature, no evidence has been found in this study that CGRP release is increased as a consequence of ischemia or ischemic pain.
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PMID:Acute ischemic chest pain is not associated with increased calcitonin gene-related peptide (CGRP) levels in peripheral plasma nor in the coronary circulation. 1054 Sep 19

The aim of this study was to investigate, if transient spinal ischemia and a period of 4-day reperfusion will change the distribution pattern of substance P in the spinal cord of rabbits. Strongly enhanced staining of substance P positive nerve structures appeared in the superficial dorsal horn (laminae I, II), the Lissauer's tract, the pericentral region (lamina X), and in the areas of autonomic nuclei (sympathetic-intermediolateral--IML nucleus and parasympathetic-sacral parasympathetic nucleus--SPN) in the control group. Transient spinal ischemia was produced by occlusion of the abdominal aorta just below the left renal artery. Neuropathology of the lesion 4 days after transient ischemia was characterized by selective necrosis of gray matter in the central part of dorsal horn and medial portions of anterior gray matter. Areas with the most dense accumulation of substance P positive structures stayed almost intact. Therefore, no significant change in the distribution pattern of substance P was found in the spinal cord of animals with ischemia-reperfusion-induced injury.
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PMID:The influence of transient spinal ischemia on substance P positive nerve structures. 1070 43

The present symposium during Brain 99 was convened to explore the current aspects of the neural (extrinsic and intrinsic) and chemical control of the microvasculature in the brain with specific relevance to stimuli and rapid flow responses. N. Suzuki demonstrated the presence of neurokinin-1 receptors along the axons of vasoactive intestinal polypeptide-containing cerebrovascular parasympathetic nerves. Since the receptors were activated by substance P, calcitonin gene-related peptide and neurokinin released from coexisting sensory nerve fibers, the parasympathetic (vasodilating) fibers could effect rapid local flow increases. N. Suzuki, however, considered this as part of an elaborate defensive network protecting the brain from invasions by noxious substances. E. Hamel discussed the responses of the microvessels to neurotransmitters and suggested that nitric oxide (NO) released from intrinsic neurons may serve as a relay in the flow activation responses by intracerebral cholinergic fibers originating in the basal forebrain nuclei. D. Busija summarized a vasodilating system of activated N-methyl-D-asparate receptors located on neurons involving Ca influx-NO production, and activated ATP-sensitive potassium channels located in the vascular system. According to Busija, such interactions were disrupted during hypoxia and ischemia due to cyclooxygenase-derived superoxide anion. M. Lauritzen observed a 10 times larger increase in blood flow on stimulation of the climbing nerve as compared with that following the parallel nerve stimulation. The former transmitters are considered by him to be NO and K, and the latter NO and adenosine. Each speaker singled out NO as a common mediator for the microvasculature in the rapid local flow increases.
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PMID:Regulation of cerebral microcirculation--update. 1075 Mar 78

To test the hypothesis of an involvement of tachykinins in destabilization and hyperexcitation of neuronal circuits, gliosis, and neuroinflammation during cerebral ischemia, we investigated cell-specific expressional changes of the genes encoding substance P (SP), neurokinin B (NKB), and the tachykinin/neurokinin receptors (NK1, NK2, and NK3) after middle cerebral artery occlusion (MCAO) in the rat. Our analysis by quantitative in situ hybridization, immunohistochemistry, and confocal microscopy was concentrated on cerebrocortical areas that survive primary infarction but undergo secondary damage. Here, SP-encoding preprotachykinin-A and NK1 mRNA levels and SP-like immunoreactivity were transiently increased in GABAergic interneurons at 2 d after MCAO. Coincidently, MCAO caused a marked expression of SP and NK1 in a subpopulation of glutamatergic pyramidal cells, and in some neurons SP and NK1 mRNAs were coinduced. Elevated levels of the NKB-encoding preprotachykinin-B mRNA and of NKB-like immunoreactivity at 2 and 7 d after MCAO were confined to GABAergic interneurons. In parallel, the expression of NK3 was markedly downregulated in pyramidal neurons. MCAO caused transient NK1 expression in activated cerebrovenular endothelium within and adjacent to the infarct. NK1 expression was absent from activated astroglia or microglia. The differential ischemia-induced plasticity of the tachykinin system in distinct inhibitory and excitatory cerebrocortical circuits suggests that it may be involved in the balance of endogenous neuroprotection and neurotoxicity by enhancing GABAergic inhibitory circuits or by facilitating glutamate-mediated hyperexcitability. The transient induction of NK1 in cerebrovenular endothelium may contribute to ischemia-induced edema and leukocyte diapedesis. Brain tachykinin receptors are proposed as potential drug targets in stroke.
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PMID:Adaptive plasticity in tachykinin and tachykinin receptor expression after focal cerebral ischemia is differentially linked to gabaergic and glutamatergic cerebrocortical circuits and cerebrovenular endothelium. 1115 66

Since serotonin (5-HT) is implicated in exacerbating acute coronary syndromes, we studied the reactivity of atrial coronary arterioles (70-140 microm) of atherosclerotic patients undergoing cardiac surgery to 5-HT, substance P (Sub P), and sodium nitroprusside by video-microscopy. Before ischemia, 5-HT-induced relaxation was not affected by NS398 (cyclooxygenase inhibitor), H2O2 or U63557A (thromboxane A2 synthase inhibitor), but was reduced by L-NNA. 5-HT elicited a potent contractile response after ischemia that was inhibited by NS398, Indo, and U63557A. While Sub P relaxation was decreased after ischemia, SNP relaxation was unchanged. The mRNA steady-state levels of NOS-3, NOS-2, prostacyclin synthase, and COX- 1 were not altered by ischemia. COX-2 mRNA and protein levels (Westernblotting), however, were increased (mean +/- SEM) 2.4 +/- 0.4 and 3.2 +/- 0.7 fold, respectively, in ischemic atrium corroborating with the immunohistochemistry of atrial tissue. It is concluded that myocardial ischemia enhanced contractile response of coronary arterioles to 5-HT maybe due to the stimulated prostaglandin release (likely thromboxane A2) secondary to induction of COX-2 expression. These findings may have implications regarding the cause of coronary spasm during acute myocardial ischemia.
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PMID:Serotonin-induced human coronary microvascular contraction during acute myocardial ischemia is blocked by COX-2 inhibition. 1121 33

Actions mediated by the renin-angiotensin system may be inhibited at various levels: renin itself may be inhibited, angiotensin-I (A-1) conversion to angiotensin-II (A-II), or binding of A-II at the A-II type 1 (A-II1) receptor. The angiotensin-converting enzyme (ACE) inhibitors and the A-II1 receptor antagonists are now clinically established. Because ACE is a relatively unspecific peptidase which catalyses the breakdown of A-I, bradykinin and neuropeptides like substance P and neurotensin, the effects of ACE inhibitors go far beyond the prevention of A-II production. On the other hand, in certain tissues like vascular and cardiac tissue, A-II is produced by other enzymes, for instance chymase, and ACE inhibitors do not consistently prevent A-II production. The action of A-II1 receptor antagonists may also not be confined to prevention of binding of A-II at the A-II1 receptor, as by rebound more A-II may bind at the A-II type 2 (A-II2) receptor and thus mediate until now not well defined effects. Thus, anti-ischemic actions of these drugs may be related to multiple mechanisms. Inhibition of A-II effects at the A-II1 receptor may prevent systemic and coronary vasoconstriction and growth effects of A-II on various cell types. In addition, A-II may potentiate, by pre- and postsynaptic mechanisms, activation of the sympathetic nervous system. Prevention of breakdown of bradykinin, substance P and neurotensin may result in direct vasodilation or release of nitrous oxide from the endothelium. Thus, growth-inhibiting effects may also be mediated. All these mechanisms seem to direct to a reduction of cardiac load by vasodilation and to a limitation of cardiovascular cell growth. While the systemic circulating renin-angiotensin system is probably responsible for control of cardiac load, local systems seem to control cell growth. Systemic effects seem to depend on activation of the renin-angiotensin system which has been shown in various ischemic syndromes. Activation of various components of the renin-angiotensin system has been demonstrated in myocardial ischemia, acute myocardial infarction and coronary occlusion and reperfusion models as well as in chronic left ventricular dysfunction post-myocardial infarction. While animal models of stress-induced myocardial ischemia have revealed predominantly positive results, clinical studies, which mostly were small and not well controlled, were equivocal. Large clinical trials with ACE inhibitors in acute myocardial infarction showed small benefits over placebo. Hypotension seems to be a critical side-effect in this situation. Experimental models show protective effects of both ACE inhibitors and A-II1 receptor antagonists in the situation of ischemia and reperfusion. New data on large clinical trials in patients at risk of cardiovascular events but normal left ventricular function demonstrate clear benefits of an ACE inhibitor. Large clinical trials in patients with chronic left ventricular dysfunction post-myocardial infarction show reduction of ischemic events.
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PMID:Anti-ischemic potential of drugs related to the renin-angiotensin system. 1139 74

Nonsteroid anti-inflammatory drugs (NSAIDs) are major drugs against inflammation and pain. They are well known inhibitors of cyclooxygenases (COXs). However, many studies indicate that they may also act on other targets. Acidosis is observed in inflammatory conditions such as chronic joint inflammation, in tumors and after ischemia, and greatly contributes to pain and hyperalgesia. Administration of NSAIDs reduces low-pH-induced pain. The acid sensitivity of nociceptors is associated with activation of H(+)-gated ion channels. Several of these, cloned recently, correspond to the acid-sensing ion channels (ASICs) and others to the vanilloid receptor family. This paper shows (1) that ASIC mRNAs are present in many small sensory neurons along with substance P and isolectin B4 and that, in case of inflammation, ASIC1a appears in some larger Abeta fibers, (2) that NSAIDs prevent the large increase of ASIC expression in sensory neurons induced by inflammation, and (3) that NSAIDs such as aspirin, diclofenac, and flurbiprofen directly inhibit ASIC currents on sensory neurons and when cloned ASICs are heterologously expressed. These results suggest that the combined capacity to block COXs and inhibit both inflammation-induced expression and activity of ASICs present in nociceptors is an important factor in the action of NSAIDs against pain.
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PMID:Nonsteroid anti-inflammatory drugs inhibit both the activity and the inflammation-induced expression of acid-sensing ion channels in nociceptors. 1158 75

In the past year there have been many advances in the area of small bowel physiology and pathology and therapy. In preparation for this review, over 1500 papers were assessed. The focus is on presenting clinically useful information for the practicing gastroenterologist. Selected important clinical learning points include the following: (1) glutamine may restore the AIDs-associated increased intestinal permeability to normal; (2) substance P is a major mediator of diarrhea caused by Costridium difficile toxin A, acting by binding to a G-protein-coupled receptor, and represents a possible 2therapeutic target; (3) the serological diagnosis of celiac disease has been greatly enhanced with the use of anti-endomysial antibody testing, and the recent antitransglutaminase; (4) a quarter of patients with celiac disease may have secondary pancreatic insufficiency and require enzyme replacement therapy; (5) in the patient with unexplained elevation in the serum transaminase concentration, consider celiac disease as an obscure possibility; (6) bosentan and endothelin receptor agonist may prove to be useful in reducing gut ischemia in patients with septic shock; and (7) the administration of recombinant human fibroblast growth factor-2 may prove to be useful to prevent radiation damage to the gastrointestinal tract.
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PMID:Small bowel review: diseases of the small intestine. 1176 46

The present article concentrates on mechanisms that lead to the excitation of nociceptors in soft tissues and nociceptive neurones in the spinal dorsal horn. These mechanisms may contribute to the so-called unspecific low back pain. Properties of nociceptors in soft tissues: A nociceptive ending in soft tissue contains a multitude of receptor molecules in its membrane. The molecular receptors include binding sites for algesic substances that are released during painful stimulation or pathologic alterations of the tissue: bradykinin (BK), serotonin (5-HT), prostaglandin E2 (PG E2), adenosine triphosphate (ATP) and protons (H(+)). The excitation and sensitisation of nociceptors by these substances can be explained by the binding of the substances to the receptor molecules in the membrane of the receptive ending and ensuing opening of ion channels or activation of metabolic cascades. Purinergic receptor molecules in the membrane of nociceptors are activated by ATP. These receptors may be of particular importance for deep somatic pain, because ATP is present in large amounts in muscle tissue and is released during muscle damage. ATP-sensitive nociceptors appear to be distinct from nociceptors that can be excited by protons. The conduction of nociceptive information from muscle to the spinal cord is partly carried by unmyelinated fibres that possess tetrodotoxin-resistant (TTX-r) Na(+)-channels. Therefore, a drug that specifically blocks TTX-r Na(+)-channels would be a new attractive tool in the treatment of patients with deep somatic pain. Chronic muscle lesions such as a myositis have been shown to be associated with a higher innervation density of the tissue with free nerve endings that contain the neuropeptide substance P (SP). Many of these endings are likely to be nociceptors. Since a painful stimulus that acts on a muscle with increased nociceptor density will excite more nociceptors and elicit more pain, the increase in nociceptor density constitutes a peripheral mechanism for hyperalgesia. In muscle free nerve endings - many of which are nociceptive - the neuropeptides SP, calcitonin gene-related peptide (CGRP) and somatostatin have been shown to be present. These substances are released from the receptive endings in muscle when they are stimulated. SP and CGRP have a strong effect on blood vessels and induce local vasodilatation and oedema. The local oedema in the vicinity of the nociceptor is associated with the release of BK from plasma proteins, which increases the excitability of the nerve ending (see below). Thus, a local vicious cycle forms that may contribute to the formation of trigger points. Sensitisation of nociceptors and peripheral hyperalgesia: Nociceptors are easily sensitised, i.e. following a conditioning stimulus they are more sensitive to the unconditioned stimulus. In animals and humans, the responses to injections of BK can be increased by 5-HT or PG E2. The responses of muscle nociceptors to mechanical stimuli are likewise enhanced after administration of BK. During overuse, ischemia or inflammation of soft tissues, the tissue concentrations of BK, PG E2, and 5-HT are elevated and sensitise muscle nociceptors. A sensitised nociceptor is excited and elicits pain when innocuous mechanical stimuli act on the muscle, e.g. during contractions or stretch. Therefore, in chronically altered soft tissues, weak everyday stimuli are likely to cause pain. Mechanisms at the spinal level: In experiments on rats in which a myositis of the gastrocnemius-soleus (GS) muscle was induced experimentally, the effects of a peripheral painful lesion on the discharge behaviour of sensory dorsal horn neurones were studied. One of the main effects of the myositis was an expansion of the input (target) region of the muscle nerve, i.e. the population of dorsal horn neurones responding to an electrical standard stimulus applied to the GS muscle nerve grew larger. One reason for the myositis-induced expansion of the input region is hyperexcitability of the neurones caused by the release of SP and glutamate from the spinal terminals of muscle afferents with ensuing activation of NMDA channels in dorsal horn neurones (central sensitisation). The central sensitisation is of clinical importance because it can explain the hyperalgesia and spread of pain in patients. In contrast to excitability, the resting activity of dorsal horn neurones - which is likely to induce spontaneous pain in patients - does not appear to depend on the release of SP and glutamate but on the concentration of nitric oxide (NO) in the spinal cord. A pharmacological block of the NO synthesis led to a significant increase in background activity without affecting the excitability of the dorsal horn neurones. Such an increase in background activity was observed exclusively in nociceptive neurones, i.e. a local lack of NO in the spinal cord induces spontaneous pain. According to data from animal experiments, a decrease in the spinal NO concentration occurs as a sequel of a chronic muscle lesion; therefore, a lack of NO is a probable factor for the induction of chronic spontaneous pain. Normally, lesion-induced pain subsides and does not develop into chronic pain. The mechanisms governing the return to normal neuronal behaviour after a peripheral lesion are not well studied. Probably, the activation of inhibitory mechanisms, e.g. increased spinal synthesis of GABA or elevated activity of the descending antinociceptive system contribute to the restoration of normal function. The final step in the transition from acute to chronic pain are structural changes that perpetuate the functional changes. In the rat myositis model, an increase in the number of synapses on the surface of NO-snythesizing cells was present 8 h following induction of the myositis. These data show that structural changes appear quite early in the development of a painful disorder. A novel hypothesis for the development of chronic pain states that a strong nociceptive input to the spinal cord leads to cell death predominantly in inhibitory interneurones. Most of these interneurones are assumed to be tonically active; when their number decreases, the nociceptive neurones are chronically disinhibited and elicit continuous pain also in the absence of a noxious stimulus.
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PMID:[Pathophysiology of low back pain and the transition to the chronic state - experimental data and new concepts]. 1179 44


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